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TOG
The journal for continuing professional development
from the RCOG
The CPD journal from the RCOG ISSN 1467-2561/1744-4667 (online)
http://onlinetog.org http://onlinetog.org
Volume 25 Issue 1 2023
Contents
Editorial 47 Human papillomavirus-independent cervical cancer and its

SBA
precursor lesions
3 Editorial Ieera Madan Aggarwal, Yen Ching Yeo, Zheng Yuan Ng
Jo Morrison
59 Thromboprophylaxis in gynaecology: a review of current
SBA
evidence
Editor’s Pick Divya Nambiar, Jecko Thachil, Wai Yoong,
Deepa Balachandran Nair
4 Spotlight on… maternal medicine
Kate Harding
Tips and Techniques

Commentary 72 Management of Bartholin’s cyst and abscess
Ayesha Bati-Paracha, Mona Sharma
6 Facilitating HIV testing in colposcopy clinics to improve
identification of HIV in a hidden population
Emily Keating, Sophie Forsyth, Jessica Daniel, Emma Torbe
CPD
78 CPD questions for volume 25 issue 1
Reviews
SBA
8 Management of term breech presentation MBRRACE-UK update
Paul Timmons, Victoria Wallis, Shawn Walker, 82 Key messages from the UK and Ireland Confidential Enquiries
Djavid Alleemudder into Maternal Death and Morbidity 2022
19 Valvular heart disease in pregnancy Marian Knight
SBA
Paul Timmons, Gemma Partridge, Alastair McKelvey,
Hamish Lyall, Monica Morosan, Leisa Freeman
And finally…
28 Pitfalls of prenatal diagnosis associated with mosaicism
SBA
Kelly Reilly, Samantha Doyle, Susan J Hamilton, Mark D Kilby, 85 Medicine and the media
Fionnuala Mone James Drife
38 Premenstrual disorders including premenstrual syndrome and

SBA
premenstrual dysphoric disorder
Nidhi Goswami, Kalpana Upadhyay, Paula Briggs,
Elizabeth Osborn, Nick Panay
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The Obstetrician & Gynaecologist 10.1111/tog.12856 http://onlinetog.org Editorial
Editorial
I write this editorial with a sense of both eagerness and Reilly et al. discuss the implications of fetal placental Editorial Board
UK
trepidation, as the new Editor-in-Chief-elect for TOG, mosaicism, which affects 2–3% of pregnancies, and how this
Kate Harding FRCOG
aware that I have taken on a big responsibility and have can affect the interpretation of non-invasive prenatal testing Guy’s and St Thomas’ NHS Foundation
Trust, London (Editor-in-Chief)
even bigger shoes to fill (albeit of relatively small feet!). I (NIPT) and chorionic villus sampling. They describe how
Jo Morrison BM BCh MA MRCOG DPhil (Oxon)
am indebted to Kate Harding, the current Editor-in- care is required in selecting the optimal invasive test and Musgrove Park Hospital, Taunton
(Deputy Editor-in-Chief)
Chief (EiC) for her help, encouragement and sage advice how to avoid over-interpretation of abnormal results.
George Attilakos
over the years. She has led TOG and her team through
MD MRCOG
Nambiar et al. outline the evidence around venous University College London Hospitals NHS
extremely difficult times, but hands over TOG in a great thromboembolism (VTE) and gynaecological surgery. Foundation Trust, London
Shagaf Bakour MD FRCOG
position, and I hope that I am able to continue her One very useful section is their discussion of hormone City Hospital, Birmingham
legacy with the help of the editorial team and board. I replacement therapy (HRT) and surgery, which does not Rasiah Bharathan MBBS MSc MRCS MRCOG
Royal Surrey County Hospital, Guildford
am extremely grateful that she will continue in an significantly increase the risk of VTE, and they note that Evelyn Ferguson MBChB MRCP DFFP MRCOG RCOG/RCR
emeritus role, so will remain my ‘phone a friend’. In the the Society of Obstetricians and Gynaecologists of Dip Adv Obs US PGCertMedEd
NHS Lanarkshire
meantime, we aim to appoint a new Deputy EiC, with a Canada (SOGC) do not recommend cessation of HRT Kannamannadiar Jayaprakasan MBBS MD DNB MRCOG
more obstetric or generalist focus to their clinical work. before surgery. I shall be sharing this excellent article PhD
Royal Derby Hospital, Derby
Reading through the reviews in this edition of TOG has with our pre-operative assessment team, since I get Swati Jha MD FRCOG
Sheffield Teaching Hospitals NHS Foundation Trust,
brought me a certain amount of deja vu, since some of asked about this frequently! Sheffield
these topics, including HIV testing in pregnancy and Bartholin’s cysts are very common, affecting 2% of Justin Konje FMCOG (Nig) FWACS MRCOG
University of Leicester, Leicester
management of the term breech, were ‘hot topics’ when I women. Bati-Paracha and Sharma discuss management, (Lead CPD Editor)
was revising for the MRCOG. I hope that several of the including outpatient management with Word or Jacobi Bid Kumar FRCOG
Wrexham Maelor Hospital, Wrexham
reviews in this edition will be useful to those now going ring catheters, avoiding general anaesthetic and surgery for Aarthi Mohan MRCOG
through their exams. many. Bartholin’s duct and gland cancers are very rare, but University Hospitals Bristol NHS Foundation
Trust, Bristol
It’s interesting to reflect how much knowledge we it is important to consider the biopsy of solid or irregular Nicola Mullin MFFP FRCOG
now take for granted, and how management of HIV, lesions; British Gynaecological Cancer Society Guidelines 2 Countess of Chester Hospital NHS
Foundation Trust, Chester
especially, has been completely transformed. I write this advise against excision of suspicious lesions without Kate Navaratnam MBChB (hons) MRCOG DRCOG DFSRH
on the 31st anniversary of Freddie Mercury’s death. It is histology, since this may compromise future care. PhD
Institute of Translational Medicine, University of Liverpool,
sad to remember how many we lost from this disease Goswami et al.’s important review addresses the Liverpool
before the introduction of antiretroviral therapy made it causes and management of premenstrual dysphoric Nikoletta Panagiotopoulou
Royal Victoria Hospital, Belfast
MD MRCOG
a chronic condition with excellent prognosis and gave us disorder. This is an important topic which affects 3–8% Adalina Sacco MBBS MRCOG MRCP MD
the ability to prevent horizontal and vertical of women and can be ‘a chronic, debilitating disorder University College London Hospitals, London (Trainee
Representative)
transmission. However, in order to do this, we need to with severe emotional and physical symptoms and Thomas Tang MD MRCOG
identify those in vulnerable groups with the disease, who functional impairment’. I hope that this article will help Regional Fertility Centre, Royal Maternity
Hospital, Belfast
may have minimal healthcare access. HIV testing is to increase general awareness and be useful to those in Philip Toozs-Hobson MBBS MRCOG MFFP BSCCP MD
addressed by Keating et al. Whereas opt-out testing is both primary and secondary care, so that women can be FRCOG
Birmingham Women’s and Children’s NHS Foundation
now routine in UK obstetric care, we have not helped and not feel dismissed. Trust, Birmingham
universally adopted testing for those with CIN, for Writing the January TOG editorial is set to be my new Ephia Yasmin MRCOG
University College London Hospitals NHS
which HIV is a treatable risk factor. Having met Advent tradition for a while, to be completed before the rest Foundation Trust, London
opposition to the introduction of routine HIV testing of the holiday season preparations. As my neighbour has just Wai Yoong MD FRCOG
North Middlesex University Hospital, London
for those with high grade or persistent CIN, this article turned on their Christmas lights, hopefully, I will have
will hopefully help to convince those who have not yet completed this before the TOG editorial team put me on International
Richard Brown
adopted the British Association of Sexual Health and Santa’s naughty list! Given the events of the past year, I’m MBBS DFSRH FRCOG FACOG
McGill University Health Centre, Montreal, Canada
HIV (BASHH), British HIV Association (BHIVA) and sure many of us will be wishing for peace, health, happiness Amr El-Shalakany MSc MD FRCOG
British Infection Association (BIA) recommendations. and action on climate change for 2023. Ain Shams University Maternity Hospital,
Cairo, Egypt
The review on term breech presentation by P Carman Lai MRCOG FHKCOG FHKAM (O&G) Cert RCOG
Timmons et al. discusses how much things have changed References (Maternal and Fetal Medicine)
Gold Coast University Hospital, Southport, Australia
since the publication of the Term Breech trial1 and notes Henry Murray MRCOG
that, as breech delivery is now a vanishing skill, it would 1 Hannah ME, Hannah WJ, Hewson SA, Hodnett ED, Saigal S, Australia
not be possible to repeat this pivotal study. However, this Willan AR. Planned caesarean section versus planned vaginal N Rajamaheswari MD DGO MCh (Urology)
Director, Urogynaecology Research Center
has implications for maternal safety, and the options for birth for breech presentation at term: a randomised Pvt Ltd, India
multicentre trial. Term Breech Trial Collaborative Group.
management of women with breech presentation are Duru Shah MD FCPS FICS FICOG DGO DFP FICMCH
Lancet. 2000;356(9239):1375-83. Jaslok Hospital, Sir Hurkinsondas Hospital
discussed in this comprehensive review. and Breach Candy Research Centers, India
2 Morrison J, Baldwin P, Buckley L, et al. British Gynaecological
Timmons et al. summarise the management of women Cancer Society (BGCS) vulval cancer guidelines:
David Shaker FRCSEd FRCOG FRANZCOG
University of Queensland, Rockhampton
with valvular heart disease in pregnancy and discuss the Recommendations for practice. Eur J Obstet Gynecol Reprod Base Hospital and Mater Private Hospital,
Australia
importance of prenatal counselling. Biol. 2020;252:502-25. Jason Waugh MRCOG (Emeritus Editor)
Auckland, New Zealand
Deputy Editor-in-Chief
Jo Morrison
ª 2023 Royal College of Obstetricians and Gynaecologists. 3

DOI: 10.1111/tog.12851 2023;25:4–5
Editor's Pick
http://onlinetog.org
Spotlight on. . . maternal medicine

Kate Harding FRCOG* Guy’s and St Thomas’s NHS Foundation Trust, London SE1 7EH, UK
*Correspondence: Kate Harding. Email: kate.harding8@nhs.net
Back in 2015 I was asked to write the first ‘Spotlight on. . . leading cause of direct maternal mortality in the UK. An
maternal medicine’ – here I am reprising it in 2022. It has important recommendation is to “allow sufficient
given me great delight to look back at The Obstetrician and opportunity in electronic records systems for free text
Gynaecologist (TOG)’s publishing history over the last 7 years written comment rather than relying solely on ‘tick
to see the ongoing commitment by way of relevant, high- boxes’”.1 We need to improve our ability to ask relevant
quality, authoritative articles on subjects ranging from questions at the right time (and feel empowered to know how
suicide to sepsis. There are many such articles, so I have to respond to positive answers). Bambridge et al. in 2017
chosen to focus on the ones relevant to the most recent wrote an excellent review titled ‘Perinatal mental health: how
MBRRACE-UK (Mothers and Babies: Reducing Risk through to ask and how to help’ (TOG 2017;19:147–53), which
Audits and Confidential Enquiries across the UK) Maternal provides guidance for anyone who is worried about how to
Mortality Surveillance and Confidential Enquiry Report.1 ask the right questions and does not know what to do to help
TOG has been privileged to feature regular articles from the woman who discloses that she has thoughts of self-harm.
Prof Marian Knight informing us on the highlights from
MBRRACE-UK and the UK obstetric surveillance system
Cardiac disease and thrombosis
(UKOSS). Many of you will have seen the recent MBRRACE-
UK report, which again highlights suicide, cardiac disease, Cardiac disease (particularly acquired rather than congenital)
thrombosis and neurological disease (commonly epilepsy) as remains a leading cause of maternal mortality and morbidity.
the commonest causes of maternal death in the UK. These Roberts et al. published on palpitations in 2019 (TOG
subjects, and more, have been covered in TOG. 2019;21:263–70), an article which chimes perfectly with one
of the recommendations from the MBRRACE-UK 2022
report. Cardiomyopathy is another rare but devastating
Overarching topics
condition, eloquently described by Kulkarni et al. in 2021
A number of articles cover general subjects and some are (TOG 2021;23:278–89). In 2013 TOG published an article by
more disease/condition specific. I particularly like the recent Wuntakal et al. (TOG 2013;15:247–55) on myocardial
article by Lucy McKillop on maternal medicine networks in infarction in pregnancy – still important, still causing
the UK (TOG 2021;23:86–8). I hope these networks will maternal death.
continue to develop and flourish, providing high-quality, The impact of MBRRACE-UK reports on clinical practice
evidence-based care to our sickest women. may be seen in the greatly increased use of thromboprophylaxis
Knowing who to image and being able to answer questions in the UK. Despite this, thrombosis remains a leading cause of
on safety is vital if we are to reassure our patients (and maternal death. The 2021 article by Crosby et al. TOG
convince the radiologists) that imaging is the correct 2021;23:206–12) is well written, clear and good revision on
investigation. Reading the article by Eastwood and Mohan diagnosis and treatment of antenatal thrombosis.
on imaging in pregnancy (TOG 2019;21:255–62) should help
you answer all questions. If everything goes wrong we need
Infection and trauma
the support of our pathologists to help understand what has
happened. To get the most out of an autopsy we need to One of the most popular TOG articles published in recent
understand what the pathologist does and how to help them, years (as judged by number of downloads) is on maternal
so I strongly suggest reading the article by Sebastian Lucas on sepsis and written by Greer et al. (TOG 2020;22:45–55). I
maternal autopsy in the UK (TOG 2019;21:127–34). strongly recommend it both for its clear explanation of
the pathophysiology of sepsis and its discussion of the
surrounding controversies. It is important to remember that
Mental health
it is not just viral infections that kill women and cause severe
In the MBRRACE-UK 2022 report there is a focus on women morbidity. As yet, there is no TOG review article on COVID-
with mental health problems, as maternal suicide is now the 19 in pregnancy as there was a realistic concern that in this
4 ª 2023 Royal College of Obstetricians and Gynaecologists.

Editor’s Pick
fast moving field any article would be out of date by the time well as on pregnancy following treatment for malignancy
it was published. While trauma is an uncommon cause of (Wallace et al., TOG 2016;18:283–9).
maternal death, I can’t leave out the article by Tibbott et al.
(TOG 2021;23:258–64); this article should be shared with our
Diabetes
colleagues in the emergency department and with our
ambulance services to ensure best practice for these rare Diabetic ketoacidosis (DKA) is covered in depth in the
but life threatening emergencies. 2022 MBBRACE-UK report. The article by Mohan et al. in
2017 (TOG 2017;19:55–62) on management of DKA in in
pregnancy can be your starting point in updating yourselves
Cancer
on this topic.
Most women we look after in pregnancy are young and I am confident that if asked again (in 7–10 years) to write
healthy, but all obstetricians will encounter pregnant women another spotlight on maternal medicine there will be another
who have previously had cancer. Sometime we will also need large selection of articles to choose from – I hope I will not
to support a woman, and her family, through a concurrent leave out your personal favourite.
pregnancy and malignancy (new diagnosis or recurrence).
These cases are always emotional and we must remember the
Reference
needs of the team as well as the family when it comes to
support. We are fortunate to have had excellent articles in the 1 Knight M, Bunch K, Patel R, Shakespeare J, Kotnis R, Kenyon S, Kurinczuk JJ
last 7 years on gynaecological cancer and pregnancy, by (Eds.) on behalf of MBRRACE-UK. Saving Lives, Improving Mothers’ Care Core
Report - Lessons learned to inform maternity care from the UK and Ireland
China et al. (TOG 2017;19:139–46), Tirlapur et al. (TOG Confidential Enquiries into Maternal Deaths and Morbidity 2018-20. Oxford:
2017;19:299–305) and Howe et al. (TOG 2022;24:31–39), as National Perinatal Epidemiology Unit, University of Oxford 2022.

DOI: 10.1111/tog.12852 2023;25:6–7
Commentary
Facilitating HIV testing in colposcopy clinics to improve

identification of HIV in a hidden population
Emily Keating MSc DTMH DFSRH,a Sophie Forsyth MRCOG DipGUM DipHIV DFSRH,b
Jessica Daniel MRCP DipGUM DipHIV DFSRH,b Emma Torbe MRCOG PGDip*c
a
Specialty Trainee in Community Sexual & Reproductive Health, Great Western Hospitals NHS Foundation Trust, Marlborough Road, Swindon
SN3 6BB, UK
b
Consultant in Sexual Health and HIV, Great Western Hospitals NHS Foundation Trust, Marlborough Road, Swindon SN3 6BB, UK
c
Consultant in Obstetrics and Gynaecology, Great Western Hospitals NHS Foundation Trust, Marlborough Road, Swindon SN3 6BB, UK
*Correspondence: Emma Torbe. Email: e.torbe@nhs.net
Accepted on 19 July 2022. Published online 10 December 2022
Please cite this paper as: Keating E, Forsyth S, Daniel J, Torbe E. Facilitating HIV testing in colposcopy clinics to improve identification of HIV in a hidden
population. The Obstetrician & Gynaecologist 2023;25:6–7. https://doi.org/10.1111/tog.12852
In 2021, the UK Government published a human status influences management of both cervical screening
immunodeficiency virus (HIV) action plan to reduce new intervals and cervical dysplasia.
infections by 80% by 2025 and eliminate transmission in the
UK by the end of the decade.1,2 Key to the success of this pledge
HIV: the background
is the identification of people living with undiagnosed HIV.
In 2020, 51% of women diagnosed with HIV were New HIV diagnoses in the UK peaked in 2014. Since then, there
diagnosed at a late stage of infection, compared with 38% has been a large reduction in the number of new cases.7 This is
of men.3 Late diagnosis, defined as a CD4 count of <350 cells/ largely due to expanded testing, condom use, prompt
mm3 or an AIDs-defining illness at diagnosis, is associated antiretroviral treatment (ART) and pre-exposure prophylaxis
with a ten-fold increased risk of dying within the first year (PrEP), now available on the NHS.7,8 On diagnosis, individuals
and a reduction in life expectancy of 10 years.4 are now started rapidly on ART because of the significant
To combat inequalities in reducing undiagnosed HIV health benefits of quick initiation.9 People living with HIV on
infection across geography, ethnicity and particular exposure ART with a suppressed viral load cannot transmit the virus.
groups, 2020 HIV testing guidelines5 produced by the British
Association of Sexual Health and HIV (BASHH), British HIV
HIV: the challenge
Association (BHIVA) and British Infection Association (BIA)
recommend non-discriminatory HIV testing for all As the incidence of HIV has reduced in the UK, it is
individuals presenting with an HIV ‘indicator’ condition. becoming increasingly challenging to identify those living
An indicator condition is any medical condition with an with undiagnosed HIV. Opt-out testing has been proved to
undiagnosed HIV seroprevalence >1 per 1000. be acceptable: uptake of HIV testing in antenatal services
One HIV indicator condition is cervical dysplasia. A exceeded 99%.1
scoping review found HIV prevalence among those with ‘Look back’ case reviews of newly diagnosed individuals
cervical dysplasia above the 0.1% threshold for HIV testing in show that clinicians miss opportunities to diagnose HIV,
high-income settings.6 Gynaecologists seeing individuals with rather than individuals declining a test.10 In our local unit, a
cervical dysplasia are well placed to facilitate HIV testing in review of cervical screening history and previous colposcopy
line with the national pledge to scale up testing in high-risk assessment for all women diagnosed with HIV between 2015
populations. Currently, however, HIV testing is not routinely and 2020 concluded that 5% of women had a diagnosis of
offered or recommended at colposcopy services in the UK. cervical dysplasia prior to their HIV diagnosis. All were
Testing for HIV at colposcopy services is key to reducing diagnosed with HIV at a late stage of infection. This mirrors
late HIV diagnosis among women: for some potentially the data published more than a decade ago.11 It is significant
vulnerable groups, this might be one of a limited number of that findings have not changed in the colposcopy setting in
interactions with healthcare providers. In addition, HIV view of the reduction in HIV incidence nationally.

Barriers to offering HIV testing in colposcopy services Acknowledgements
include a lack of guidance within colposcopy guidelines, a lack The authors would like to acknowledge the contribution of
of confidence of colposcopy staff in counselling around HIV Rachel Westwick, Consultant in Sexual and Reproductive
testing,12,13 fragmentation in commissioning, and a lack of Health at Great Western Hospital, Swindon.
care pathways across gynaecology and sexual health services.
References
Interventions
1 Public Health England. HIV in the United Kingdom: Towards Zero HIV
There is a need for: transmissions by 2030. 2019 report. London: PHE Publications; 2019
[https://assets.publishing.service.gov.uk/government/uploads/system/
Local colposcopy services to work with sexual health uploads/attachment_data/file/858559/
services to devise a local HIV testing and results HIV_in_the_UK_2019_towards_zero_HIV_transmissions_by_2030.pdf].
management strategy. This could include patient 2 Department of Health and Social Care. Press Release: Over £23 million
investment to end new HIV infections by 2030. London: UK Government;
information leaflets detailing how patients can access 2021 [https://www.gov.uk/government/news/over-23-million-investment-
HIV testing via their local sexual health department, or to-end-new-hiv-infections-by-2030].
freely available postal test kits. 3 UK Health Security Agency. United Kingdom National HIV surveillance data
tables. London: UK Health Security Agency; 2020 [https://assets.publishing.
Clear local pathways into sexual health services and patient service.gov.uk/government/uploads/system/uploads/attachment_data/file/
support and information in the event of a positive 835144/National_Tables_2019_updated.ods].
HIV test. 4 Chadborn T, Delpech V, Sabin C, Sinka K, Evans B. The late diagnosis and
consequent short-term mortality of HIV-infected heterosexuals (England
National guidelines for testing within colposcopy services and Wales, 2000-2004). AIDS 2006;20:2371–9.
with associated resources to help train colposcopy staff. 5 BHIVA/BASHH/BIA. Adult HIV testing guidelines. Guideline writing group; 2020
We call for a consensus statement between national [https://www.bhiva.org/file/5dfceab350819/HIV-Testing-Guidelines.pdf].
6 IFilippidis P, Francini K, Jacot-Guillarmod M, Mathevet P, Lhopitallier L,
colposcopy guidelines and BHIVA, BASHH and BIA. Cavassini M, Darling KEA. HIV testing in termination of pregnancy and
colposcopy services: a scoping review. Sex Transm Infect. 2022;98:
143–9.
Conclusion 7 Public Health England. Trends in new HIV diagnoses and in people receiving
HIV-related care in the United Kingdom: data to the end of December 2019.
Testing on diagnosis of indicator conditions is fundamental Health Protection Report. Report Volume 14, Number 20. 2020. Available
to achieve the UK’s new HIV ambition, in conjunction with from: https://assets.publishing.service.gov.uk/government/uploads/system/
combination prevention. uploads/attachment_data/file/959330/hpr2020_hiv19.pdf [accessed
November 2021].
The national picture and local findings highlight that 8 British HIV Association, British Association for Sexual Health and HIV
recommending an HIV test on diagnosis of cervical dysplasia guideline writing group. BHIVA/BASHH guidelines on the use of HIV pre-
is part of healthcare providers’ duty of care. There are exposure prophylaxis (PrEP); 2018 [https://www.bhiva.org/file/
5b729cd592060/2018-PrEP-Guidelines.pdf].
multiple barriers, but these need to be overcome. 9 NSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, Emery S,
Grund B, Sharma S, Avihingsanon A, Cooper DA, F€atkenheuer G, Llibre JM,
Contribution to authorship Molina JM, Munderi P, Schechter M, Wood R, Klingman KL, Collins S, Lane
ET instigated the article. EK researched and wrote the main HC, Phillips AN, Neaton JD. Initiation of Antiretroviral Therapy in Early
Asymptomatic HIV Infection. N Engl J Med. 2015 27;373:795–807.
content of the article. ET, JD and SF reviewed, contributed to 10 BHIVA Audit and standards sub-committee. Taking action on late
and edited the article. All authors read and approved the diagnoses. Survey of ‘look back’ reviews and audit of individuals diagnosed
final version. with advanced HIV. BHIVA; 2016 [https://bhiva.org/file/qtGkXrxjUglWm/
LateDiagnosesV3.pptx].
11 Briggs A, Partridge D, Bates S. HIV testing in colposcopy and termination of
Disclosure of interests pregnancy services: a missed opportunity? J Fam Plann Reprod Health Care.
SF has received financial sponsorship and consultancy fees 2011;37:201–3.
12 Sadler L. HIV testing in colposcopy- results from the survey of BSCCP
from ViiV Healthcare. JD has received financial award from members. The British Society for Colposcopy and Cervical Pathology; 2015
ViiV Healthcare. ET is a member of the BSCCP Certification [https://www.bsccp.org.uk/colposcopy-resources/hiv-testing-in-colposcopy-
and Training Committee; however, views expressed in this results-from-the-survey-of-bsccp-members].
13 Van de Laar R, Jordans C, Rokx C, Van Beekhuizen HJ, Van Doorn HC. 206
commentary are her own and she is not representing the HIV testing in cervical dysplasia, practitioners’ opinion. Int J Gynecol Cancer
BSCCP. EK has no conflicts of interest. 2021;31:A154.

DOI: 10.1111/tog.12845 2023;25:8–18
Review
Management of term breech presentation

Paul Timmons MBChB MRCOG,a* Victoria Wallis MBBS,
b
Shawn Walker RM PhD,
c
Djavid Alleemudder MBChB MRCS (Ed) MRCOG BScd

a
Senior Clinical Fellow, Obstetrics and Gynaecology, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK
b
Specialist Trainee Year 6, Obstetrics and Gynaecology, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK
c
Senior Research Fellow & NIHR Advanced Fellow, King’s College London, London, UK and Honorary Consultant Midwife, Chelsea and
Westminster Hospital NHS Foundation Trust, London, UK
d
Consultant Obstetrician and Gynaecologist, Ipswich Hospital, East Suffolk and North Essex NHS Foundation Trust, Ipswich, UK
*Correspondence: Paul Timmons. Email: paul.timmons@nhs.net
Accepted on 6 March 2022. Published online 24 November 2022
Key content To understand the principles of physiological breech

While most breech babies are delivered by caesarean section, a birth.
small number are born vaginally. To appreciate the variation in management of term breech
Detailed counselling and an accoucher skilled in vaginal breech presentation internationally and understand the impact of
birth (VBB) are essential for offering the modality. various publications.
External cephalic version (ECV) is safe, acceptable to most women,
Ethical issues
has few contraindications and increases vaginal birth rates.
Undiagnosed term breech presentation can largely be prevented by
With falling rates of VBB, and many units now unable to offer
the modality, questions surround the appropriateness of
routine third-trimester ultrasound.
national guidance continuing to present vaginal breech
Research is needed to evaluate the efficacy of VBB simulation
as routine.
training in clinical practice. Conversations around breech birth isolate discussion of risk to the
Learning objectives fetus. Maternal risk, which may extend beyond the current
To understand the evidence base around breech presentation at pregnancy, cannot be overlooked.
term, including ECV, VBB, caesarean section and adjunctive
Keywords: assisted vaginal delivery / breech delivery / caesarean
methods of cephalic version.
To understand the prerequisites for, and contraindications
section
to, VBB.
Please cite this paper as: Timmons P, Wallis V, Walker S, Alleemudder D. Management of term breech presentation. The Obstetrician & Gynaecologist 2023;25:8–
18. https://doi.org/10.1111/tog.12845
a few women will continue to deliver breech babies vaginally.

Introduction
The need exists for a robust understanding of the
Up to 5% of fetuses are in a breech presentation at term. practicalities of, as well as the evidence around, vaginal
Despite the relative frequency with which it occurs, optimum breech, by the obstetrician who will be called upon to counsel
management of this obstetric conundrum remains women and attend their births.
contentious. This debate is nothing new: there has been This article provides an update on breech presentation at
controversy surrounding breech presentation in obstetric term, with a particular focus on vaginal breech. The
practice since Hippocrates warned of its dangers in 400BC;1 management of the preterm breech carries its own extensive
the intervening two-and-a-half millennia have done little to consideration and lies outside the scope of this work.
put the matter to rest.
Opinions on vaginal breech birth (VBB) in contemporary
Breech presentation: an overview
obstetrics are wide ranging. Enthusiasm for the practice
among UK practitioners has been, for some time, in free-fall, Numerous distinct subtypes of breech presentation are
although a small cohort continue to champion its cause and described; however, terminology varies depending on
mourn its decline. Wherever individual beliefs lie on this source and confusion is compounded by the nonstatic
spectrum, the fact remains that either by choice or necessity, nature of fetal position:2

Timmons et al.
Extended or frank breech accounts for two-thirds of all

breech presentations. The buttocks present with the hips
fully flexed, knees extended and feet by the
head (Figure 1).
Flexed/complete and semi-flexed/incomplete breech
account for most of the remaining one-third. The
buttocks present, though the fetus is in a cross-legged
position with both hips flexed and one or both knees
flexed. One or both feet are positioned near, and present
with, the buttocks (Figure 2 and Figure 3).
Standing, footling and kneeling breech: one or both hips
are extended, with one or both feet leading and the fetal
pelvis non-engaged. More rarely, the knees may present
where the hips are extended. Such breech variants are
widely considered a contraindication to vaginal birth as
there is no wide ‘presenting part’ to effectively dilate the
cervix and the risk of cord prolapse is higher than with
other subtypes (Figures 4, 5, and 6).
Box 1 provides a list of the risk factors for
breech presentation.
Rates of VBB in the UK have steadily fallen since the mid-
1990s, accounting for ~0.3% of all births (or ~10% of breech
births) in England and Wales in 2019–2020. This trend is not
Figure 2. Breech presentation: flexed/complete.
universally replicated: rates of term VBB throughout Europe
range from the near negligible to around 25% in France and
the Netherlands and over 30% in Norway. The median is
10.4% across the whole continent.5 Table 1 shows the rates of
VBB in selected European countries.
Figure 3. Breech presentation: semi-flexed/incomplete.
No discussion of breech birth in the modern era could

avoid mentioning the landmark Term Breech Trial.3,6–8 This
Figure 1. Breech presentation: extended/frank. randomised controlled trial (RCT) randomised over 2000

Figure 4. Breech presentation: standing. Figure 6. Breech presentation: kneeling.
Box 1. Risk factors for breech presentation2–4
Nulliparity
Caucasian ethnicity
Congenital uterine malformation
Multifibroid uterus
Raised maternal body mass index
Oligohydramnios
Polyhydramnios
Small for gestational age
attitude and practice around the management of term breech

presentation. On review of the stated outcomes of the trial,
this is unsurprising: significantly increased rates of
perinatal/neonatal mortality and serious neonatal morbidity
were reported among infants of women randomised to VBB
(5% versus 1.6%), with no significant differences in maternal
mortality or serious maternal morbidity.
These findings have not gone unchallenged. In the two
decades since publication, numerous authors have raised
considerable concerns over both procedural aspects of the
trial and its findings. These are shown in Box 2.
The aforementioned variation in rates of VBB seen across
Figure 5. Breech presentation: footling. Europe may be in part associated with the publication of several
studies subsequent to the TBT, which appear to demonstrate a
women at over 120 centres in 26 countries to either planned greater safety profile for vaginal breech, especially in the setting
caesarean section or VBB. When published in The Lancet in of stricter selection criteria and the mandatory presence of a
2000, this study led to fundamental, global shifts in both skilled birth attendant. Indeed, in secondary analysis of the

Timmons et al.
differences in combined outcomes for fetal/neonatal

Table 1. Selected rates of vaginal breech birth in Europe5
morbidity and mortality. This study concluded that, “in
Country Rate of vaginal breech birth (%) places where planned vaginal delivery is a common practice
and strict selection criteria are met before and during labour,
planned vaginal delivery of singleton fetuses in breech
Norway 31.0
presentation at term remains a safe option that can be
Finland 26.8 offered to women”. Fundamental aspects of French practice
in vaginal breech are, however, worth acknowledging in
France 24.8 interpretation of such findings in a UK context. While
Netherlands 23.9 induction of breech labour is not recommended in the Royal
College of Obstetricians and Gynaecologists (RCOG)
Sweden 12.6 guidelines, and augmentation is only permissible in certain
circumstances, both form a cornerstone of French practice
Germany 9.0
and are recommended by the College National des
Italy 6.7 Gynecologues et Obstetriciens Francßais (CNGOF).
Interestingly, French practice also advocates routine
Czechia 6.0
pelvimetry at term for women considering VBB, though the
postulated benefits of such imaging are unproven.3
Numerous subsequent smaller studies in Europe, Australia
and the USA have reported similar findings.11–17
TBT, the presence of a practitioner experienced in vaginal
breech was found to be a protective factor.9
The management of breech presentation at
Perhaps the most important of such studies was
term
PREMODA, a large intention-to-treat analysis of over 8000
women (of whom over 2500 planned vaginal breech birth Most women with a breech-presenting fetus at term are
with a 71% success rate) in France and Belgium by Goffinet presented with a choice of three options for management:
et al.10 in 2006, which failed to demonstrate significant external cephalic version (ECV), caesarean section or VBB.
Box 2. Procedural criticisms of the Term Breech Trial (TBT)3,6–8
A lack of adherence to inclusion criteria.

The study protocol dictated that only live, singleton fetuses should be included, yet among the 16 perinatal deaths reported were two sets of twins,
one anencephalic fetus and at least one stillborn infant believed to have died before onset of labour.
Over-representation of macrosomia in the vaginal birth group.

Of fetuses randomised to planned vaginal birth, 5.8% weighed >4000 g at birth. Numerous international guidelines and other similar studies have
considered an estimated fetal weight > 3800 g a contraindication to VBB.
Significant interinstitutional variance in standards of care.

Participating centres were deemed to provide either a ‘high standard of care’ (where caesarean birth could be performed within 10 minutes and
there was access to immediate neonatal resuscitation including endotracheal intubation) or ‘usual standard of care’ (where such criteria could not
be fulfilled). Of the centres included in the study, 64.8% provided ‘usual’ care, which raises questions of the applicability of the results in obstetric
centres in the developed world.
Experience of accoucher.
Almost 20% of fetuses in the vaginal breech group were delivered without the oversight of an experienced obstetrician. Adverse outcomes were
overrepresented in this cohort.
Relationship between mode of birth and cause of death.

There is evidence to suggest that more than half of all perinatal deaths in the vaginal breech group were wholly unrelated to mode of birth, including
several infants who died from sudden infant death syndrome some weeks following an uncomplicated birth, among others. These are detailed in
full by Glezerman (2006).6
Definition and implications of ‘morbidity’.

Eighteen infants in the vaginal birth group were identified as having sustained ‘significant morbidity’ on account of isolated hypotonia at birth. In at
least seven cases, this resolved spontaneously within 2 hours. In a 2-year follow up by the original authors of the TBT, it was acknowledged that
“most children with serious neonatal morbidity survive and develop normally”.

External cephalic version

Box 3. Factors influencing success of external cephalic version
ECV – the turning a breech baby to cephalic by manipulation
(ECV)4,24
of the maternal abdomen – is often presented as first-line
management for breech presentation at term because its Factors increasing success of ECV
attempt significantly increases the likelihood of a vaginal High provider experience
birth.18 ECV is a resource-light, cost-effective intervention that Multiparity
Increased maternal age
can be easily taught, expected to ‘correct’ approximately 50% Non engagement of the breech
of term breech presentations,19 and is acceptable to most Pre-procedural tocolysis
women; uptake in an 18-year retrospective review at a large Low maternal body-weight
hospital in Oxford, UK, was 90% among eligible candidates. In Posterior placenta
Flexed (complete breech)
the same study, only 3.9% of women were deemed ineligible Amniotic fluid index (AFI) >10
for ECV. Considerable heterogeneity in quoted relative or
absolute contraindications to the procedure exists between Factors decreasing success of ECV
Nulliparity
international guidelines (see Table 2).20,21 Maternal obesity
Though numerous algorithms have been developed to Extended (frank) breech
enable individualised prediction of success of ECV, none are Footling breech
of adequate predictive value to be used routinely in clinical
practice. While, in theory, such a tool may be beneficial in
counselling women, a lower likelihood of success should not, caesarean section in the 24 hours following ECV is
in itself, preclude an attempt.22,23 Factors known to increase low (0.5%).18
and decrease the likelihood of successful ECV, respectively, Current UK guidance is to offer ECV from 36 weeks of
are given in Box 3. gestation in primigravidae and from 37 weeks of gestation in
Women considering ECV can be reassured that the risk of multigravidae.22 Several studies have compared ECV
both fetal and maternal complications from the procedure is performed at 34+0–35+6. Following ECV, assessment at 37+0
low, with no reported increases in rates of low Apgar scores, onwards showed increased rates of cephalic presentation, both
low umbilical vein pH, admission to neonatal unit or immediately and at birth, with earlier ECV, although there was
perinatal death among exposed fetuses.18 A degree of no reduction in eventual rates of caesarean delivery.25,26 A
maternal discomfort is not uncommon, although the subsequent 2015 Cochrane review on preterm ECV concluded
procedure is usually well tolerated. Postprocedural fetal that while this was associated with decreased rates of
distress is described, although the absolute risk of emergency noncephalic presentation at term compared with both term
Table 2. Relative and absolute contraindications to external cephalic version (ECV) by guideline21
Maternal factors Guideline Fetal factors Guideline
Uterine anomaly ACOG, NVOG, RANZCOG Oligohydramnios ACOG, NVOG, RANZCOG, RCOG
Pre-eclampsia / Hypertension ACOG, RANZCOG, RCOG Growth restriction ACOG, RANZCOG, RCOG
Antepartum bleeding ACOG, RANZCOG, RCOG Ruptured membranes ACOG, NVOG, RCOG
History of abruption NVOG Abnormal cardiotocography NVOG, RANZCOG, RCOG
Cardiac disease ACOG Major congenital anomaly ACOG, RANZCOG, RCOG
Obesity ACOG Hyperextension of the neck ACOG
Previous caesarean section ACOG Macrosomia (>4 kg) ACOG
Restrictive nuchal cord RANZCOG
ACOG = American College of Obstetricians and Gynecologists (USA); NVOG = Nederlandse Vereniging voor Obstetrie en Gynaecologie
(Netherlands); RANZCOG = Royal Australian and New Zealand College of Obstetricians and Gynaecologists (Australia, New Zealand); RCOG = Royal
College of Obstetricians and Gynaecologists (UK).

Timmons et al.
ECV and no ECV, an increased risk of preterm birth (6.6% women of its existence as an adjunctive measure to
versus 4.3%) with resultant consequences for neonatal conventional therapy, albeit one of uncertain benefit.
morbidity, was also demonstrated.27
ECV should only be undertaken where facility for recourse
Caesarean section
to immediate caesarean birth exists if required. However, the
Most infants in a breech presentation at term will be
routine preoperative preparations for this (fasting, intravenous
delivered by caesarean section, either as a primary maternal
[IV] access etc.) are not necessary. Pre- and postprocedural
choice or following unsuccessful ECV. Confirmation of
fetal cardiotocography (CTG) is recommended; an immediate,
presentation by ultrasound immediately before surgery
transient fetal bradycardia duration of <3 minutes is common,
should be undertaken, as spontaneous reversion to cephalic
although should prompt further monitoring.27 A total of four
occurs in around 8% of cases (although only 3–7% where
attempts at version within a 10-minute period should be
ECV has been attempted and unsuccessful; rates of reversion
considered the upper limit and, where a trainee is performing
to breech following successful ECV are similarly ~3%).33–35 It
the procedure under supervision, latter attempts may be
is good practice to discuss such an eventuality at the time of
conducted by a more experienced operator. Rhesus D negative
initial counselling and ensure a clear plan is documented in
women should be offered anti-D immunoglobulin within
the event this should occur. Many women will have made
72 hours, unless the fetus is also known to be Rhesus D
extensive preparation around their date for caesarean birth
negative. Postprocedural Kleihaur testing to identify women
and to continue with this may, at the time, be the most
who require additional anti-D is advised. Large, catastrophic
appealing choice, even though the indication no longer
fetomaternal haemorrhage following ECV is rare, but has been
persists. Similarly, advance discussion and documentation of
reported in case studies.22,28
the woman’s wishes in the event of spontaneous labour prior
Following successful ECV, there is no reason for women
to caesarean section is recommended.
not to follow a low-risk pathway for labour and delivery,
While most breech deliveries at caesarean section are
assuming no other indications for high-risk obstetric care
straightforward, additional steps may be required in some
exist. Some studies have suggested increased rates of obstetric
cases, and largely mimic those described for VBB (e.g. Løvset
intervention in labour for such women over spontaneous
or Mauriceau-Smellie-Veit manoeuvres). Extension of the
cephalic presentation, but this is inconsistently described and
uterine incision following delivery of the body and/or the use
the explanation as to why, poorly defined.27,29,30
of forceps, is occasionally required to release an entrapped
fetal head. Avoidance of hyperextension of the neck and
Alternatives/adjuncts to external cephalic version
undue pressure on the thorax/abdomen are similarly
Numerous alternative means of encouraging cephalic version
recommended for safe caesarean breech birth.
are described, although the evidence to support each is
limited – at best – and, in some cases, absent altogether.
Moxibustion is an ancient Chinese therapy involving Vaginal breech birth
burning dried mugwort at a specific acupuncture point at the The RCOG Green top guideline on management of breech
tip of the fifth toe (Bladder 67). It is hypothesised that this presentation3 recommends that women with a breech fetus
encourages production of placental estrogens and who either decline ECV, or in whom ECV is unsuccessful,
prostaglandins, which, in turn, stimulate both uterine receive unbiased counselling about the relative safety of both
contractility and fetal activity. A 2012 Cochrane review vaginal breech and caesarean section for mother and baby,
highlighted the absence of high-quality trial data evaluating respectively. Available evidence indicates that, with such
the efficacy of moxibustion. However, it did acknowledge a counselling, one-third or more of women would prefer to
reduction in nonvertex presentation, need for oxytocin and plan a VBB;36 however, literature on women’s experiences of
birth by caesarean section where moxibustion is combined attempting to do so indicates that many feel they are
with other techniques, including acupuncture and postural routinely encouraged to have an ECV or caesarean section,
management.31 RCOG guidance supports the use of and feel judged if they choose to have a VBB.37,38
moxibustion between 33 and 35 weeks of gestation.22 The presence of a birth attendant who is experienced in
A further 2012 Cochrane review on the effectiveness of vaginal breech is essential if VBB is offered as an option and,
postural management strategies failed to demonstrate benefit where this cannot be provided, referral to a centre able to
in the reduction of nonvertex presentation or caesarean offer the modality should be made, if this is the woman’s
section rate. However, it highlighted that the few studies on preference. Presentation of caesarean section delivery as the
the subject were of insufficient size to draw any definitive default is only advised by RCOG guidance either where a
conclusion and highlighted a need for further research in this separate indication for this already exists, or in the presence
area.20 In the absence of any evidence to suggest that such of specific additional risk factors.3
practice is harmful, it would not seem unreasonable to advise Box 4 provides some additional risk factors for VBB.

supine positioning. A nonsignificant reduction in serious

Box 4. Additional risk factors for vaginal breech birth
perineal injury was also observed in one study.39,40 Most
Hyperextension of the fetal neck on ultrasound birth attendants faced with VBB, however, are unfamiliar
Estimated fetal weight >3800 g with this approach, largely because most teaching on the
Estimated fetal weight <10th centile subject involves demonstration and rehearsal of manoeuvres
Footling breech presentation
Evidence of antenatal fetal compromise
in dorsal positions.31 Evidence has shown that conversion
from upright to dorsal positioning, if required, can be
achieved within seconds, thus the woman’s choice of
Concerns surrounding the safety of VBB centre on the birth positioning in the second stage need not initially be
itself, rather than any considerable differences in intrapartum care restricted by provider experience with manoeuvres in a
compared with cephalic labour. Entrapment of the aftercoming given position.41
head is the primary consideration, although practitioners should Physiological breech birth describes an approach to vaginal
be familiar with the various manoeuvres described to facilitate breech centred on the optimisation and restoration of the
release where this arises, as well as the use of adjuncts such as normal physiological process. Intervention, if required, is
alternative maternal positioning or forceps. No specific guidance performed in response to specific clinical indications, which
exists on instrument choice where forceps are required, so this are themselves based on evidence of what is considered
should be governed primarily by operator familiarity – given the ‘normal’ breech birth physiology.41 Attempts to qualify such
relative station of the ‘presenting part’ in this context, either outlet normality include one study analysing over 40 successful
(e.g. Wrigley’s) or midcavity forceps (e.g. Neville-Barnes, Rhodes upright VBB videos to identify features common to each and
or Kiellands) may be equally appropriate. facilitate development of an algorithm to guide birth
attendants (see Figure 7).41
Physiological breech birth In supporting physiological breech birth, it should be
In recent years, trends around VBB have moved away from recognised that while traditional teaching on the subject
the historical norm of dorsal lithotomy towards so-called emphasises the importance of maintaining sacroanterior
‘physiological’ breech birth using upright positioning.39 positioning throughout, it is, in fact, normal for birth of the
Upright breech birth is associated with a significantly fetal pelvis to occur in the transverse or oblique plane and
reduced need for manoeuvres, neonatal birth injury and subsequently rotate. Complete rotation to sacroanterior
shortening of the second stage by over 40% than traditional occurs in around two-thirds of cases by the time of descent
Figure 7. Physiological breech algorithm41

Timmons et al.
to the fetal nipple/scapula line. Where this fails to occur, term are referred for review by a multidisciplinary team of
rotational manoeuvres to release the entrapped fetal arms specialist obstetricians and midwives with comparatively
should be initiated. higher levels of expertise in one or more aspects of breech
A delay of 90 seconds or more at any stage following birth care, including individualised counselling, ECV and/or
of the fetal pelvis is likely to require intervention.33 Thus, a intrapartum care for VBB.
more cautious approach is required in supporting VBB using Evidence supports increased ECV success rates with
physiological principles than is recommended by RCOG operator experience. In one Dutch study on the impact of
guidelines, which suggests intervention either where “there is introducing a dedicated ECV team of obstetricians and
evidence of poor fetal condition, or if there is a delay of more midwives, overall success rates of ECV improved from 39.8%
than 5 minutes from delivery of the buttocks to the head, or to 69.5%. The greatest increase was seen in nulliparous
of more than 3 minutes from the umbilicus to the head.”3 women (23.5% to 58.5%).23,24 A further Dutch review of
Unlike cephalic birth, where following delivery of the fetal over 2500 ECV procedures demonstrated similar success rates
head the uterine cavity remains distended by the fetal body, among suitably trained midwives and obstetricians. This
the reverse does not occur in breech birth. In the absence of indicates a role for midwife-led ECV services/clinics, which
myometrial distension, the positive feedback loop that drives may have cost-saving implications. Evidence suggests that an
parturition is fundamentally altered, and the uterus may ECV service is cost-effective at even modest success
initiate the third stage of labour prior to completion of the rates (>32%).44
second. Practitioners with experience of undertaking preterm While there are examples of breech clinics geared
breech birth at caesarean section may be familiar with this specifically towards supporting vaginal breech rather than
mechanism as, in this context, uterine involution begins ECV alone, robust data on the effectiveness of such clinics,
following delivery of the torso, leading to difficulty in particularly in UK practice, is currently lacking. In Brussels,
releasing the aftercoming head. In light of this, the Derisbourg and colleagues44 analysed vaginal breech rates
conventional wisdom of advising women to refrain from before and after the introduction of such a service. They
pushing between uterine contractions following birth of the found a significant increase in both planned and eventual
torso, may warrant re-evaluation: birth of the head is not VBB rates (7.4% to 53% and 4.3% to 43.5%, respectively)
driven primarily by myometrial contractility, and with no significant difference in neonatal outcomes. A
unnecessary delay at this stage may lead to placental National Institute for Health and Care Research (NIHR)-
separation before completion of delivery.41 funded feasibility study to test this model in UK settings is
currently underway.45
Analgesia and monitoring
A woman’s choice of pain relief in labour need not be limited
Education in vaginal breech birth
by breech presentation. Almost all modalities utilised in
cephalic labour have also been shown to be of benefit in A principal limitation on the development of dedicated
breech labour.42 There is no evidence to suggest that epidural services for offering vaginal breech birth is operator
analgesia is associated with any worsening of outcomes, but it experience. RCOG guidance, alongside findings from large
may limit options in terms of positioning.9 While studies including PREMODA10 and the Term Breech Trial3,6–8
physiological breech is often discussed in the context of are clear that the presence of a suitably trained operator is an
upright positioning, this is not imperative, and the principles essential prerequisite to offering planned VBB. How this
described may be followed irrespective of maternal position training is achieved and maintained in the modern era is
or analgesic choice. less clear.3,10,46
Continuous monitoring of the fetus during breech labour The decline in VBB rates in the UK has led to trainee
is recommended in all cases. While this is conventionally by obstetricians and midwives lacking in both exposure and
way of an abdominal transducer, there is good evidence to experience. This has inevitable consequences for perinatal
support the use of a fetal electrode, where appropriate, for outcomes of both planned and the unplanned, but
both conventional CTG as well as ST-segment analysis inevitable, VBB.
(STAN) monitoring of the fetal electrocardiogram (ECG) Simulation training is effective for midwives and
where available.43 obstetricians to acquire the skills needed for management
of the unplanned vaginal breech delivery, with improved
scores in technique and safety.47–49 However, evidence
Breech clinics
suggests that while experience and confidence in vaginal
There is a collective move across obstetrics towards greater breech increases with the number of procedures performed;
use of specialist clinics. A breech clinic is a care pathway to this is not reflected in intention to offer these procedures in
which all women with a breech-presenting fetus at or near clinical practice. Senior trainees are also less likely to want to

manage VBB owing to apprehension about adverse outcomes undiagnosed breech in labour, had a VBB nor an emergency
and potential medicolegal consequences.47 intrapartum caesarean section for undiagnosed breech. This
Simulation training of VBB is well suited because of the suggests that universal implementation of such screening
uncommon but inevitable nature of the event.48 The could all but eliminate undiagnosed breech presentation. The
challenge in acquiring the skills required for VBB is authors suggest that 40 such ultrasound examinations would
ensuring the optimal frequency of conducting simulation be required to prevent one undiagnosed breech presentation.
for this high-acuity but low-frequency occurrence. A By extrapolation of their data, almost 15 000 such cases,
prospective cohort study of Canadian residents showed and 7–8 neonatal deaths, could be prevented in
significant improvement in VBB skills from pre-training to England annually.56
both the immediate and delayed post-training assessment Salim and colleagues57 analysed almost 28 000 pregnancies
(between 10 and 26 weeks later), although there was a before (14 444) and after (13 381) the introduction of
significant decline in skills between the immediate and universal ultrasound screening from 35 weeks of gestation.
delayed post-training assessments.50 Currently, there is no They similarly found a marked reduction, though not
recommendation as to how often obstetric trainees should elimination (22.3% to 4.7%), in undiagnosed breech, with
undergo VBB simulation; typically, it occurs during yearly a resultant fall in vaginal breech rates (10.3% to 5.3%). No
mandatory training, either by local departmental teaching or differences in neonatal outcomes were observed, although the
using practical, hands-on simulation training package study was inadequately powered to identify a significant
resources such as PROMPT (Practical Obstetric Multi- difference in serious adverse events. Curiously, despite a
Professional Training), MOET (Managing Obstetric comprehensive ECV service, no significant reduction in rates
Emergencies and Trauma) or Breech Birth Network of breech presentation at birth (2.7% versus 2.6%) was
Training on Physiological Breech Birth.51 These packages observed in this cohort.57
integrate video, textbook resources and practical simulation
training, with teamwork and human factors elements.
Ethical considerations
However, not all training packages for obstetric
emergencies are equal, or necessarily effective.52 Despite A commonly encountered critique of reviews examining
evidence of improvements in objective assessments of skill the relative safety of VBB versus caesarean delivery is the
and behaviour change after training in VBB, there is a lack of limitation of risk calculation to that pregnancy for the infant
evidence demonstrating the effectiveness of VBB training alone and not in the context of the woman’s wider obstetric
strategies on neonatal and maternal outcomes.53–55 future. In most women, primary caesarean section is usually
accepted as a straightforward procedure carrying a low risk
of serious maternal morbidity or mortality. However, from a
Can the undiagnosed term breech be
global perspective this is not universally the case: for many
prevented?
women in low-resource settings, primary caesarean birth
Appropriate counselling of the woman with a breech- remains a high-risk procedure, yet is undertaken widely for
presenting fetus at term is vital to ensure she has the breech presentation alone.58 Furthermore, most women who
information required to make an informed choice about her deliver their first child by caesarean section will go on to do
options. This is best undertaken in the non-acute setting – the same in subsequent pregnancies, with an increased risk
not least because of the increased rates of adverse outcomes of serious complication, including blood transfusion,
associated with undiagnosed noncephalic presentations,4 but visceral injury, uterine rupture, abnormally invasive
the understanding and retention of information given to a placentation and death for the mother, as well as low
woman first diagnosed with a breech fetus when presenting umbilical artery pH, Apgar score <7 at 5 minutes and
in active labour, with resultant implications for the validity of neonatal unit admission for her baby.58,59 Proponents of
consent, is unquestionably suboptimal. caesarean breech birth contest that no number of additional
Numerous benefits of routine, universal, third trimester caesarean sections to avoid serious harm to one baby by
ultrasound screening have recently been postulated – VBB is too many, but maternal risk associated with
including several authors who specifically examined the caesarean section cannot be ignored altogether. One Dutch
effect on rates of undiagnosed breech presentation. As part of study reported on four cases of maternal death over 2 years
the Pregnancy Outcome Prediction study, Wastlund et al.56 occurring as a consequence of caesarean section undertaken
analysed over 3800 nulliparous women who underwent a for breech presentation.60,61
screening ultrasound at 36 weeks of gestation. At this scan, The paucity of high-quality, objective RCT evidence on the
4.6% of women had a breech-presenting fetus, and in more relative safety of term vaginal breech versus caesarean section
than half of these women, there had been no prior clinical for the fetus presents a challenge to the practitioner who is
suspicion. None of the women studied subsequently had an tasked with performing the requisite ‘unbiased’ counselling.

Timmons et al.
There is ample evidence that elective caesarean section is safer References

for the cephalic fetus than vaginal birth, yet (with a cautionary
1 Paul C. The baby is for turning: external cephalic version. BJOG
note on the Pandora’s box that such a suggestion may prise 2017;124:773.
open) we are far readier to acknowledge the maternal 2 Sentilhes L, Schmitz T, Azria E, Gallot D, Ducarme G, Korb D, et al. Breech
implications of offering routine caesarean section to all presentation: Clinical practice guidelines from the French College of
Gynaecologists and Obstetricians (CNGOF). Eur J Obstet Gynecol Reprod
women with this in mind – this despite the relative risk of Biol 2020;252:599–604.
perinatal mortality in elective caesarean, cephalic vaginal and 3 Royal College of Obstetricians and Gynaecologists (RCOG). Management of
breech vaginal birth being equal (0.5, 1.0 and 2.0 per 1000, breech presentation. Green top guideline 20B. London: RCOG; 2017 [https://
www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg20b/].
respectively). Such reluctance might reflect more our own 4 De Castro H, Ciobanu A, Formuso C, Akolekar R, Nicolaides K. Value of
anxieties about the causes of each – adverse outcomes in routine ultrasound examination at 35–37 weeks’ gestation in diagnosis of
cephalic vaginal birth are more often secondary to a failure to non-cephalic presentation. Ultrasound Obstet Gynecol. 2020;55:248–56.
5 Macfarlane AJ, Blondel B, Mohangoo AD, Cuttini M, Nijhuis J, Novak Z, et al.
recognise and act on concerns, rather than an inability to Wide differences in mode of delivery within Europe: risk-stratified analyses
correct a recognised problem (such as entrapment of the of aggregated routine data from the Euro-Peristat study. BJOG
aftercoming head) in VBB. 2016;123:559–68.
6 Glezerman M. Five years to the term breech trial: the rise and fall of a
We need not shy away from being open with women about randomized controlled trial. Am J Obstet Gynecol 2006;194:20–5.
these conundrums. The principal limitation in offering VBB, 7 Lawson GW. The term breech trial ten years on: primum non nocere? Birth
or truly unbiased counselling to women, is invariably our 2012;39:3–9.
8 Whyte H, Hannah ME, Saigal S, Hannah WJ, Hewson S, Amankwah K, et al.
own confidence (or lack thereof) in our ability to support the Outcomes of children at 2 years after planned cesarean birth versus planned
modality secondary to limited exposure. For most vaginal birth for breech presentation at term: the International Randomized
practitioners, experience in performing VBB is gained Term Breech Trial. Am J Obstet Gynecol 2004;191:864–71.
9 Su M, McLeod L, Ross S, Willan A, Hannah WJ, Hutton E, et al. Factors
through unplanned, emergency cases, which seldom occur associated with adverse perinatal outcome in the Term Breech Trial. Am J
with sufficient frequency to acquire competence in offering Obstet Gynecol 2003;189:740–5.
the modality electively. Clearly, there are ethical 10 Goffinet F, Carayol M, Foidart J, Alexander S, Uzan S, Subtil D, et al. Is
planned vaginal delivery for breech presentation at term still an option?
considerations in offering a mode of birth to women that Results of an observational prospective survey in France and Belgium. Am J
we are not truly competent to support, yet cannot attain such Obstet Gynecol 2006;194:1002–11.
competence without the further exposure that more readily 11 Giuliani A, Sch€ oll WM, Basver A, Tamussino KF. Mode of delivery and
outcome of 699 term singleton breech deliveries at a single center. Am J
offering the modality would bring. Whether or not sufficient Obstet Gynecol 2002;187:1694–8.
competence in supporting the unplanned, emergency breech 12 Alarab M, Regan C, O’Connell MP, Keane DP, O’Herlihy C, Foley ME.
or women who actively seek vaginal breech after counselling Singleton vaginal breech delivery at term: still a safe option. Obstet Gynecol
2004;103:407–12.
can be attained through simulation training is a matter of 13 Sanchez-Ramos L, Wells TL, Adair CD, Arcelin G, Kaunitz AM, Wells DS.
some debate. Route of breech delivery and maternal and neonatal outcomes. Int J
Gynaecol Obstet 2001;73:7–14.
14 Gannard-Pechin E, Ramanah R, Desmarets M, Maillet R, Riethmuller D. La
propos d’une serie continue de
presentation du siege singleton a terme. A
Conclusion 418 cas. J Gynecol Obstet Biol Reprod (Paris). 2013;42:685–92.
15 Doyle NM, Riggs JW, Ramin SM, Sosa MA, Gilstrap LC 3rd. Outcomes of
The catch-22 of VBB should be obvious to most: the crucial term vaginal breech delivery. Am J Perinatol 2005;22:325–8.
requisite for offering this option to women with assurances of 16 Toivonen E, Palom€aki O, Huhtala H, Uotila J. Selective vaginal breech delivery
at term - still an option. Acta Obstet Gynecol Scand 2012;91:1177–83.
its safety profile, the practitioner with appropriate experience 17 Borbolla Foster A, Bagust A, Bisits A, Holland M, Welsh A. Lessons to be
and skill, is a dying breed – and, in many settings, already learnt in managing the breech presentation at term: an 11-year single-
extinct. Whether there is scope for recovery from such a centre retrospective study. Aust N Z J Obstet Gynaecol 2014;54:333–9.
18 Hofmeyr GJ, Kulier R, West HM. External cephalic version for breech
position, and whether or not the Term Breech Trial is
presentation at term. Cochrane Database Syst Rev 2015;(4):CD000083.
permitted the last word on the subject, depends on whether 19 Tan JM, Macario A, Carvalho B, Druzin ML, El-Sayed YY. Cost-effectiveness
there is appetite for change and whether we can fill the blanks of external cephalic version for term breech presentation. BMC Pregnancy
Childbirth 2010;10:3.
in the evidence of efficacy for training strategies outwith the
20 Melo P, Georgiou E, Hedditch A, Ellaway P, Impey L. External cephalic
clinical setting. version at term: a cohort study of 18 years’ experience. BJOG
2018;126:493–9.
21 Rosman AN, Guijt A, Vlemmix F, Rijnders M, Mol BW, Kok M.
Disclosure of interests Contraindications for external cephalic version in breech position at term: a
There are no conflicts of interest. systematic review. Acta Obstet Gynecol Scand 2013;92:137–42.
22 Royal College of Obstetricians and Gynaecologists (RCOG). External cephalic
version and reducing the incidence of term breech presentation. Green top
Contribution to authorship guideline 20A. London: RCOG; 2017 [https://www.rcog.org.uk/en/guidelines-
PT and VW researched and wrote the article. SW researched research-services/guidelines/gtg20a/].
23 Bogner G, Xu F, Simbrunner C, Bacherer A, Reisenberger K. Single-institute
and edited the article. DA edited the article. All authors
experience, management, success rate, and outcome after external cephalic
approved the final version. version at term. Int J Gynecol Obstet 2011;116:134–7.

24 Thissen D, Swinkels P, Dullemond RC, van der Steeg JW. Introduction of a 44 Derisbourg S, Costa E, De Luca L, Amirgholami S, Bogne Kamdem V,
dedicated team increases the success rate of external cephalic version: A Vercoutere A, et al. Impact of implementation of a breech clinic in a tertiary
prospective cohort study. Eur J Obstet Gynecol Reprod Biol 2019; 236:193–7. hospital. BMC Pregnancy Childbirth 2020;20:435.optibreech
25 Lavie A, Reicher L, Avraham S, Ram M, Maslovitz S. Success rates of early 45 The Optibreech Project [https://optibreech.uk/].
versus late initiation of external cephalic version. Int J Gynecol Obstet 46 Hannah M, Hannah W, Hewson S, Hodnett E, Saigal S, Willan A. Planned
2019;145:116–21. caesarean section versus planned vaginal birth for breech presentation at
26 Hutton E, Hannah M, Ross S, Delisle M, Carson G, Windrim R, et al. The Early term: a randomised multicentre trial. Lancet 2000;356:1375–83.
External Cephalic Version (ECV) 2 Trial: an international multicentre 47 Chinnock M, Robson S. Obstetric trainees’ experience in vaginal breech
randomised controlled trial of timing of ECV for breech pregnancies. BJOG delivery: implications for future practice. Obstet Gynecol 2007;
2011;118:564–77. 110:900–3.
27 Hruban L, Jank u P, Jordanova K, Huptych M, Jouzova A, Gerychova R, et al. 48 Deering S, Brown J, Hodor J, Satin AJ. Simulation training and resident
The effect of transient fetal bradycardia and other heart rate changes during performance of singleton vaginal breech delivery. Obstet Gynecol
and after external cephalic version on perinatal outcomes. Eur J Obstet 2006;107:86–9.
Gynecol Reprod Biol 2020;245:39–44. 49 Hardy L, Garratt JL, Crossley B, Copson S, Nathan E, Calvert K, et al. A
28 Qureshi H, Massey E, Kirwan D, Davies T, Robson S, White J, et al. BCSH retrospective cohort study of the impact of In Time obstetric simulation
guideline for the use of anti-D immunoglobulin for the prevention of training on management of vaginal breech deliveries. Aust NZ J Obstet
haemolytic disease of the fetus and newborn. Transfusion Med 2014;24:8–20. Gynaecol 2020;60:704–8.
29 Krueger S, Simioni J, Griffith L, Hutton E. Labour outcomes after successful 50 Stone H, Crane J, Johnston K, Craig C. Retention of vaginal breech delivery
external cephalic version compared with spontaneous cephalic version. J skills taught in simulation. J Obstet Gynaecol Can 2018;40:205–10.
Obstet Gynaecol Can 2018;40:61–7. 51 Walker S, Reading C, Siverwood-Cope O, Cochrane V. Physiological breech
30 de Hundt M, Velzel J, de Groot CJ, Mol BW, Kok M. Mode of delivery after birth: Evaluation of a training programme for birth professionals. Pract
successful external cephalic version: a systematic review and meta-analysis. Midwife 2017;20:25–8.
Obstet Gynecol 2014;123:1327–3. 52 Fransen AF, van de Ven J, Banga FR, Mol BWJ, Oei SG. Multi-professional
31 Coyle ME, Smith CA, Peat B. Cephalic version by moxibustion for breech simulation-based team training in obstetric emergencies for improving
presentation. Cochrane Database Syst Rev. 2012;(5):CD003928. patient outcomes and trainees’ performance. Cochrane Database Syst Rev
32 Hofmeyr GJ, Kulier R. Cephalic version by postural management for breech 2020;(12):CD011545.
presentation. Cochrane Database Syst Rev 2012;(10):CD000051. 53 Walker S, Breslin E, Scamell M, Parker P. Effectiveness of vaginal breech birth
33 Ferreira JC, Borowski D, Czuba B, Cnota W, Wloch A, Sodowski K, et al. The training strategies: An integrative review of the literature. Birth
evolution of fetal presentation during pregnancy: a retrospective, descriptive 2017;44:101–9.
cross-sectional study. Acta Obstet Gynecol Scand 2015;94:660–3. 54 Walker LJ, Fetherston CM, McMurray A. Perceived changes in the
34 Westgren M, Edvall H, Nordstro €m L, Svalenius E, Ranstam J. Spontaneous knowledge and confidence of doctors and midwives to manage obstetric
cephalic version of breech presentation in the last trimester. BJOG emergencies following completion of an Advanced Life Support in
1985;92:19–22. Obstetrics course in Australia. Aust N Z J Obstet Gynaecol 2013;53:
35 Ben-Meir A, Elram T, Tsafrir A, Elchalal U, Ezra Y. The incidence of 525–31.
spontaneous version after failed external cephalic version. Am J Obstet 55 Crofts JF, Ellis D, Draycott TJ, Winter C, Hunt LP, Akande VA. Change in
Gynecol 2007;196:157.e1–3. knowledge of midwives and obstetricians following obstetric emergency
36 Abdessalami S, Rota H, Pereira GD, Roest J, Rosman AN. The influence of training: a randomised controlled trial of local hospital, simulation centre
counseling on the mode of breech birth: A single-center observational and teamwork training. BJOG 2007;114:1534–41.
prospective study in The Netherlands. Midwifery 2017;55:96–102. 56 Wastlund D, Moraitis A, Dacey A, Sovio U, Wilson E, Smith G. Screening for
37 Guittier MJ, Bonnet J, Jarabo G, Boulvain M, Irion O, Hudelson P. Breech breech presentation using universal late-pregnancy ultrasonography: A
presentation and choice of mode of childbirth: a qualitative study of prospective cohort study and cost effectiveness analysis. PLOS Med
women’s experiences. Midwifery 2011;27:e208–13. 2019;16:e1002778.
38 Petrovska K, Watts NP, Catling C, Bisits A, Homer CS. ’Stress, anger, fear and 57 Salim I, Staines-Urias E, Mathewlynn S, Drukker L, Vatish M, Impey L. The
injustice’: An international qualitative survey of women’s experiences impact of a routine late third trimester growth scan on the incidence,
planning a vaginal breech birth. Midwifery 2017;44:41–7. diagnosis, and management of breech presentation in Oxfordshire, UK: A
39 Leeman L. State of the breech in 2020: Guidelines support maternal choice, cohort study, PLOS Med 2021;18:e1003503.
but skills are lost. Birth 2020;47:165–8. 58 van Roosmalen J, Meguid T. The dilemma of vaginal breech delivery
40 Louwen F, Daviss BA, Johnson KC, Reitter A. Does breech delivery in an worldwide. Lancet 2014;383:1863–4.
upright position instead of on the back improve outcomes and avoid 59 Macharey G, Toijonen A, Hinnenberg P, Gissler M, Heinonen S, Ziller V. Term
cesareans? Int J Gynecol Obstet 2017;136:151–61. cesarean breech delivery in the first pregnancy is associated with an
41 Reitter A, Halliday A, Walker S. Practical insight into upright breech birth increased risk for maternal and neonatal morbidity in the subsequent
from birth videos: A structured analysis. Birth 2020;47:211–9. delivery: a national cohort study. Arch Gynecol Obstet 2020;302:
42 Baez Suarez A, Martın Castillo E, Garcıa And
ujar J, Garcıa Hernandez JA, 85–91.
Quintana Montesdeoca MP, Loro Ferrer JF. Evaluation of the effectiveness of 60 Burke G. The end of vaginal breech delivery. BJOG 2006;113:969–72.
transcutaneous nerve stimulation during labor in breech presentation: a 61 Schutte JM, Steegers EA, Santema JG, Schuitemaker NW, van Roosmalen J;
case series. J Matern Fetal Neonatal Med 2021;34:24–30. Maternal Mortality Committee Of The Netherlands Society Of Obstetrics.
43 Kessler J, Moster D, Albrechtsen S. Intrapartum monitoring with Maternal deaths after elective cesarean section for breech presentation in
cardiotocography and ST-waveform analysis in breech presentation: an the Netherlands. Acta Obstet Gynecol Scand 2007;86:240–3.
observational study. BJOG 2015;122:528–35.

DOI: 10.1111/tog.12857 2023;25:19–27
Review
Valvular heart disease in pregnancy

Paul Timmons MBChB MRCOG,a* Gemma Partridge BM MRCOG,b Alastair McKelvey MBBCh BAO MRCOG,c
Hamish Lyall MBChB MRCP FRCPath,d Monica Morosan MD FRCA,e Leisa Freeman MBChB FRCP FESC FHEA FRCOGf
a
Subspecialty Fellow, Maternal-Fetal Medicine, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, Norfolk NR4 7UY, UK
b
Consultant Obstetrician, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, Norfolk NR4 7UY, UK
c
Consultant in Obstetrics and Maternal-Fetal Medicine, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, Norfolk NR4
7UY, UK
d
Consultant Haematologist, Department of Haematology, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, Norfolk
NR4 7UY, UK
e
Consultant Anaesthetist, Department of Anaesthetics, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, Norfolk NR4
7UY, UK
f
Consultant Cardiologist, Department of Cardiology, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, Norfolk NR4
7UY, UK
*Correspondence. Paul Timmons. Email: paul.timmons@nnuh.nhs.uk
Accepted on 15 June 2022.
Key content counselling regarding decisions around pregnancy for women with
Pregnancy-induced changes in haemodynamic physiology can valve pathology.
place considerable strain on cardiac function in some women with To understand how valve disease affects pregnancy and
valvular disease. vice versa.
Regurgitant valve lesions are usually better tolerated in pregnancy To gain insight into the anaesthetic and haematological
than stenotic lesions, although the risk of obstetric complications is considerations for managing women with valvular
increased in both. disease.
Pre-conception counselling is essential for all women with
valvular disease. Ethical issues
Optimising anticoagulation is a particular challenge in women What is the optimum anticoagulation regimen for women with
with mechanical valves. mechanical heart valves in pregnancy that balances both maternal
and fetal risks?
Learning objectives
To understand the World Health Organization (WHO) Keywords: analgesia / haematology / medical disorders in
classification of maternal cardiac disease and how this affects pregnancy / maternal physiology / obstetric
Please cite this paper as: Timmons P, Partridge G, McKelvey A, Lyall H, Morosan M, Freeman L. Valvular heart disease in pregnancy. The Obstetrician &
Gynaecologist 2023;25:19–27. https://doi.org/10.1111/tog.12857
interplay between severity of disease, prepregnancy

Introduction
symptomatology and treatment required.
The haemodynamic changes of pregnancy can present
considerable challenges to cardiac function, particularly in
Stenotic valve lesions
the presence of underlying valvular heart disease. These
challenges include the requirement to increase cardiac The predominant causes of stenotic valve lesions in women
output, reduce systemic vascular resistance and tolerate a of childbearing age are rheumatic heart disease for mitral
significant increase in circulating volume. Without careful lesions and congenital bicuspid valves with superimposed
planning and management, these normal physiological calcification for aortic lesions, respectively.1,2
adaptations can lead to cardiac decompensation in women As the circulating volume increases during normal
with valvular disease. As a rule, regurgitant lesions are pregnancy, there is a concurrent rise in both cardiac preload
better tolerated than stenotic lesions, and right-sided and the pressure gradient across the cardiac valves. Owing to
(pulmonary/tricuspid valve) lesions are better tolerated the reduced ability to increase cardiac output accordingly in
than left-sided (mitral/aortic valve) lesions. The risk of stenotic lesions, these changes may lead to pulmonary venous
adverse effects on mother and fetus depends on the congestion and, eventually, pulmonary oedema.

Regurgitant valve lesions Table 1. New York Heart Association Functional Classification7
In women of childbearing age, both aortic and mitral Class Patient symptoms
regurgitation typically arise as complications of rheumatic,
congenital or degenerative disease.1
I No limitations on physical activity
Women with regurgitant valve lesions usually tolerate Ordinary physical activity does not cause undue fatigue,
pregnancy well because there is minimal impact on their palpitation or dyspnoea
ability to increase cardiac output compared with stenotic
valves. The exceptions are the few women with severe II Slight limitation of physical activity
Comfortable at rest
regurgitation, cardiac symptoms (for example, shortness of Ordinary physical activity results in fatigue, palpitation or
breath) or secondary compromise to left ventricular function, dyspnoea
who are at increased risk of cardiac failure.3,4
III Marked limitation of physical activity
Comfortable at rest
Pre-conception counselling Less than ordinary activity causes fatigue, palpitation or
dyspnoea
Pre-conception counselling is essential for all women with
underlying cardiac disease to evaluate the risk to mother and IV Unable to carry on any physical activity without discomfort
Symptoms of heart failure at rest
fetus. It also enables informed discussion and decision- If any physical activity is undertaken, discomfort increases
making about whether to embark upon pregnancy and how
this will be managed, if so.5,6
Women with valvular heart disease should have the
opportunity to meet with a cardiologist specialising in the
management of cardiac disease in pregnancy, an obstetrician severe (valve area <1.0 cm2) mitral stenosis (see Table 3).4,9
with expertise in maternal medicine and an obstetric physician. Sustained atrial fibrillation is uncommon, occurring in less
As a minimum, an electrocardiogram (ECG), echocardiogram than 10%, but can contribute to the development of heart
and exercise tolerance test (where appropriate) should be failure and thromboembolic events where it does occur.
performed in all such women as part of a baseline, Mortality from mitral stenosis in pregnancy is around 0–3%
prepregnancy assessment of cardiac function.6 among women in developed nations, with predictors for the
Pre-conception care and pregnancy planning should be development of complications including New York Heart
individualised according to the underlying diagnosis, Association (NYHA) functional class ≥II, systolic pulmonary
ventricular/valvular function, functional class (see Table 1) arterial pressure >30 mmHg, severe stenosis and advanced
and the presence of comorbidities. Disease-specific maternal maternal age.4,9,10
risk should be assessed using the modified World Health Even in the absence of symptoms, women with severe (valve
Organization (mWHO) classification (see Table 2). area <1.0 cm2) mitral stenosis should usually be counselled
Women with cardiac disease should be informed that they against pregnancy, suitable contraception should be provided
are at increased risk of obstetric complications, which may (typically a long-acting reversible contraceptive [LARC]),10 and
include iatrogenic preterm birth, hypertensive disease and their condition optimised by prepregnancy percutaneous
postpartum haemorrhage. Adverse consequences for the fetus balloon valvotomy or valve replacement where necessary.
occur in as many as 30% of cases of maternal cardiac disease The primary fetal considerations in maternal mitral
and correlate with maternal disease severity6,8 – these include stenosis are prematurity, which occurs in 20–30%, and
complications arising secondary to preterm birth, fetal FGR in up to 30%.6
growth restriction (FGR) and the effects of maternal
medication.9 Serial growth scanning of the fetus – Aortic stenosis
provisionally on a 4-weekly basis from 28 weeks of Aortic stenosis, the commonest cause of left ventricular
gestation – in all cases of stenotic valvular disease and in outflow tract obstruction,12,13 is defined as thickening of the
those with symptomatic regurgitant disease is advised owing aortic valve with an antegrade velocity across the valve of at
to an increased risk of FGR (up to 30%) in such fetuses.6 least 2.0 m/sec.14 Early symptoms include reduced exercise
tolerance and cardiac dyspnoea on exertion; however, the
Mitral stenosis progressive nature of the lesion in the absence of treatment
Women with mild mitral valve stenosis should be informed leads to worsening left ventricular hypertrophy, end-stage
that pregnancy is usually well tolerated; however, heart failure cardiac failure and its characteristic symptom profile
occurs in one-third of pregnant women with moderate (valve (including resting dyspnoea, angina, and syncope).14 A
area <1.5 cm2) mitral stenosis and in half of women with physiological increase in the echocardiographic gradient

Timmons et al.
Table 2. Modified World Health Organization classification of maternal cardiovascular risk (external figure)6
Class Risk of pregnancy Examples of conditions
I No detectable increased risk of maternal Uncomplicated or mild:

mortality and no/mild increase in morbidity Pulmonary stenosis
Patent ductus arteriosus
Mitral valve prolapse
Successfully repaired simple lesions (atrial or ventricular septal defect, patent ductus arteriosus,
anomalous pulmonary venous drainage)
II Small increased risk of maternal mortality or Unoperated atrial or ventricular septal defect Class II – III depending on individual:
moderate increase in morbidity Repaired tetralogy of Fallot Mild LV impairment
Most arrthymias Hypertrophic cardiomyopathy
Native or tissue valvular disease not classed
III Significantly increased risk of maternal Mechanical valve WHO I or IV
mortality or severe morbidity Systemic right ventricle Marfan syndrome without aortic dilatation
Expert counselling required – if pregnancy Fontan circulation Aorta <45 mm in aortic disease associated
decided upon, intensive specialist cardiac Cyanotic heart disease (unrepaired) with bicuspid aortic valve
and obstetric monitoring required Other complex congenital heart disease Repaired coarctation
throughout pregnancy, childbirth and the Aortic dilatation 40–45 mm in Marfan
puerperium syndrome
Aortic dilatation 45–50 mm in aortic disease
associated with bicuspid aortic valve
IV Extremely high risk of maternal mortality or Pulmonary arterial hypertension of any cause
severe morbidity – pregnancy Severe systemic ventricular dysfunction (LVEF <30%)
contraindicated Previous peripartum cardiomyopathy with any residual impairment of LV function
If pregnancy occurs, termination should be Severe mitral stenosis
discussed. If pregnancy continues, care for as Severe symptomatic aortic stenosis
for Class III Marfan syndrome with aortic dilatation >45 mm
Aortic diltation >50 mm in aortic disease associated with bicuspid aortic valve
Native severe coarctation
period may indicate both the severity of underlying disease

Table 3. Severity of mitral valve stenosis determined by valve area10
and the risk of cardiac complications during pregnancy.17
Severity of mitral valve stenosis Valve area (cm2) Where NT-proBNP is elevated prepregnancy (which may
indicate subclinical cardiac compromise),17 intervention
should be considered before pregnancy is planned; if within
Mild >1.5
normal limits, NT-proBNP measurements may be valuable as
Moderate 1.0–1.5 the pregnancy progresses in differentiating cardiac
breathlessness from other causes.17
Severe <1.0 In women who are asymptomatic of aortic stenosis prior
to pregnancy (and have mild or moderate disease), the risk of
heart failure is low (less than 10%) compared with 25% in
women with symptoms.18 Even in severe aortic stenosis, a
across the valve is a normal feature of pregnancy and not, as woman with normal prepregnancy exercise tolerance and
may be erroneously suspected, a marker of worsening preserved left ventricular function should be expected to
stenosis. In fact, absence of this increase (or any decrease) tolerate pregnancy well and not be discouraged from
should raise suspicion of a failing left ventricle.15,16 pregnancy. Conversely, women with symptomatic, severe
A physician-supervised Bruce protocol exercise test should aortic stenosis, a reduced exercise test or impaired left
be undertaken as part of the pre-conception risk assessment; ventricular function should be counselled against pregnancy,
successful completion of this test suggests an ability to offered contraception and surgical treatment performed.13,14
appropriately augment blood pressure with exercise and Surgical intervention may involve either balloon
indicates a degree of cardiac reserve. Likewise, measurement valvotomy or valve replacement. The choice of valve
of the cardiac biomarker NT-proBNP in the pre-conception replacement procedure should be a multidisciplinary

decision involving a maternal cardiologist and the wider Mechanical replacement valves represent a more long-term
adult congenital cardiac disease multidisciplinary team.19 option, but confer additional risk to women and their fetuses
Pregnancy accelerates decline in valve function in women during pregnancy – primarily as a result of the risk of valve
with a tissue bioprothesis, while those with a prosthetic thrombus and the resultant need for lifelong anticoagulation.
(metal) valve will require anticoagulation throughout.6 ROPAC data highlighted that women with a mechanical
While aortic root dilatation in pregnancy and the resultant valve had a 58% chance of an ‘event-free’ pregnancy
risk of aortic dissection are most considered in the context of compared with 79% of women with a bioprosthesis.21
Marfan syndrome, this may also occur because of bicuspid
aortic valve stenosis. There is no firm consensus on when to
Antenatal management
offer prepregnancy aortic root surgery for such patients,
although European Society of Cardiology (ESC) guidelines Mitral stenosis
advise against pregnancy in women with Marfan syndrome Women should be reviewed at a frequency determined
where the root dilatation is >45 mm (the risk of dissection primarily by disease severity, and care delivered – ideally –
from the Registry of Pregnancy and Cardiac Disease within the setting of a dedicated, multidisciplinary maternal
[ROPAC] data appears reassuringly minimal below this cut cardiology clinic. Women with asymptomatic, mild mitral
off).20 ESC guidelines classify an aortic root dilatation stenosis may be seen once in each trimester, while those with
between 45 and 50 mm in women with a bicuspid valve as more severe disease or symptoms should be reviewed at least
WHO Class III, indicating a ‘significantly increased’ risk of monthly.6 A routine review should include a full clinical
mortality or severe morbidity, and as WHO Class II-III assessment, echocardiography and screening for FGR.
depending on individual characteristics where <45 mm. Root
dilatation >50 mm is WHO Class IV and such women Medical
should be actively counselled against pregnancy.6 Women with moderate-to-severe mitral stenosis will
Women should be advised that preterm birth and FGR occur probably need therapeutic anticoagulation owing to the
in 20–25% of mothers with moderate or severe aortic stenosis.18 risk of atrial fibrillation secondary to left atrial enlargement,
Transmission of congenital cardiac defects to infants born to as will any women with a history of embolism or left atrial
mothers with left ventricular outflow tract pathology is of the thrombus. Anticoagulation with low-molecular-weight
order of around 10% – fetal echocardiography should heparin (LMWH) should be also considered in women
accordingly be offered routinely to such women.17 with significant left atrial enlargement (≥60 mL/m2) or
congestive heart failure, even in the absence of
Aortic and mitral regurgitation an arrhythmia.6
Mild regurgitant valve disease is usually well tolerated in In women with symptoms refractory to treatment with
pregnancy owing to peripheral vasodilatation and reduced beta-blockers, diuretics may be considered. While diuretics
systemic vascular resistance. However, women with are infrequently employed in pregnancy, there is sufficient
moderate-to-severe disease, who are symptomatic or have safety data support their use where required; however,
impaired left ventricular function should be informed that caution should be exercised to avoid hypotension, excessive
they are at higher risk of developing cardiac failure during volume depletion and reduced placental perfusion with
pregnancy (20–25%).3,4 FGR occurs in 5–10% of women overzealous diuresis.17 Women who develop symptoms of
with regurgitant valve lesions, although there is no reported clinically significant pulmonary hypertension should be
increase in the risk of other obstetric complications.4,6 referred to a specialist centre.
Surgical
Valve replacement
Surgical intervention is best undertaken prepregnancy, with
For women who require prepregnancy valve replacement, the intervention during pregnancy reserved for women with
discussion is more complex. Wider multidisciplinary NYHA class III/IV and/or systolic pulmonary artery pressures
involvement, including a cardiothoracic surgical team, of ≥50 mmHg, despite medical intervention. Percutaneous
is imperative. mitral balloon valvuloplasty is the intervention of choice
A woman with a bioprosthetic valve who is during pregnancy, but should be reserved only for those in
haemodynamically stable has the advantage of not requiring whom medical therapy has failed.17 While this leads to
anticoagulation during pregnancy. Furthermore, the risk of improvements in both valve area and gradient, increased
cardiovascular complications is low in the absence of rates of mitral regurgitation, atrial fibrillation,
bioprosthesis dysfunction; however, up to one-third of thromboembolism and cardiac tamponade are also
bioprotheses will fail within 10–15 years of implantation described.22 There is, unsurprisingly, significant fetal risk
and, accordingly, many women will require repeat surgery. associated with the cardiopulmonary bypass required for

Timmons et al.
valvular surgery undertaken during pregnancy – fetal Postpartum, through management of haemorrhage and
mortality rates of up to 30% are described.23 location of care (whether intensive therapy unit, coronary
care or high dependency unit, depending on
Aortic stenosis local arrangements).
These women should be followed up regularly during
pregnancy; in severe disease, the frequency of cardiac (and Stenotic valve lesions
echocardiographic) assessment should be monthly or A stenotic valve will lead to a fixed cardiac output. As well as
bimonthly depending on the symptom profile. Women decreasing tolerance to the cardiovascular changes of
who have been assessed pre-conception and advised that pregnancy previously discussed, the heart similarly cannot
they will tolerate pregnancy well can be reviewed every 3 compensate as efficiently for the decrease in preload associated
months throughout.6 with regional anaesthetic-related hypotension. Both spinal and
epidural anaesthesia lead to a sympathetic block, which
Medical manifests as venous dilatation and fluid stasis in the lower
As with mitral stenosis, activity should be reduced and limbs, further compounded by aortocaval compression.
medical management with beta-blockers and/or diuretics Careful avoidance of hypotension is required whenever
initiated in the presence of any evidence of incipient regional anaesthesia is indicated.24 Strategies include:
cardiac failure.17 Use of invasive monitoring (such as an arterial line), which
can detect real-time changes in blood pressure.
Surgical Careful titration of an epidural/spinal catheter or a low-
Percutaneous valvuloplasty is the practical intervention of dose combined spinal-epidural (CSE): this involves
choice in women who continue to experience severe administering a lower dose of anaesthesia into the spinal
symptoms despite maximal medical therapy. Where this is space and augmenting the level of the sensory block by
not possible, and the woman has life-threatening symptoms, administering saline or local anaesthesia via the epidural
consideration should be given to termination of pregnancy or catheter to ‘squeeze’ the spinal sac and extend the
early delivery by caesarean section (depending on gestation) block cephalad.
and subsequent valve surgery. Epidural anaesthesia in isolation risks an incomplete nerve
block and, particularly for caesarean delivery, a spinal
Mitral and aortic regurgitation component is preferred. General anaesthesia should be
administered in severe lesions. The heart rate should be
Medical maintained in the slower range in valvular stenosis (since
Symptomatic management of heart failure fluid overload can coronary artery perfusion occurs in diastole and a shorter
be achieved with diuretics.22 diastolic time leads to impaired filling, particularly in a low
cardiac output state) and cardiac preload maintained.
Surgical
If required, surgical valve repair should be undertaken Regurgitant valve lesions
prepregnancy. In cases of acute, severe regurgitation with Regurgitant lesions are usually better tolerated because
heart failure refractory to medical therapy, surgery during anaesthesia leads to a drop in systemic vascular resistance,
pregnancy may be unavoidable, though ideally, where which will reduce regurgitant flow. Furthermore, avoidance
required, delivery should precede this. Decisions around of bradycardia (in a high spinal block, for example) will
timing of surgery and delivery should be individualised, promote forward flow. There are no issues with regional
considering gestational age and severity of cardiac disease.22 anaesthesia unless the cardiac lesion is associated with
significant left ventricular dysfunction.
Right-sided lesions nominally have a lesser effect on
Anaesthetic considerations for valvular
anaesthetic provision, providing the function of the right
disease in pregnancy
ventricle is preserved. However, they are often one component
Anaesthetic involvement in pregnant women with valve of more complex lesions requiring multidisciplinary planning.
disorders may occur at various stages:
Antenatally, as part of the multidisciplinary team or during Anticoagulation and anaesthesia
any admissions with cardiac symptoms or complications. The presence of residual anticoagulation has considerable
Intrapartum, for provision of labour analgesia and implications for the delivery of regional anaesthesia. In
institution of invasive monitoring in selected cases. women receiving therapeutic anticoagulation, 24 hours
Perioperatively – administration of anaesthesia (either should elapse between the last dose of LMWH and
regional or general anaesthesia depending on the case). institution of neuroaxial anaesthesia.25 If a woman presents

in those with mechanical heart valves is already

Box 1. Summary of anaesthetic aims in valvular heart disease
contraindicated outwith pregnancy.29,30
Maintenance of a heart rate adequate for the lesion LMWH can be considered as an alternative to warfarin
Avoidance of hypotension and breakthrough pain because it does not cross the placenta and is safe for the fetus;
Strict fluid management (pulmonary oedema occurs readily and however, it carries an increased risk of TECs (around 10%) for
haemorrhage is poorly tolerated)
Adequate cessation of anticoagulation (facilitating placement of the mother.21,28,31 LMWH for prosthetic valve replacements
regional anaesthesia) must be administered by subcutaneous injection twice daily
with regular peak and trough levels of antifactor Xa used to
guide dose adjustment. Recommended peak anti-Xa levels are
0.8–1.2 IU/ml, although a level of 1.0–1.2 IU/ml for non-aortic
within 24 hours from the last dose of LMWH, remifentanil valves has also been advocated.28, 31 Measuring trough levels
patient-controlled anaesthesia may be considered for labour may also be beneficial.31 Doses of LMWH required for this
analgesia with recourse to general anaesthesia for caesarean purpose are >50% higher than standard weight-based doses
delivery if required. When induction of labour with used for treatment of venous thromboembolism.32 TECs can
appropriate cessation of anticoagulation is possible, the occur at any time during pregnancy and are frequently
preferred mode of labour analgesia would be a reliable reported in the first trimester.33 Therefore, prompt and
epidural with a supplementary spinal, epidural top-up or sustained therapeutic anti-Xa levels are needed when LMWH
CSE) for operative birth if required, depending on the case. is used.
In women taking warfarin, an international normalised Three anticoagulation strategies are commonly
ration (INR) of less than 1.5 prior to institution of encountered in clinical practice:
neuroaxial anaesthesia should be achieved. Box 1 provides VKA throughout pregnancy: to reverse the anticoagulant
a summary of anaesthetic aims in valvular heart disease. effect in mother and baby, a switch to twice daily LMWH
is made around 2 weeks before delivery.
Anticoagulation in women with valvular heart LMWH in first trimester, VKA 2nd and 3rd trimester: VKAs
disease continue to be used while trying to conceive with regular
Anticoagulation for valvular disease in pregnancy is most pregnancy testing. VKAs are stopped and switched to
employed in women with mechanical prosthetic valves, LMWH (twice daily) before the 6th week of gestation. After
although also in women with atrial fibrillation complicating week 12, VKAs are restarted with a switch to LMWH prior
native valvular disease or mitral stenosis with high to delivery made as above.
risk features.6 LMWH throughout pregnancy: VKAs continue to be taken
Mechanical valve prostheses require anticoagulation to while trying to conceive, switching to twice daily LMWH
prevent valvular thrombosis and resultant thromboembolic after a positive pregnancy test. LMWH is continued
complications (TECs), including valve failure, arterial until delivery.
thromboembolism (such as stroke, myocardial infarction, Reviews of various anticoagulation strategies demonstrate
limb ischaemia) and death. Vitamin K antagonists (VKAs) that while LMWH has better fetal outcomes, it is associated
such as warfarin, are the most effective drugs for preventing with higher maternal morbidity and mortality than with
such complications; however, they cross the placenta, are warfarin.31 European Society of Cardiology (ESC, 2018)6 and
teratogenic and result in fetal anticoagulation. Warfarin use American Heart Association (2014)14 guidelines advise
in pregnancy is associated with fetal anomalies and an stratifying by warfarin dose >5 milligrams/day to assist in
increased risk of both early and late pregnancy loss.26 The choice of regimen used, as above this dose, the risk of warfarin
characteristic phenotype of warfarin embryopathy is well embryopathy is markedly increased. Other patient-specific
documented and encompasses nasal hypoplasia, shortening factors warranting consideration include maternal preference,
of the long bones and digits as well as stippled long bone valve thrombogenicity (position and type), anticoagulation
epiphyses. This is most encountered where warfarin exposure compliance, availability of LMWH monitoring, previous
occurs between 6–12 weeks of gestation, although a risk of pregnancy and TEC history.
central nervous system and ocular abnormalities with In considering optimum anticoagulation regimens, the
consequential neurodevelopmental impairment is described impact of each on the woman’s quality of life should not be
with exposure at later gestations. Where warfarin exposure overlooked – multiple daily injections of LMWH are a
occurs in the first trimester, the overall rate of fetal anomaly considerable undertaking, as are repeated trips to a healthcare
is around 5–6%, but the precise incidence appears to setting for blood tests. The woman’s preference should form
correlate with total dose.26-28 While the use of ‘direct’ oral a key part of all multidisciplinary discussions in this area.
anticoagulants such as rivaroxaban is contraindicated in Delivery requires interruption of anticoagulation. Some
pregnancy owing to concerns around fetal toxicity, their use centres advocate a switch to UFH infusion, withheld during

Timmons et al.
labour and resumed after birth, but this carries a significant undesirable. In such cases, caesarean section, while not
risk of postpartum haemorrhage and wound haematoma. without its own risk profile, does have the advantage that
The optimum regimen for minimising these risks while anticoagulant therapy can be more easily controlled around
protecting the valve has not been determined. A prospective the time of birth.
British study using data from the UK Obstetric Surveillance Where emergency delivery of a woman who has been
System (UKOSS) evaluated 58 pregnancies in women with taking warfarin within the preceding 2 weeks is required,
mechanical valves during the triennium 2013–2015.31 Five ESC guidelines advocate caesarean delivery owing to the risks
maternal deaths occurred (9%); 41% of women had serious of bleeding (particularly intracerebral) in the neonate
maternal morbidity – either a TEC or postpartum secondary to residual anticoagulation.6 Close liaison with
haemorrhage. Adverse fetal outcomes occurred in 43%. haematology in such circumstances is essential.
Variation in anticoagulation monitoring was observed, with
subsequent commentary asking whether improvements in Endocarditis risk
anticoagulation practice and specialist centre management Although historically, antibiotic prophylaxis was advised for
may improve outcomes.34,35 labour and delivery in women with cardiac valvular disease,
evidence for bacteraemia is lacking. All women now receive
routine antibiotic prophylaxis before caesarean delivery36 and,
Intrapartum care
except for women with a personal history of infective
Mode of delivery endocarditis, specific additional prophylaxis is no
An individualised multidisciplinary care plan should be longer recommended.37
created for all patients. Broad principles may be used to
advise on the safest intended mode of delivery based on usual Third stage fluid shifts
obstetric indications, patient choice and cardiological Peripartum monitoring of blood pressure and pulse
assessment of ability to tolerate the second stage of labour. throughout is mandatory. Invasive arterial blood pressure
The plan for antenatal, intrapartum and postpartum care monitoring may be appropriate in more severe
should be kept with the woman’s notes, regularly reviewed valvular disease.
and should include a contingency plan for unexpected/ The third stage of labour carries a potential for significant
emergency delivery. The mother’s wishes and obstetric history fluid shifts, which should be anticipated in the
(if any) should be taken into consideration when developing multidisciplinary care plan. The use of diuretics may be
any such plan. Revisions may be made according to factors required in severely stenotic mitral lesions to prevent the
such as fetal growth and maternal adaptation to pregnancy. autotransfusion caused by uterine involution from
Ideally, for women receiving therapeutic anticoagulation, the precipitating pulmonary oedema; however, conversely,
window during which no anticoagulation is given should be avoidance of volume depletion in postpartum haemorrhage
kept to a minimum. to maintain cardiac preload in women with aortic stenosis is
In cases of mild/moderate valvular dysfunction, especially similarly imperative.
in those not on therapeutic anticoagulation, normal vaginal
delivery is usually appropriate. Where vaginal birth is
Postpartum management
intended, the use of instruments to shorten the active
second stage of labour may be considered if there is severe Oxytocic drugs
hypertension, or if it is felt that prolonged episodes of the The multidisciplinary care plan should outline, as standard,
Valsalva manoeuvre (or sustained increases in cardiac the uterotonic agents that may and may not be used,
output) would be poorly tolerated. Continuous assessment including specifying the dose and volume of intravenous
of the maternal condition throughout labour, especially in oxytocin to be given after delivery. The authors recommend
the second stage, is key to informing such decision-making. the use of a concentrated oxytocin infusion to avoid rapid
An hour dedicated to passive descent of the fetus, especially haemodynamic changes. Ergometrine should be avoided in
in women with regional analgesia, may similarly contribute women with arrhythmia or who are at high risk of aortic
to shortening the second stage without the need for recourse dissection, and carboprost in women with asthma or raised
to operative vaginal birth. The 2018 ESC guidelines state, “It pulmonary artery pressures. Misoprostol is usually safe,
is recommended to anticipate the timing of delivery to ensure although cardiac output may be increased by shivering,
safe and effective peripartum anticoagulation”;24 therefore it which is a common side effect.
is important to be realistic regarding the duration of the
overall birth processes, including induction of labour. For Anticoagulation and haemorrhage
example, a prolonged induction in a preterm, nulliparous Clear instructions for the dose and timing of anticoagulation
woman at high risk of valvular thrombosis, would be after different contingencies of delivery and anaesthesia are

crucial for women with prosthetic valves, in whom been conclusively shown. Indeed, this is unlikely as both
resumption of effective anticoagulation as soon as safely increases and decreases in the INR have been reported.38
possible will minimise the risk of TECs. Postpartum
haemorrhage (both primary and secondary) poses a
Conclusion
particular challenge in women with valvular disease,
especially those on therapeutic anticoagulation. Close and Care for women with valvular heart disease should be
early liaison between senior obstetricians, haematologists and individualised and include regular multidisciplinary input in
anaesthetists is crucial to balance the need to prevent life- a centre with experience in providing care for high risk
threatening blood loss against sustaining valvular thrombosis cardiac patients during before, during and after pregnancy.
from suboptimal anticoagulation. Consideration should be
given to reversal of anticoagulation if haemorrhage is not Disclosure of interests
effectively controlled with the usual obstetric measures and There are no conflicts of interest.
specific haematological advice on how to do so should be
sought early. Contribution to authorship
GP, PT AM, HL and MM researched and wrote the article; LF
Lactation edited the article. All authors approved the final version.
Lactation should be encouraged in patients with valvular
heart disease. Although warfarin is present in breast milk at a
References
concentration of 10% of plasma, it is an inactive metabolite
and poses little risk to the infant. 1 Olson LJ, Subramanian R, Ackermann DM, Orszulak TA, Edwards WD.
Surgical pathology of the mitral valve: a study of 712 cases spanning
21 years. Mayo Clin Proc 1987;62:22–34.
Contraception 2 Horstkotte D, Niehues R, Strauer BE. Pathomorphological aspects, aetiology
Planning of pregnancy with appropriate pre-conception and natural history of acquired mitral valve stenosis. Eur Heart J 1991;12
support is crucial in women with valvular heart disease – Suppl B:55–60.
3 Lesniak-Sobelga A, Tracz W, KostKiewicz M, Podolec P, Pasowicz M. Clinical
selection of an appropriate and effective contraceptive and echocardiographic assessment of pregnant women with valvular hear
method is accordingly, of the upmost importance. Deferral diseases – maternal and fetal outcome. Int J Cardiol 2004;94:15–23.
of pregnancy may be necessary to enable valve replacement or 4 Van Hagen IM, Thorne SA, Taha N, Youssef G, Elnagar A, Gabriel H, et al.
Pregnancy outcomes in women with rheumatic mitral valve disease: Results
to allow timely changes in teratogenic drugs to reduce the from the Registry of Pregnancy and Cardiac Disease. Circulation
potential for adverse effects. 2018;137:806–16.
Depending on the planned mode of delivery, severity of 5 Roos-Hesselink JW, Budts W, Walker F, De Backer JFA, Swan L, Stones W,
et al. Organisation of care for pregnancy in patients with congenital heart
valvular disease and maternal obstetric history and future disease. Heart 2017;103:1854–9.
wishes, sterilisation at the time of an elective caesarean 6 Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, Blomstr€ om-Lundqvist
delivery may be appropriate. Alternatively, where both C, Cıfkova R, De Bonis M, et al. 2018 ESC Guidelines for the management of
cardiovascular diseases during pregnancy. Eur Heart J. 2018;39:3165–241.
partners are certain the family is complete, a male partner 7 Fox AC, Gorlin R, Levin RI, New York Heart Association. Criteria committee.
may undergo vasectomy which carries the benefit of a Nomenclature and criteria for diagnosis of diseases of the heart and great
considerably lower failure fate. Barrier contraception offers vessels. 9th ed. Boston, MA: Lippincott Williams and Wilkins; 1994.
8 Siu SC, Sermer M, Colman JM, Alvarez AN, Mercier LA, Morton BC, et al.
concurrent protection against sexually transmitted infection Prospective multicenter study of pregnancy outcomes in women with heart
and is a useful adjunct to longer term contraceptive options disease. Circulation 2001;104:515–21.
but is less effective in isolation. Oral combined contraceptives 9 Hameed A, Karalp IS, Tummula PP, Wani OR, Canetti M, Akhter MW, et al.
The effect of valvular heart disease on maternal and fetal outcome of
are usually not appropriate, given the prothrombotic effect of pregnancy. J Am Coll Cardiol 2001;37:893–9.
the estrogen component.10 Long acting progestogens, 10 Silversides CK, Colman JM, Sermer M, Siu SC. Cardiac risk in pregnant
including the implant and injection, are a reliable and safe women with rheumatic mitral stenosis. Am J Cardiol 2003;91:1382–5.
11 Jakes AD, Coad F, Nelson-Piercy C. A review of contraceptive methods for
choice. Intrauterine devices, such as the copper coil and women with cardiac disease. Obstet Gynaecol 2018;20:21–9.
levonorgestrel-containing device (the latter particularly 12 Lindman BR, Clavel MA, Mathieu P, Iung B, Lancellotti P, Otto CM, et al.
useful in anticoagulated women owing to its additional Calcific aortic stenosis. Nat Rev Dis Primers 2016;2:16006.
13 Baumgartner H, Hung J, Bermejo J, Chambers JB, Evangelista A, Griffin BP,
benefits in controlling menstruation) are also very effective, et al. Echocardiographic assessment of valve stenosis: EAE/ASE
though carry a small risk of syncope from cervical recommendations for clinical practice. J Am Soc Echocardiography.
stimulation during insertion and should therefore be fitted 2009;22:1–23.
14 Otto CM, Nishimura RA, Bonow RO, Carabello BA, Erwin JP 3rd, Gentile F,
only in the hospital setting. Both intrauterine devices and the et al. 2020 ACC/AHA guideline for the management of patients with
progestogen implant can be fitted at the time of elective valvular heart disease: a report of the American College of Cardiology/
caesarean section. American Heart Association Joint Committee on Clinical Practice Guidelines.
Circulation 2021;143:e35–71.
Some studies have suggested an effect from progestogens 15 Nelson-Piercy C. Handbook of Obstetric Medicine. 6th Ed. Boca Raton, FL:
on INR levels in women on warfarin, but no true link has CRC Press; 2021.

Timmons et al.
16 Frise C, Collins S. Oxford Specialty Handbooks: Obstetric Medicine. Oxford: 28 Scheres LJJ, Bistervels IM, Middeldorp S. Everything the clinician needs to
Oxford University Press; 2020. know about evidence-based anticoagulation in pregnancy. Blood Rev
17 Elkayam U, Goland S, Pieper PG, Silverside CK. High-risk cardiac disease in 2019;33:82–97.
pregnancy: Part I. J Am Coll Cardiol 2016;68:396–410. 29 Lameijer H, Aalberts JJJ, van Veldhuisen DJ, Meijer K, Pieper PG. Efficacy and
18 Orwat S, Diller GP, van Hagen IM, Schmidt R, Tobler D, Greutmann M, et al. safety of direct oral anticoagulants during pregnancy; a systematic literature
Risk of pregnancy in moderate and severe aortic stenosis: From the review. Thromb Res 2018;169:123–7.
multinational ROPAC registry. J Am Coll Cardiol 2016;68:1727–37. 30 Catterall F, Ames PR, Isles C. Warfarin in patients with mechanical heart
19 Carvajal HG, Lindley KJ, Shah T, Brar AK, Barger PM, Billadello JJ, et al. valves. BMJ 2020;15:371.
Impact of pregnancy on autograft dilatation and aortic valve function 31 D’Souza R, Ostro J, Shah PS, Silversides CK, Malinowski A, Murphy KE, et al.
following the Ross procedure. Congenit Heart Dis 2018;13:217–21. Anticoagulation for pregnant women with mechanical heart valves: a
20 Campens L, Baris L, Scott NS, Broberg CS, Bondue A, Jondeau G, et al. systematic review and meta-analysis. Eur Heart J 2017;38:1509–16.
Pregnancy outcome in thoracic aortic disease data from the Registry of 32 Quinn J, Von Klemperer K, Brooks R, Peebles D, Walker F, Cohen H. Use of
Pregnancy and Cardiac disease. Heart 2021;107:1704–9. high intensity adjusted dose low molecular weight heparin in women with
21 van Hagen IM, Roos-Hesselink JW, Ruys TP, Merz WM, Goland S, Gabriel H, mechanical heart valves during pregnancy: a single-center experience.
et al. Pregnancy in women with a mechanical heart valve: data of the Haematologica 2009;94:1608–12.
European Society of Cardiology Registry of Pregnancy and Cardiac Disease 33 Vause S, Clarke B, Tower C, Hay C, Knight M, (on behalf of UKOSS). Pregnancy
(ROPAC). Circulation 2015;132:132–42. outcomes in women with mechanical prosthetic heart valves: a prospective
22 Elkayam U, Bitar F. Valvular heart disease and pregnancy part I: native valves. descriptive population based study using the United Kingdom Obstetric
J Am Coll Cardiol 2005;46:223–30. Surveillance System (UKOSS) data collection system. BJOG 2017;124:1411–9.
23 Weiss BM, von Segesser LK, Alon E, Seifert B, Turina MI. Outcome of 34 Cauldwell M, Steer P. Care in the UK for pregnant women with mechanical
cardiovascular surgery and pregnancy: a systematic review of the period prosthetic valves needs urgent improvement. BJOG 2017;124:1420.
1984-1996. Am J Obstet Gynecol 1998;179:1643–53. 35 McLintock C. Anticoagulant options in pregnancy for women with
24 Dennis A. Valvular heart disease in pregnancy. Int J Obstet Anesth mechanical valves. BJOG 2017;124:1421.
2016;25:4–8. 36 National Institute for Health and Care Excellence (NICE). Intrapartum care for
25 Association of Anaesthetists of Great Britain and Ireland, Obstetric healthy women and babies. Clinical guideline [CG190]. London: NICE; 2014.
Anaesthetists’ Association, Regional Anaesthesia UK. Regional anaesthesia 37 Habib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta JP, Del Zotti F,
in patients with abnormalities of anticoagulation. Anaesthesia et al. 2015 ESC guidelines for the management of infective endocarditis:
2013;68:966–72. The Task Force for the Management of Infective Endocarditis of the
26 McLintock C. Anticoagulant choices in pregnant women with mechanical European Society of Cardiology (ESC) Endorsed by: European Association for
heart valves: Balancing maternal and fetal risks – the difference the dose Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear
makes. Thromb Res 2013;131:S8–10. Medicine (EANM). Eur Heart J 2015;36:3075–128.
27 Dhillon SK, Edwards J, Wilkie J, Bungard TJ. High versus low-dose warfarin- 38 Faculty of Sexual and Reproductive Health (FSRH). FSRH clinical guideline:
related teratogenicity: a case report and systematic review. J Obstet Contraceptive choices for women with cardiac disease (June 2014). London:
Gynaecol Can 2018;40:1348–57. FSRH; 2014.

DOI: 10.1111/tog.12850 2023;25:28–37
Review
Pitfalls of prenatal diagnosis associated with mosaicism

Kelly Reilly MBBChBAO MRCOG DipCE,a Samantha Doyle MD MRCPI MSc,b,c Susan J Hamilton BSC Genetics DpiRCPath,d
Mark D Kilby DSc MB BS MD FRCP I FRCOG,e,f Fionnuala Mone PhD MSc (Genomics) MRCOG FRCPI PGCEg*
a
ST6 Obstetrics and Gynaecology, and Clinical Research Fellow, Centre for Public Health, Queen’s University Belfast, Institute of Clinical Science
Block A, Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BA, UK
b
Consultant in Clinical Genetics and Genomics, National Maternity Hospital, Holles Street, Dublin 2, Ireland
c
Consultant in Clinical Genetics, National Maternity Hospital, Holles Street, Dublin 2, Ireland
d
Principal Genomic Scientist, West Midlands Regional Genetics Laboratory, Birmingham Women’s and Children’s NHS Foundation Trust,
Birmingham BT15 2TG, UK
e
Dame Hilda Lloyd Professor of Fetal Medicine, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University
of Birmingham, Edgbaston, Birmingham, UK
f
Fetal Medicine Centre, Birmingham Women’s and Children’s Foundation Trust, Birmingham, B15 2TG, UK
g
Clinical Lecturer in Maternal Fetal Medicine, Centre for Public Health, Queen’s University Belfast, Institute of Clinical Science, BT12 6BA, Belfast,
Block A, Royal Victoria Hospital, UK
*Correspondence: Fionnuala Mone. Email: f.mone@qub.ac.uk
Accepted on 28 June 2022. Published online 20 December 2022
Key content To appreciate underlying principles in NIPT and genomic testing

Fetal placental mosaicism, of which confined placental mosaicism strategies in relation to mosaicism.
is a subtype, occurs in 2–3% of pregnancies. To follow suggested clinical management principles in relation to
Confined placental mosaicism may lead to a false positive result on prenatal test counselling.
non-invasive prenatal testing (NIPT) for common aneuploidies.
Ethical issues
The risk of mosaicism in a chorionic villus sample (CVS) following
Clinicians face a dilemma following a high-risk NIPT result in the
a positive NIPT result is 2, 4, 22 and 59% for trisomy 21, 18, 13
setting of normal ultrasound. Awaiting long-term culture, as
and 45, X respectively.
opposed to short-term culture on CVS, or amniocentesis delays
Following a positive NIPT result in the absence of a significant fetal
potential termination of pregnancy.
structural anomaly (FSA), care is required in selecting the optimal
Sex chromosome abnormalities on NIPT without an identifiable
diagnostic invasive test. Discussion of the limitations and
FSA cannot be interpreted reliably. Hence, NIPT should not be
implications is essential and referral to clinical genetics may
offered for sex chromosome aneuploidy.
be warranted.
Keywords: aneuploidy / chorionic villus sampling / confined
Learning objectives

placental mosaicism / fetal placental mosaicism / non-invasive
To understand the embryological causes for and types of fetal
prenatal testing
placental mosaicism.
Please cite this paper as: Reilly K, Doyle S, Hamilton SJ, Kilby MD, Mone F. Pitfalls of prenatal diagnosis associated with mosaicism. The Obstetrician &
trisomy 21, 18 or 13 on first trimester combined screening.3

Introduction
cffDNA analyses the fetal fraction of DNA in maternal blood,
Non-invasive prenatal testing (NIPT), also known as cell-free derived from apoptosis of the external layer of the placenta,
fetal DNA (cffDNA) testing, has transformed prenatal or trophoblast.4,5 When used as part of universal screening,
screening internationally for common chromosomal interpretation of NIPT in the setting of a normal first
anomalies and has considerably reduced the need for trimester anatomy ultrasound may be challenging.
invasive testing.1 However, some have described it as a Different methods exist for reporting the accuracy of NIPT,
‘disruptive technology’.2 NIPT is currently approved by the depending on the statistical assessment used and the evidence
National Health Service (NHS) Fetal Anomaly Screening evaluated: sensitivity and specificity, positive predictive value
Programme (FASP) in England, Scotland and Wales as a (PPV) and negative predictive value (NPV), and false positive
contingent screening test in those at high risk (defined as a and false negative rates. These may be confusing for clinicians
risk from 1 in 2 to 1 in 150 on combined screening) of providing pre-test and post-test counselling. The PPV is
28 ª 2022 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
Reilly et al.
useful because it accounts for the sensitivity of the test, the and extrafetal compartments that occurs shortly after
pre-test risk and the prevalence of the trisomy in question. fertilisation.9 If it occurs beforehand, it can lead to true
These aspects must be considered when counselling patients, fetal mosaicism (TFM), where the abnormal cell line is
because the accuracy is less optimal in those groups deemed present in placenta and fetus or fetus alone; or CPM when it
to be low risk by combined screening.6 Other reasons for is isolated to the placenta.4 CPM is the commonest type of
reduced accuracy include maternal chromosome mosaicism, mosaicism; extrafetal (i.e., placental) tissues undergo more
inadequate (low) fetal fraction, maternal malignancy and mitotic divisions and therefore are at greater risk of
vanishing twin (caused by silent twin miscarriage). NDJ errors.4
Persistently inadequate fetal fraction (<4%) at second blood Mosaicism (encompassing CPM and TFM) occurs in
draw is also associated with an increased risk of trisomy 13 1–2% of chorionic villus samples. The incidence of CPM
and 18, as well as assisted reproductive techniques and from chorionic villus sampling (CVS) is 0.02% based on
elevated maternal body mass index.4 The commonest reason current laboratory processing procedures.14 The incidence
for a retrospectively false positive NIPT result is secondary to of CPM increases with advancing gestation, most notable
confined placental mosaicism (CPM), which is a subtype of beyond 20 weeks, potentially explained by somatic
chromosomal mosaicism.7 mosaicism. For this reason, beyond 15 weeks, amniocentesis
is the recommended invasive test.15 When analysing a CVS
sample, both layers of the placenta are normally reviewed.
The biological basis of chromosomal
This involves the cytotrophoblast, originating from the
mosaicism
trophoblast (external placental layer), and the mesenchymal
Chromosomal mosaicism occurs when two or more cell lines core, which is more representative of the fetal karyotype
exhibiting different karyotypes (chromosome complements) because it has a similar embryological origin.1,4,16 CPM can
are detected in a single embryo.8,9 This is associated with be further classified (Table 1). CPM Type 1 is typically only
either a non-disjunction (NDJ) error (that is, failure of sister evident on short-term culture (STC), CPM Type 2 on long-
chromatids to separate correctly) during mitotic cell division, term culture (LTC) and CPM Type 3 in both LTC and STC.4
or during meiosis with an NDJ error followed by a CPM 1 and 2 are the commonest types.17 By performing a
postzygotic mitotic trisomic rescue.7–9 The former is the CVS following a high-risk NIPT result, CPM types 1 and 3
primary mechanism for chromosomal mosaicism. This may be detected, which can lead to a false positive result
occurs when an initially normal diploid embryo with 46 (Table 1). This phenomenon is commoner for trisomy 13, 18
chromosomes undergoes an error during mitosis, creating a and the sex chromosomes.4 TFM is mainly identified via
trisomic cell line and a monosomic cell line, as well as the second trimester amniocentesis to identify fetal cells and can
unaffected cells having a normal chromosome complement. also be further classified.4 For all TFM types, the fetus is
In the case of the 44 autosomes, the monosomic cell line is abnormal, versus CPM where the fetus is normal (Table 1).
naturally disadvantaged and discontinues, leaving the CPM alone is associated with an increased risk of FGR and
trisomic and normal cell lines. In NDJ involving the X fetal loss, warranting regular fetal growth assessment
chromosome, however, all cell lines tend to in pregnancy.18,19
continue (Figure 1).8-10
The second mechanism is when a meiotic NDJ error
Prenatal aneuploidy testing methods
occurs followed by a postzygotic mitotic trisomy rescue via
anaphase lag where a diploid complement is restored.10,11 Initially, genetic analysis of prenatal samples is typically
Depending on the chromosome lost, this could lead to performed via quantitative fluorescence polymerase chain
biparental (one maternal and one paternal chromosome) or reaction (QF-PCR).20 This requires a small amount of DNA,
uniparental disomy (both chromosomes from the one which is amplified and displayed as peaks via an automated
parent).8,12 Uncommonly, uniparental disomy (UPD) may method. A normal diploid sample will typically reveal two
have a phenotypic effect on the fetus, leading to imprinting peaks in a 1:1 ratio for each chromosome analysed, whereas
disorders, a greater incidence of autosomal recessive trisomy may present with three peaks (1:1:1 ratio), a 2:1 ratio
disorders and fetal growth restriction (FGR).8,12 peak or rarely a homozygous pattern with a single peak.21
The rapid turnaround time (24–48 hours) and automation of
QF-PCR means it has now taken over the STC aspect of
Subtypes of fetal placental mosaicism
analysis of CVS samples.22 Owing to the reporting of
An abnormal cell line can be present in both the fetus and discrepancies between LTC karyotypes and QF-PCR results,
placenta, only in the fetus, or only in the placenta (Figure 2). UK-wide sample preparation has been streamlined so that the
This depends on the timing of the NDJ error and whether it sample used is representative of the biopsy and that the
occurs after or before the embryological separation of fetal mesenchymal core, in particular, is present in adequate
ª 2022 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists. 29
Confined placental mosaicism
(a) (b) (c)
Mitotic non Mitotic non Meiotic non

disjunction disjunction (sex disjunction
(autosomes) chromosomes)
NON DISJUNCTION
MEIOSIS
(GAMETES)
46, N 46, XX 47,+chr
ZYGOTE
TRISOMY RESCUE
NON DISJUNCTION NON DISJUNCTION
/ANAPHASE LAG
47,+chr 45,-chr 47,XXX 45,X
47,+chr 46,N
MITOSIS
46,N 46,XX
Present Present Present

MOSAIC 46,N/47,+chr
46,N/47,+chr 46,XX/47,XXX/45,X
Figure 1. Mechanisms of chromosomal mosaicism. Reproduced from Grati (2014)8 with permission. (a) mitotic non disjunction error involving an
autosome (mosaic 46,N/47,+chr); (b) mitotic non disjunction error involving a sex chromosome (mosaic 45,X/47,XXX/46,XX); (c) meiotic non-
disjunction error followed by trisomy rescue (mosaic 46,N/47,+chr).
amounts in the specimen.14,17,23–26 QF-PCR may reveal structural anomaly (FSA) and the absence of aneuploidy on
suspicion of CPM through the presence of abnormal biallelic QF-PCR, a chromosome microarray should be the next
trisomy, in which case the laboratory report may be returned investigation performed.23
recommending a full culture.8,27 The gold standard testing
strategies for genetic CVS analysis are to analyse both the
False positive and negative NIPT results
cytotrophoblast and the mesenchyme via QF-PCR and LTC/
karyotype (mesenchymal core). However, notably, QF-PCR Autosomal aneuploidy
is considered a standalone diagnostic test for most Rates of false positive and negative (retrospectively
aneuploidy cases; specifically, in the presence of a 1:1:1 identified) results in respective aneuploidies are
marker pattern indicating trisomy of meiotic origin (that is, demonstrated in Table 2. These show wide variation,
the chromosomal condition was present at conception and dependent on (i) the specific chromosome affected, (ii) the
reflects the fetal genotype) (Figure 3).27 In the case of a fetal woman’s pre-test risk based upon first trimester screening
Reilly et al.
Complete Confined placental

fetal-placental concordance mosaicism
Fetal-placental Non-mosaic fetus, Fetal mosaicism,

mosaicism mosaic placenta non-mosaic placenta
Fetal mosaicism, Complete

normal placenta fetal-placental discordance
Figure 2. Types of fetal placental mosaicism. Reproduced with permission from Gardner, Sutherland and Shaffer (2011).13 Green indicates an
aneuploid cell line while white represents euploid.
represent the cytotrophoblast, risking a persistently false

Table 1. Different types of confined placental mosaicism/true fetal
mosaicism and the associated chorionic villus sampling and non- positive result if CPM is present. The implications of this will
invasive prenatal testing results be discussed (Figure 4).17 Where there is no clear evidence of
a meiotic origin to a positive result, mesenchymal core
Type Cytotrophoblast Mesenchyme Fetus NIPT result
culture and testing results should be awaited to
confirm karyotype.
CPM 1 Abnormal Normal Normal False positive
Sex chromosome aneuploidy
CPM 2 Normal Abnormal Normal Normal Monosomy X (45,X), Klinefelter syndrome (47,XXY or 48,
CPM 3 Abnormal Abnormal Normal False positive XXYY), Triple X syndrome (47,XXX) and 47,XYY are
classified as sex chromosome aneuploidies (SCA).30 With
TFM 4 Abnormal Normal Abnormal Abnormal NIPT, the detection rates for SCA aneuploidies are less
accurate than for autosomal aneuploidies.31,32 This is
TFM 5 Normal Abnormal Abnormal False negative
consistent with the low PPV of cffDNA for Monosomy X,
TFM 6 Abnormal Abnormal Abnormal Abnormal which has false positive NIPT rates as high as 91%.4,33 Factors
contributing to false SCA NIPT results include previously
CPM = combined placental mosaicism; NIPT = non-invasive prenatal undiagnosed maternal SCA associated with a normal
testing; TFM = true fetal mosaicism. Adapted and reproduced from phenotype, and mosaicism.34
Grati (2014)8 with permission.
Proposed prenatal management

(statistically a low risk of aneuploidy on first trimester Existing guidance and choice of confirmatory
screening confers a greater risk of false result on NIPT) and; invasive test
(iii) the presence or absence of a FSA.6,17,27 Reasons for false Current FASP recommendations for women with a high-risk
positive and negative NIPT results are demonstrated in combined or quadruple test include (i) no testing; (ii)
Box 1.28,29 NIPT is based upon ‘free fetal DNA’ released into invasive testing or (iii) additional screening with NIPT.27
the maternal circulation and derived from the placental Henceforth, women with a high-risk NIPT result may be
cytotrophoblast. UK best practice involves QF-PCR testing of offered (i) no testing or (ii) invasive testing. The challenge of
both cell lineages in a CVS, however it may still only which pathway for selection of the invasive test depends on
D21S11 D13S628 D13S634 D18S535

240 320 400 480
D13S742 D18S1002 D13S305

240 320 400 480
Figure 3. A QF-PCR electropherogram demonstrating trisomy 18. Three spikes are detected by probe sets D18S535 and D18S1002 (triallelic)
indicating trisomy 18.
Reilly et al.
Table 2. Performance of non-invasive prenatal testing for aneuploidy and low and high-risk pre-test screening groups
Risk of
mosaicism Detected
in a CVS mosaicism
False False after a high on CVS + fetal
negative positive Sensitivity Specificity PPV risk NIPT confirmation
Aneuploidy Risk rate rate (%) (%) (95% CI) result (%) by amniocentesis (%)
T21 High risk 1/135 1/7372 >99.9 99.8 94.1 (92.3–95.9) 2 44

Low risk 81.3 (77.3–88.4)
T18 High risk 1/64 1/7472 97.4 99.6 89 4 14

Low risk 68
T13 High risk 1/136 1/1754 87.5 >99 85 22 4

Low risk 61
MX (45,X) High risk 1/14 1/1421 95 99 39 59 26

Low risk 26
CPM = confined placental mosaicism; CVS = chorionic villus sampling; MX = monosomy X; NIPT = non-invasive prenatal testing; PPV = positive
predictive value.
DNA with a triallelic marker pattern on the

Box 1. Reasons for false positive and negative non-invasive
prenatal testing (NIPT) results electropherogram is considered diagnostic, although this
depends on which cell lines are assessed, and LTC with
Reasons for false positive tests karyotype is confirmatory. Trisomy 13 and 18 are different
Confined placental mosaicism because of the higher risk of CPM. Hence, in instances where
Maternal chromosome mosaicism no FSA is identified, careful counselling and documentation
Inadequate fetal fraction must be performed by the clinician. Advice from clinical
Maternal malignancy
Vanishing twin
genetics may be to offer (i) CVS with QF-PCR and LTC/
karyotype analysis performed in line with current guidance38
Reasons for false negative tests
or (ii) amniocentesis. This counselling should include the
Mosaicism risks and benefits of both the procedure and the risk of CPM,
Early gestational age of sample how to interpret the results, and the importance of the
Inadequate fetal fraction- increased maternal body mass index
Prolonged storage of samples
correct interpretation of these results.
Amniocentesis assesses DNA of truly fetal origin
(amniocytes), as opposed to CVS which assesses placental
cells (although fetal-placental mosaicism is possible but rare).
(a) the type of aneuploidy (i.e., trisomy 21, 13 or 18) and (b) NIPT testing is available from as early as 9 weeks of gestation
the presence of identifiable FSAs. In trisomy 21, first- and as part of the FASP evaluative roll out, up to 21 weeks
trimester screening for assessment of nuchal translucency and 6 days.39 Amniocentesis is not normally performed until
with secondary ultrasound markers has a sensitivity as high as after 15 weeks of gestation, with CVS performed from
91.7% for a false positive rate of 3%35, which is similar to 11 weeks of gestation. Sometimes, insufficient DNA can be
trisomy 13 and 18. Hence, clinicians must exert extreme obtained from amniocentesis at 15 weeks, so it is suggested it
caution in instances of a high-risk NIPT result and no be performed at 16 weeks of gestation in preference.40 This
identifiable FSA.36 Currently, first trimester detailed anatomy aforementioned scenario is highly complex and poses a
scanning is not part of the FASP screening programme, so scientific and clinical dilemma because the implications of
detection of anomalies in the first trimester is limited. making a false diagnosis, although unlikely, are considerable.
Continuing work by the National Congenital Anomaly and In such instances, liaison with the scientific staff in the
Rare Disease Registration Service collects data and quality genetics laboratory and clinical genetics service is advisable
assurance for detection of congenital anomalies and their and management may differ on a case-by-case basis. A
prevalence.37 For trisomy 21, QF-PCR analysis from fetal further challenge occurs in the instance of twin pregnancy
testing, and both informed counselling and full written

consent should be obtained. In the absence of an FSA,
patients must also be advised of the standard prenatal
screening pathway and options available to them, as well as
the pros and cons of each test. In relation to NIPT, as well as
false positive and negative results, the possibility of need for
re-draw or inability to obtain a result should also be outlined
and documented. With a positive NIPT result, post-test
counselling should be conducted by a fetal medicine specialist
with the chromosome, procedure-specific risks outlined to
the patient pertaining to risk with invasive testing (Table 2).
Laboratory reporting
Recent guidance recommends that genetic laboratory reports
should include (i) a full and clear interpretation of the test
results, taking into account any appropriate information
provided; (ii) and any further tests that may be indicated to
improve the accuracy of the interpretation. Furthermore, (iii)
Normal Abnormal Falsely abnormal
support should be available via/from clinical genetics where
fetus cytotrophoblast cfDNA
required.42 Clinical guidance is provided on laboratory
fragments in reports to alert the clinician to the risk of the potential for
maternal false positive and negative results associated with mosaicism.
Figure 4. Illustration portraying how false positive results occur in In CVS analysis, if the clinical scientist has identified a
non-invasive prenatal testing in confined placental mosaicism Types 1 potential for a false positive abnormal result (caused by a
and 3. Adapted and reproduced from Grati (2016)4 with permission. marker ratio pattern suggestive of a postzygotic mitotic
error), they should specifically inform the clinician of the
increased risk of CPM.23 In this instance, it is advised to
where there is an FSA and a high-risk NIPT result. Here, if await further karyotypic analysis by culture or, indeed, await
the patient requests selective reduction, most notably in an amniocentesis.23 Ideally, in suspected CPM or following a
monochorionic twin pregnancy where risk of demise or QF-PCR result that is not straightforward, it may be
impairment to the non-anomalous fetus (which although advisable for the obstetrician to liaise with a fetal medicine
rare, can be heterokaryotypic)41 is high, then an invasive specialist, laboratory scientist and, if required, clinical
diagnostic test of both fetuses should be considered in the geneticist in a multidisciplinary team setting such as a fetal
first instance, unless the FSA is so severe that grounds of medicine genetic clinic. The implications of acting upon a
Clause E of the Abortion Act are clearly met without such false positive result are considerable. Clear and directive
additional information. reporting by the laboratory of the test findings is thus
Updated best practice guidance for prenatal testing, mandatory so that clinical misinterpretation can be
interpretation and counselling is due to be published by the minimalised. Ideally, this is agreed nationally to avoid
Royal College of Obstetricians and Gynaecologists (RCOG) regional variability.
in 2022. Guidance regarding management of monochorionic
twin pregnancy and prenatal molecular and cytogenetic test
evaluation is also forthcoming from the Association for
Ethical implications
Clinical Genomic Science. The National Institute for Health and Care Excellence
(NICE) stipulates that abortion services should be available
Prenatal counselling to women who require them without delay – ideally
Patients must receive robust pre-test and post-test providing a termination of pregnancy (TOP) within 1 week
counselling regarding the risk of CPM and false positive of assessment.43 Where there is a potential false positive
findings by an appropriately trained clinician. Potential NIPT result, clinicians face a dilemma for women requesting
longer turnaround time to await LTC – or even TOP, which may have to be delayed by some weeks to permit
amniocentesis – must be discussed from the outset to appropriate testing to determine if the grounds for Clause E
manage expectations. Clinicians offering NIPT should of the Abortion Act are met, most notably in the absence of
remain up to date regarding the challenges surrounding an identifiable FSA. On the contrary, if TOP is performed
Reilly et al.
when there is a truly false positive result, the implications of midtrimester scan.27,39 Evidence regarding the optimal
this are more significant for the woman; hence, delaying screening strategy is conflicting. The American College of
pending further investigations is ethically the optimal Obstetricians and Gynecologists and Society for Maternal–
pathway. The woman can still decline the clinician’s advice Fetal Medicine both recommend that all women are offered
if further testing is required and proceed with TOP if under screening and testing for chromosomal abnormalities in the
24 weeks of gestation; however, this would fall under form of cffDNA, regardless of the level of risk.49 Based upon
alternative grounds, not Clause E, and would still require the principles of screening, for a test to be deemed suitable it
the support of two clinicians to proceed. Where there is no must fulfil the criteria as set out by Wilson and Jungner.50 A
FSA and trisomy 21 is suspected, clinicians may struggle to screening test is judged suitable and appropriate by many
ethically support TOP under Clause E because of the wide markers including sensitivity, specificity, PPV and NPV.
phenotypic spectrum of Down syndrome – particularly if NIPT has been shown to be more sensitive and specific for
there is a greater risk of fetal mosaicism where the phenotype trisomies 21, 18 and 13 in high-risk populations.51 Owing to
expressed may be very mild, if evident whatsoever.44 In this the generalised low prevalence of aneuploidy and risk of
instance, TOP may be supported under Clause C. biological phenomena such as CPM associated with the
A further ethical challenge posed by abnormal NIPT results chance of false positive or negative NIPT results, modelling
that do not fit with the fetal phenotype, is the potential for suggests that use of NIPT as a first line test rather than
underlying maternal chromosomal mosaicism and maternal contingent screening following standard first trimester
malignancy.7 Therein lies a further dilemma for the clinician: screening could lead to more unnecessary invasive testing,
do they practise ‘nonmaleficence’ and not break bad news to a with associated loss of a euploid fetus.52 In addition, a
woman (at a notably vulnerable time in life) regarding universal NIPT approach would probably lead to
potential malignancy based upon a test that is not designed considerably more challenging cases for clinicians in
to screen for it, or ‘beneficence’, and open the doors to further relation to counselling as to the optimal invasive testing
investigation and potential treatments.45 If previously strategy. A further issue regarding a universal NIPT screening
unknown maternal chromosomal mosaicism is detected, this approach is how pre-eclampsia screening might fit in, as this
can have profound effects on not only the woman’s mental would negate the requirement for serum tests for pregnancy
health, but her future health and – potentially – her medical associated plasma protein-A (PAPP-A). Although uterine
insurance.46 Such moral complexities highlight the importance artery Doppler may be a more optimal pre-eclampsia and
of a thorough consenting process by an appropriately FGR screening strategy, PAPP-A may the only available
trained professional.46 screening method within some centres. Hence, by ceasing the
Immunomodulatory drugs (excluding immunoglobulin) combined test, pre-eclampsia and FGR screening with
can lead to false positive NIPT results. If the benefit of initiation of prophylaxis and subsequent monitoring may
holding these drugs prior to testing outweighs the potential be lost.53 In 2019, the UK National Screening Committee
risks to the patient owing to their medical condition recommended a 3-year evaluation of the introduction of
worsening, then there is a consideration to be made for NIPT inclusive of scientific, ethical and user input to assess
halting the mother’s treatment temporarily. Advice from the its impact on the NHS FASP. Pending publication of the
relevant obstetric physician should be prospectively sought.39 evaluation’s findings, it may well become the case that
NIPT testing for the purposes of revealing fetal sex for contingent screening using NIPT moves to universal NIPT,
social reasons is unethical and associated with a high risk of a although this is awaited.48
false positive result for sex aneuploidy, hence this is
not recommended.47
Conclusion
While NIPT is a novel and exciting technology
Future considerations
revolutionising the field of prenatal diagnosis, the potential
Owing to the high sensitivity and specificity of NIPT for for false positive findings secondary to confined placental
common aneuploidies, it may be argued that an appetite is mosaicism carries uncommon but severe implications.
growing for universal first-line NIPT screening. Theoretically, Clinicians must be appropriately trained in offering
the adoption of such a screening programme may reduce the detailed pre-test and post-test counselling to women, with
number of women undergoing invasive testing and hence appropriate onward to fetal medicine specialists, and – in
reduce the miscarriage rate, as well as potentially facilitating some circumstances – clinical genetics, for the most
an earlier diagnosis.48 Currently NIPT is not used as an initial appropriate confirmatory invasive test and genetic analysis.
universal screening programme for the NHS. Women are This must be done before a woman has the opportunity to
offered the option of either the combined (first trimester) or act upon a result, most notably in the absence of an
the quadruple test (second trimester) in addition to a detailed identifiable fetal structural anomaly on ultrasound.
Disclosure of interests 9 Grati FR, Malvestiti F, Branca L, Agrati C, Maggi F, Simoni G. Chromosomal
mosaicism in the fetoplacental unit. Best Pract Res Clin Obstet Gynaecol
MDK is a member of Illumina’s International Perinatal 2017;42:39–52.
Advisory Group (but receives no payment for this) and is the 10 Kalousek DK, Langlois S, Robinson WP, Telenius A, Bernard L, Barrett IJ, et al.
fetal medicine representative for the Central and South Trisomy 7 CVS mosaicism: pregnancy outcome, placental and DNA analysis
in 14 cases. Am J Med Genet 1996;65:348–52.
genomics laboratory hub. He is also the Royal College of 11 Schinzel A, Kotzot D, Brecevic L, Robinson WP, Dutly F, Dauwerse H, et al.
Obstetricians and Gynaecologists’ (RCOG) representative on Trisomy first, translocation second, uniparental disomy and partial trisomy
the Joint Colleges Committee of Genomic and Genetic third: a new mechanism for complex chromosomal aneuploidy. Eur J Hum
Genet 1997;5:308–14.
Medicine and the RCOG Genomic Taskforce. FM and MDK 12 Engel E. Uniparental disomy revisited: The first twelve years. Am J Med
co-authored the recent RCOG Scientific Impact Paper no. 64. Genet 1993;46:670–4.
SH has co-authored the Association for Clinical Genomic 13 Gardner RJM, Sutherland GR, Shaffer LG, eds. Chromosome abnormalities
and genetic counselling. 4th ed. Oxford: Oxford University; 2011.
Science (ACGS) professional guidelines for quantitative 14 Hamilton SJ, Waters JJ. Completely discrepant results between prenatal QF-
fluorescence polymerase chain reaction (QF-PCR) for the PCR rapid aneuploidy testing and cultured cell karyotyping obtained from
diagnosis of aneuploidy best practice guidelines (2018). FM is CVS: Lessons from UK audit and re-audit of 22,221 cases. Prenat Diagn
2012;32:909–11.
editor of genetics for Ultrasound in Obstetrics & Gynecology, 15 Carroll SG, Davies T, Kyle PM, Abdel-Fattah S, Soothill PW. Fetal karyotyping
co-chair for the International Society of Prenatal Diagnosis by chorionic villus sampling after the first trimester. Br J Obstet Gynaecol
SIG for Fetal Imaging and Phenotyping as well as the BMFMS 1999;106:1035–40.
16 Coorens THH, Oliver TRW, Sanghvi R, Sovio U, Cook E, Vento-Tormo R, et al.
representative for the Fetal Genomics Group of the British Inherent mosaicism and extensive mutation of human placentas.
Society for Genomic Medicine. 2021;592:80–5.
17 Grati FR, Balaj K, Malvestiti F, Agrati C, Grimi B, Malvestiti B, et al. The type
of feto-placental aneuploidy detected by cfDNA testing may influence the
Contribution to authorship choice of confirmatory diagnostic procedure. Prenat Diagn
FM and MDK conceived and designed the manuscript. All 2015;35:994–8.
other authors contributed to drafting the article, providing 18 Del Gobbo GF, Yin Y, Choufani S, Butcher EA, Wei J, Rajcan-Separovic E,
et al. Genomic imbalances in the placenta are associated with poor fetal
final approval and agreement regarding accountability. All growth. Mol Med 2021;27:3.
authors approved the final version. 19 Kalousek DK, Howard-Peebles PN, Olson SB, Barrett IJ, Dorfmann A, Black
SH, et al. Confirmation of CVS mosaicism in term placentae and high
frequency of intrauterine growth retardation association with confined
Acknowledgements placental mosaicism. Prenat Diagn 1991;11:743–50.
The authors would like to thank Dr Stephanie Allen, Head of 20 Nicolini U, Lalatta F, Natacci F, Curcio C, Bui TH. The introduction of QF-PCR
Prenatal Diagnosis and Reproductive Medicine, West in prenatal diagnosis of fetal aneuploidies: time for reconsideration. Hum
Reprod Update. 2004;10:541–8.
Midlands Regional Genetics Laboratory, Birmingham 21 Mann K, Ogilvie CM. QF-PCR: application, overview and review of the
Women’s and Children’s NHS Foundation Trust. literature. Prenat Diagn 2012;32:309–14.
22 Atef SH, Hafez SS, Mahmoud NH, Helmy SM. Prenatal diagnosis of fetal
aneuploidies using QF-PCR: the Egyptian study. J Prenat Med 2011;5:83–9.
References 23 Mann K, Hamilton S, Evans J, Sibbring J, Dore J. ACGS best practice
guidelines for use of quantitative fluorescence-PCR for the detection of
1 Van Opstal D, Srebniak MI. Cytogenetic confirmation of a positive NIPT aneuploidy v4. London: Association for Clinical Genomic Science; 2018.
result: evidence-based choice between chorionic villus sampling and [https://www.acgs.uk.com/quality/best-practice-guidelines/].
amniocentesis depending on chromosome aberration. Expert Rev Mol Diagn 24 Waters JJ, Walsh S, Levett LJ, Liddle S, Akinfenwa Y. Complete discrepancy
2016;16:513–20. between abnormal fetal karyotypes predicted by QF-PCR rapid testing and
2 Warsof SL, Larion S, Abuhamad AZ. Overview of the impact of noninvasive karyotyped cultured cells in a first-trimester CVS. Prenat Diagn
prenatal testing on diagnostic procedures. Prenatal Diagn 2015;35: 2006;26:892–7.
972–9. 25 Grati FR, Malvestiti F, Grimi B, Gaetani E, Di Meco AM, Trotta A, et al. QF-
3 Togneri FS, Kilby MD, Young E, Court S, Williams D, Griffiths MJ, et al. PCR as a substitute for karyotyping of cytotrophoblast for the analysis of
Implementation of cell-free DNA-based non-invasive prenatal testing in a chorionic villi: advantages and limitations from a cytogenetic retrospective
National Health Service Regional Genetics Laboratory. Genet Res (Camb) audit of 44,727 first-trimester prenatal diagnoses. Prenat Diagn
2019;101:1–9. 2013;33:502–8.
4 Grati FR. Implications of fetoplacental mosaicism on cell-free DNA testing: a 26 Holgado E, Liddle S, Ballard T, Levett L. Incidence of placental mosaicism
review of a common biological phenomenon. Ultrasound Obstet Gynecol leading to discrepant results between QF-PCR and karyotyping in 22,825
2016;48:415–23. chorionic villus samples. Prenat Diagn 2011;31:1029–38.
5 Flori E, Doray B, Gautier E, Kohler M, Ernault P, Flori J, et al. Circulating cell- 27 NHS England. Prenatal diagnosis. In: Fetal anomaly screening programme
free fetal DNA in maternal serum appears to originate from cyto- and handbook. London: NHS England; 2021 [https://www.gov.uk/government/
syncytio-trophoblastic cells. Hum Reprod 2004;19:723–4. publications/fetal-anomaly-screening-programme-handbook/prenatal-
6 Wax J, Chard R, Cartin A, Litton C, Pinette MG, Lee Lucas F. Noninvasive diagnosis].
prenatal testing: the importance of pretest trisomy risk and posttest 28 Hu P, Liang D, Chen Y, Lin Y, Qiao F, Li H, et al. An enrichment method to
predictive values. Am J Obstet Gynecol 2015;212:548–9. increase cell-free fetal DNA fraction and significantly reduce false negatives
7 Grati FR, Malvestiti F, Ferreira JC, Bajaj K, Gaetani E, Agrati C, et al. and test failures for non-invasive prenatal screening: a feasibility study. J
Fetoplacental mosaicism: potential implications for false positive and false- Transl Med 2019;17:124.
negative non-invasive prenatal screening results. Genet Med 29 Van Opstal D, Srebniak MI, de Vries F, Govaerts LCP, Joosten M, et al. False
2014;16:620–4. negative NIPT results: risk figures for chromosomes 13, 18 and 21 based on
8 Grati FR. Chromosomal mosaicism in human feto-placental development: chorionic villi results in 5967 cases and literature review. PLoS One 2016;11:
implications for prenatal diagnosis. J Clin Med 2014;3:809–37. e0146794.
Reilly et al.
30 Wang Y, Li S, Wang W, Dong Y, Zhang M, Wang X, et al. Cell-free DNA 42 Cresswell L, Wallis Y, Fews G, Deans Z, Fratter C, Monkman L, et al. General
screening for sex chromosome aneuploidies by non-invasive prenatal testing genetic laboratory reporting recommendations. London: Association for
in maternal plasma. Mol Cytogenet 2020;13:10. Clinical Genomic Science; 2020 [https://www.acgs.uk.com/quality/best-
31 Grati FR, Bajaj K, Zanatta V, Malvestiti F, Malvestiti B, Marcato L, et al. practice-guidelines/].
Implications of fetoplacental mosaicism on cell-free DNA testing for sex 43 National Institute for Health and Care Excellence (NICE). 1.1 Service
chromosome aneuploidies. Prenat Diagn 2017;37:1017–27. organisation. In: Abortion care. NICE guideline [NG140]. London: NICE;
32 Nicolaides KH, Musci TJ, Struble CA, Syngelaki A, Gil MM. Assessment of 2019 [https://www.nice.org.uk/guidance/ng140/chapter/
fetal sex chromosome aneuploidy using directed cell-free DNA analysis. Fetal Recommendations#making-it-easier-to-access-services].
Diagn Ther 2014;35:1–6. 44 Royal College of Obstetricians and Gynaecologists (RCOG). The care of
33 Reiss RE, Discenza M, Foster J, Dobson L, Wilkins-Haug L. Sex chromosome women requesting induced abortion. Evidence-based Clinical Guideline No.
aneuploidy detection by noninvasive prenatal testing: helpful or hazardous? 7. London: RCOG; 2011 [https://www.rcog.org.uk/media/nwcjrf0o/
Prenat Diagn 2017;37:515–20. abortion-guideline_web_1.pdf].
34 Zhang B, Zhou Q, Chen Y, Shi Y, Zheng F, Liu J, et al. High false-positive non- 45 Benn P, Plon SE, Bianchi DW. Current controversies in prenatal diagnosis 2:
invasive prenatal screening results for sex chromosome abnormalities: Are NIPT results suggesting maternal cancer should always be disclosed. Prenat
maternal factors the culprit? Prenat Diagn 2020;40:463–9. Diagn 2019;39:339–43.
35 Wiechec M, Knafel A, Nocun A, Matyszkiewicz A, Juszczak M, Wiercinska E, 46 Bianchi D. Pregnancy: prepare for unexpected prenatal test results. Nature
et al. How effective is first-trimester screening for trisomy 21 based on 2015;522:29–30.
ultrasound only? Fetal Diagn Ther 2016;39:105–12. 47 Bowman-Smart H, Savulescu J, Gyngell C, Mand C, Delatycki MB. Sex
36 Wagner P, Sonek J, Hoopmann M, Abele H, Kagan KO. First-trimester selection and non-invasive prenatal testing: a review of current practices,
screening for trisomies 18 and 13, triploidy and Turner syndrome by evidence, and ethical issues. Ultrasound Obstet Gynecol 2020;40:398–407.
detailed early anomaly scan. Ultrasound Obstet Gynecol 2016;48: 48 UK National Screening Committee. UK NSC non-invasive prenatal testing
446–51. (NIPT) recommendation. London: UK National Screening Committee; 2016
37 Public Health England. National congenital anomaly and rare disease [https://legacyscreening.phe.org.uk/policydb_download.php?doc=570].
registration service: congenital anomaly statistics 2019. London: Public 49 American College of Obstetricians and Gynecologists’ Committee on
Health England; 2019 [https://assets.publishing.service.gov.uk/government/ Practice Bulletins—Obstetrics; Committee on Genetics; Society for Maternal-
uploads/system/uploads/attachment_data/file/1021335/NCARDRS_ Fetal Medicine. Screening for fetal chromosomal abnormalities: ACOG
congenital_anomaly_statistics_report_2019.pdf]. Practice Bulletin, Number 226. Obstet Gynecol 2020;136:e48–69.
38 Silva M, de Leeuw N, Mann K, Schuring-Blom H, Morgan S, Giardino D, 50 Wilson J, Junger G. Principles and practice of screening for disease. Geneva:
et al. European guidelines for constitutional cytogenomic analysis. Eur J World Health Organization; 1968 [https://apps.who.int/iris/bitstream/
Hum Genet 2019;27:1–16. handle/10665/37650/ WHO_PHP_34.pdf?sequence=17].
39 NHS England. Screening for Down’s syndrome, Edwards’ syndrome and 51 Taylor-Phillips S, Freeman K, Geppert J, Agbebiyi A, Uthman OA, Madan J,
Patau’s syndrome: NIPT. London: NHS England; 2021 [https://www.gov.uk/ et al. Accuracy of non-invasive prenatal testing using cell-free DNA for
government/publications/screening-for-downs-syndrome-edwards- detection of Down, Edwards and Patau syndromes: a systematic review and
syndrome-and-pataus-syndrome-non-invasive-prenatal-testing-nipt/ meta-analysis. BMJ Open 2016;6:e010002.
screening-for-downs-syndrome-edwards-syndrome-and-pataus-syndrome- 52 Mackie FL, Hemming K, Allen S, Morris RK, Kilby MD. The accuracy of cell-
nipt]. free fetal DNA-based non-invasive prenatal testing in singleton pregnancies:
40 Papp C, Papp Z. Chorionic villus sampling and amniocentesis: what are the a systematic review and bivariate meta-analysis. BJOG 2017;124:32–46.
risks in current practice? Curr Opin Obstet Gynecol 2003;15:159–65. 53 Royal College of Obstetricians and Gynaecologists (RCOG). The Investigation
41 Lewi L, Blickstein I, Van Schoubroeck D, Gloning K-P, Casteels M, and management of the small-for-gestational-age fetus. Green-top
Brandenburg H, et al. Diagnosis and management of heterokaryotypic guideline no. 31. London: RCOG; 2014 [https://www.rcog.org.uk/media/
monochorionic twins. Am J Med Genet A 2006;140:272–5. t3lmjhnl/gtg_31.pdf].
DOI: 10.1111/tog.12848 2023;25:38–46
Review
Premenstrual disorders including premenstrual syndrome

and premenstrual dysphoric disorder
Nidhi Goswami MBBS MS MRCOG,a Kalpana Upadhyay MBBS MS (O&G) FRCOG,*b Paula Briggs MBChB FFSRH FRCGP,
c
Elizabeth Osborn BSc (Hons) MSc ClinPsyD,d Nick Panay BSc FRCOG MFSRHe,f,g,h
a
Specialty Trainee in Obstetrics and Gynaecology, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK
b
Consultant in Obstetrics and Gynaecology, Wrexham Maelor Hospital, Betsi Cadwaladr University Health Board, Croesnewydd Road,
Wrexham LL13 7TD, UK
c
Consultant in Sexual and Reproductive Health, Liverpool Women’s Hospital, Crown St, Liverpool L8 7SS, UK
d
Senior Clinical Psychologist, Glan Clwyd Hospital, Betsi Cadwaladr University Health Board, Rhuddlan Road, Bodelwyddan LL18 5UJ, UK
e
Consultant Gynaecologist, Subspecialist in Reproductive Medicine and Surgery, Queen Charlotte’s & Chelsea Hospital, Du Cane Rd,
London W12 0HS, UK
f
Professor of Practice, Imperial College London, Exhibition Rd, South Kensington, London SW7 2BX, UK
g
President, International Menopause Society, Devon, UK
h
Guest Professor, Beijing Capital Medical University, Fengtai District 100054, China
*Correspondence: Kalpana Upadhyay. Email: upadhyay.kalpana@gmail.com
Accepted on 7 March 2022.
Key content Learning objectives

The spectrum of premenstrual disorders is related to hormonal To understand the pathophysiology, diagnosis and treatment
changes in the menstrual cycle and are experienced by nearly 40% options for premenstrual disorders, including PMDD.
of women. To know the different classifications of premenstrual disorders,
Approximately 3–8% of women are affected by severe including DSM-5 and World Health Organization (WHO) ICD-11
premenstrual syndrome, including premenstrual dysphoric classifications of PMDD.
disorder (PMDD); a chronic, debilitating disorder with severe To understand the potential benefits associated with
emotional and physical symptoms and functional impairment. multidisciplinary care for women with premenstrual disorders
PMDD significantly affects women’s quality of life; recent evidence like PMDD.
suggests that 86% of patients have considered suicide, with 30%
Ethical issues
having attempted suicide at least once.
In 2019, PMDD was added to the International Statistical
Should women with severe premenstrual syndrome be classified
under mental health disorders in the ICD classification?
Classification of Diseases and Related Health Problems, (ICD–11),
which validates PMDD as a legitimate diagnosis and acknowledges Keywords: premenstrual disorders / premenstrual dysphoric
growing scientific and medical understanding of this previously disorder / premenstrual syndrome
under recognised condition.
Symptom relief can often be achieved through medical
management, therefore it is important to increase awareness
among healthcare professionals at all levels.
Please cite this paper as: Goswami N, Upadhyay K, Briggs P, Osborn E, Panay N. Premenstrual disorders including premenstrual syndrome and premenstrual
dysphoric disorder. The Obstetrician & Gynaecologist 2023;25:38–46. https://doi.org/10.1111/tog.12848
premenopausal women have symptoms severe enough to be

Introduction
classed as premenstrual syndrome (PMS).4 However, only 3–
Premenstrual disorders include various psychological, 8% of women experience symptoms at the extreme end of the
behavioural and physical disorders related to the hormones spectrum. One such extreme type of premenstrual disorder is
of the menstrual cycle. The symptoms manifest during the premenstrual dysphoric disorder (PMDD).5
luteal or post ovulation phase of the cycle and typically The symptoms of PMDD may be psychological, including
resolve by the end of menstruation.1,2 Approximately 90% of depression, anxiety, mood swings, irritability and loss of
women of reproductive age experience some symptoms, confidence; or physical, including breast tenderness and
termed ‘premenstrual molimina’.3 Around 20–40% of abdominal bloating.6 It is essential to differentiate between

Goswami et al.
the physiological symptoms of the menstrual cycle and PMS genetic factors
by objectively demonstrating that the symptoms cause psychosocial factors, such as stress13
significant impairment to the individual’s quality of life. Crucial to the pathogenesis of PMS/PMDD is an increased
The symptoms of ‘lassitude and heaviness of the head’ sensitivity to hormonal fluctuations during a normal
preceding menstruation have been recognised for centuries menstrual cycle, especially to progesterone and its
(Hippocrates 370 BC), but it was only in 1953 that the term GABAergic metabolite allopregnanolone, which is secreted
‘premenstrual syndrome’ was first used by Greene and following ovulation. The observation further supports this
Dalton.7 Historically, these experiences were considered theory that symptoms do not occur during life-stages in
normal female physiology or ‘just PMS’, failing to recognise which there are no hormonal fluctuations, i.e. prepuberty,
the severity of the symptoms and devastating effects on some during pregnancy and after menopause.14
women. PMDD is now included as a distinct entity in the The aetiology of PMDD may have a genetic basis.15 Single
latest version of DSM-5 (Diagnostic and Statistical Manual of nucleotide polymorphism in the ESR1 (Estrogen Receptor
Mental Disorders 5th edition) and ICD-11 (the 11th revision Alpha) gene encoding sex steroid hormone receptors may
of the International Classification of Diseases and Related confer differential sensitivity to hormones in women who
Health Problems). Nonspecific symptoms and overlapping suffer from PMDD. More recently, it was suggested that
presentations with other medical and psychiatric conditions, sensitivity may be attributed to dysregulation and
along with lack of recognition within healthcare disciplines, overexpression of Extra Sex Combs/Enhancer of Zeste [ESC/
can delay diagnosis and treatment, contributing to E(Z)] complex gene in women with PMDD. 16 This in vitro
substantial morbidity and a social burden on society.8 study explains the potential genetic basis for PMD, but more
Here, we summarise the aetiology, diagnostic criteria and research is needed in this field.
up-to-date, evidence-based management options. Functional magnetic resonance imaging (fMRI) has
demonstrated that neurotransmitters, including serotonin
and gamma amino butyric acid (GABA), are essential in
Prevalence
the pathogenesis of PMS/PMDD.17 The GABAA receptor is
Premenstrual disorders are common in women of found throughout the brain, but is particularly concentrated
reproductive age and may be deemed physiological rather in the amygdala, part of the limbic system. Neuroimaging
than pathological. Sadler et al.9 noted that 24% of women studies reveal that the amygdala is responsible for cognition,
aged 20–34 years had symptoms of moderate-to-severe PMS. decision-making and emotional responses, with an important
Similarly, Chung et al.10 reported an incidence of 23% in role in psychological disorders.17
perimenopausal women. The ‘dysphoric’ symptoms are In animal studies, estrogen has been shown to decrease
challenging for women, and are often the reason for monoamine oxidase (MAO) activity in the brain. This leads
seeking treatment.5 PMDD, at the most severe end of the to increased serotonin and a resultant antidepressant effect.
spectrum, affects about 3–8% of women of reproductive age. Progesterone, however, has the opposite effect and is
The type and severity of premenstrual disorders are associated with depressed mood.18 Ovarian hormones are
influenced by age, race, ethnicity and health status – responsible for the ‘reproductive depression’ triad of
particularly mental health.11 Prevalence in Asian countries premenstrual, postnatal and climacteric depression, which
is reportedly slightly lower than in Europe and the USA.12 often occur in the same susceptible women.19,20
Increased amygdala reactivity during the luteal phase is a
consistent finding in women with PMDD, associated with
Aetiology
progesterone and – more importantly – its metabolite
It remains unknown why some women have a profound allopregnanolone.21 Allopregnanolone is produced from
response to normal hormone levels produced during progesterone by the sequential actions of the enzymes 5a-
the menstrual cycle. Research continues, but possible reductase type I and 3a-hydroxysteroid dehydrogenase
theories include: (Figure 1). These two enzymes are not homogenously
abnormal sensitivity of the central nervous system to expressed in the brain, but they are highly expressed and
female hormones colocalised in specific neurones in the cerebral cortex,
3α-Hydroxysteroid
5α-Reductase dehydrogenase
PROGESTERONE 5α-Dihydroprogesterone Allopregnanolone
Figure 1. Metabolism of progesterone to allopregnanolone

Premenstrual disorders
hippocampus and amygdala.22 Allopregnanolone has a

Table 1. Differences between mild/moderate and severe premenstrual
positive modulatory effect on GABAA inhibitory receptors, syndrome (PMS), including premenstrual dysphoric disorder (PMDD).
inducing an anxiolytic effect. In women with PMDD, both an Adapted from National Association for Premenstrual Syndromes
increase and decrease in neurosteroids during different (NAPS)31
phases of the menstrual cycle induce changes in the alpha-4 Mild to moderate Severe PMS including
subunit conformation of the GABAA receptor.23,24 Plasticity Parameter PMS PMDD
of GABAA receptors leads to a paradoxical effect compared
with the typical mood-elevating effect of positive modulators
of GABAA receptors.25 Severity of mood symptoms in PMDD Prevalence 50–80 3–8
(%)
is related to the serum concentration of allopregnanolone in
an inverted U-shaped curve. Negative mood symptoms occur Severity of Mild to moderate Severe
when the serum concentration of allopregnanolone is similar symptoms
to endogenous luteal phase levels, while low and high
Presenting Physical or emotional or Predominantly emotional
concentrations have a minor effect on mood.26 Preliminary symptoms both
evidence from proton magnetic resonance spectroscopy has
shown alterations in the amino acid neurotransmitters, Diagnostic None DSM-5 (PMDD)
criteria
GABA and glutamate–glutamine levels in mood-related
brain regions in women with PMDD.27 Affective May or may not be Always present
A history of previous stress exposure has also been symptoms present
implicated in the aetiology of PMS/PMDD. In a longitudinal
Who can Usually managed in Mainly need a referral to
case-control study of over 3000 women, emotional and manage primary care secondary
physical abuse were strongly correlated with moderate-to- care/multidisciplinary care
severe PMS/PMDD, while sexual abuse was less strongly
correlated.28 The mechanism linking stress to PMDD remains Treatment It can be managed with Mostly need
lifestyle modifications if pharmacological treatment
unclear, but may relate to allopregnanolone levels. These mild May also need surgery
typically increase in response to acute stress, but not in women
with PMDD.29 In animal studies, serum allopregnanolone
levels become blunted after repeated or chronic stress, but
further human research is needed.30
Relief of symptoms following the onset of menstruation

Diagnosis
Symptom-free period before ovulation
Premenstrual disorders belong to a spectrum (Table 1).31 In Symptoms causing considerable distress and impairment
2012, the International Society for Premenstrual Disorders to daily personal, professional or social commitments
(ISPMD) produced a classification of PMD, categorising it during the luteal phase.
into either ‘Core PMD’ or ‘Variants of PMD’ (Table 2).32 A
year later, the Diagnostic and Statistical Manual of Mental
Investigation
Disorders-5 (DSM-5) of the American Psychiatric
Association (2013)33 defined the diagnostic criteria for Because many symptoms of severe PMS/PMDD (irritability,
PMDD, at the most severe end of the spectrum, under anger, depression and labile mood) are the same as those
Section II (depressive disorders), distinguishing it from mild- experienced by women with other psychiatric disorders,
to-moderate PMS (Box 1). cyclicity of symptoms is key to the diagnosis.
In a landmark decision in May 2019, the World Health Prospective recording of symptoms over two cycles using
Organization (WHO) included PMDD in the 11th revision of symptom diary charts is crucial, if possible, though may not
the International Statistical Classification of Diseases, (ICD- be feasible in women at high risk of suicide. Many PMS-
11).34 PMDD is now a legitimate medical diagnosis with ICD specific charts are available for symptom recording, including
code GA34.41. PMDD is primarily listed in diseases of the the ‘Daily Record of the Severity of the Problem’ (DRSP)35
genitourinary system, and cross listed in depressive disorders, and the ‘Prospective Record of the Impact and Severity of
highlighting the importance of multidisciplinary care for Menstrual Symptoms’ (PRISM) chart.36 PreMentricS is an
these women. iPhone app to help women track symptoms before a
Essential diagnostic criteria for PMS/PMDD are: diagnosis is made and enables recording of their response
Relation of symptoms to the luteal phase of the to treatment interventions. A diagnostic approach to PMDD
ovarian cycle is shown in Box 3.

Goswami et al.
Table 2. International Society for Premenstrual Disorders classification Box 1. DSM-5 diagnostic criteria for PMDD
of premenstrual disorders (PMD)
A: Definite temporal relation to menstrual cycle
PMD category Characteristics Symptoms must be present in the last week of menstrual cycle before
the onset of menses, start to improve within few days of start of
menses and become minimum or absent in the week post-menses
Core PMD Symptoms occur in ovulatory cycles B and C: Minimum 5 out of 11 symptoms, with at least one
core symptom
Symptoms are not specified—they may be Should be present for most cycles over the past 12 months (see Box 2)
somatic and/or psychological D: Symptoms to interfere markedly with usual activities
For example, work, school, social relationships
The number of symptoms is not specified E: Symptoms are NOT a mere exacerbation of an underlying
condition
Symptoms are absent after menstruation For example, depression, anxiety
and before ovulation F: NOT attributable to the physiological effects of a substance
or other medical condition
They must recur in the luteal phase For example, drug abuse, medication, other treatment, thyroid
disorders
They must be prospectively rated (two G: PMDD should be confirmed by prospective daily symptom
cycles minimum) diary for two consecutive cycles
Symptoms must cause significant distress

or impairment; for example to work,
school, social activities, hobbies, Box 2. Symptoms of PMDD for DSM-5 criteria
interpersonal relationships
Core symptoms
Variants of PMD Marked affective lability (e.g., mood swings; feeling suddenly sad or
tearful, or increased sensitivity to rejection)
Premenstrual Symptoms of an underlying psychological Marked irritability or anger or increased interpersonal conflicts
exacerbation or somatic disorder significantly worsen Marked depressed mood, feelings of hopelessness, or self-
premenstrually deprecating thoughts
Marked anxiety, tension, and/or feelings of being keyed up or on
PMD due to Symptoms result (rarely) from ovarian edge
nonovulatory ovarian activity other than those of ovulation Additional symptoms
activity
Decreased interest in usual activities (e.g., work, school, friends,
hobbies)
Progestogen-induced Symptoms result from exogenous
Difficulty in concentrating
PMD progestogen administration
Lack of energy, easily fatigued
Marked change in appetite, food cravings
PMD with absent Symptoms arise from continued ovarian
Feeling overwhelmed or ‘out of control’
menstruation activity even though menstruation has
Changes in sleep (hypersomnia, insomnia)
been suppressed
Physical discomforts such as breast tenderness, joint/ muscle pains,
headaches, bloating, weight gain
There are several important points to consider when a overall clinical picture, a trial of medical ovarian
diagnosis PMS/PMDD is suspected. suppression with a gonadotropin releasing hormone
Prospectively complete the symptom diary over two (GnRH) agonist can be helpful by temporarily
cycles before starting treatment if possible, to avoid eliminating ovarian hormone secretion.37
recall bias. If symptoms occur after exogenous hormones, discontinue
The cyclical pattern of symptoms distinguishes PMS/ the hormones and review to exclude a medication-induced
PMDD from other psychiatric disorders. mood disorder.
Other underlying medical and psychiatric disorders There are no laboratory tests or investigations available to
should be excluded and caution should be exercised make a diagnosis of PMS/PMDD. Depending on the
during the assessment of women with a premenstrual presentation, the following medical/psychiatric conditions
exacerbation of an underlying psychiatric condition. The should be excluded as an underlying cause by taking a full
absence of a symptom-free interval makes a diagnosis of clinical history:
PMS/PMDD unlikely. Psychiatric: depression, dysthymia, anxiety, panic disorder,
When the diagnosis is in doubt, or comorbid conditions bipolar disorder, somatoform disorder, personality
cloud the precise impact of the menstrual cycle on the disorder, substance abuse

Box 3. Diagnostic approach to PMDD Box 4. Evidence-based treatment approach (adapted from6)
Prospective recording of symptoms over 2 cycles using DRSP7 or First line: reduce effect of hormone fluctuation on
similar charts to document severity of symptoms, cyclical relation to neurotransmitters
menses and symptom free period before next ovulation.
Symptoms severe enough to affect quality of life. Life style modification
Rule out other medical or mental disorders with similar Complex carbohydrate diet during luteal phase
presentation. Aerobic exercise, yoga, meditation
Use of DSM-5 criteria to diagnose PMDD Exposure to sunlight
Symptom diary to be completed before start of treatment to avoid Stop smoking/ alcohol
masking of symptoms. Cognitive behavioural therapy (CBT)
Neuromodulators (Selective serotonin reuptake inhibitor [SSRI]/
Selective norepinephrine reuptake inhibitor [SNRI] – see (Box 5)
Continuous, or
Luteal phase
Combined oral contraceptive pills (reduce fluctuations in hormone
Medical: anaemia, autoimmune diseases, chronic fatigue level)
syndrome, diabetes, seizure disorders, hypothyroidism, For women not planning pregnancy:
Short hormone free interval 24/4 regimen of drospirenone 3mg
endometriosis, allergies, ovarian cysts
and ethinyl estradiol 20 mcg. (Note: increased risk of venous
thromboembolism (VTE) with drosperinone containing COCPs)
Combined oral contraceptive pills (COCPs) in continuous/ tricyclic
Treatment pattern
Levonorgestrel (LNG) 90 microcgrams/ethinyl estradiol 20 micrograms
PMS/PMDD is a chronic condition that, for now, can only be continuously for 3 4 months without a break
cured by removing the ovaries or by ovarian failure at the Second line:
time of menopause. For most women, symptoms can be Combination therapy with SSRIs and COCPs
controlled during reproductive life. Treatments aim to Estrogen therapy – estradiol patch (100 micrograms) or estradiol gel
(3 milligrams) + micronised progesterone (200 milligrams for
achieve the greatest functional improvement possible. Based 12 days during luteal phase, orally or vaginally) or levonorgestrel
on the pathophysiology of PMS, the management options intrauterine system (LNG IUS) 52 milligrams
are either: Third line: reduce fluctuations in hormone level
to reduce the effect of hormonal fluctuations linked with GnRH analogues add-back hormone replacement therapy
(HRT) – GnRH agonists (monthly or 3-monthly injections) add-
the menstrual cycle on neurotransmitter receptors back HRT
(serotonin and GABAA), or Fourth line: reduce fluctuations in hormone levels
to inhibit the menstrual cycle by preventing ovulation. Total hysterectomy + bilateral salpingo-oophorectomy HRT – in
Optimal management depends on a precise diagnosis, refractory cases not responding to medical management.
Novel therapies (currently under research)
assessment of the severity and impact of symptoms, patient 5-a reductase inhibitor (dutasteride) – dose 2.5 mg daily (reduce
preference and response to the treatment. A multidisciplinary luteal phase increase in allopregnanolone)
team with psychiatric input can be beneficial, particularly in Iso-allepregnanolone (UC1010) – sepranolone (GABAA modulating
women at high risk of suicide and women with an alternative steroid antagonist inhibits allopregnanolone action)
Vitex agnus castus (VAC) – balances female sex hormones through
diagnosis; for example, rapid cycling bipolar disorder. It is its phytochemicals)
imperative to listen to the patient carefully and
empathetically, considering any previous treatment received
and response to treatment, and tailoring the optimum
treatment according to the patient’s needs.
Different treatment options are available (some of which peanuts, can increase the amount of serotonin
are not licensed at present); see Box 4. available centrally.39
Exposure to light
Neuromodulation Human skin has an inherent serotonergic system capable
of generating serotonin in response to light.40,41
Increase serotonin levels Mood induction/stress reduction
Increased serotonin levels can be achieved by: The interaction between serotonin synthesis and mood
Exercise is two-way, with serotonin influencing mood and mood
Exercise increases extracellular serotonin and its influencing serotonin.42
metabolite 5-HIAA in the hippocampus and cortex.38 Use of selective serotonin reuptake inhibitors (SSRIs)/
Diet serotonin and norepinephrine reuptake inhibitors (SNRIs)
A complex carbohydrate and tryptophan-rich diet, These are increasingly used as first-line therapy. A 2013
including foods like whole milk, canned tuna, cheese and Cochrane review43 suggested that SSRIs are effective in

Goswami et al.
10 mg of sepranolone. However, there was no significant

Box 5. Selective serotonin reuptake inhibitor (SSRI)/selective
norepinephrine reuptake inhibitor (SNRI; off-label use) separation of effect compared with placebo. More research is
required before the drug could be approved for clinical use.47
Regimens: Use of cognitive behavioural therapy (CBT)
Continuous PMD symptoms are caused by increased activity in the
Luteal phase (day 15–28)
Doses:
amygdala. Activity in the frontal cortex (area of thinking and
Fluoxetine 20 mg/day reasoning) and limbic system/amygdala can be influenced by
Sertraline 50–100 mg/day stabilising impulsivity and emotional symptoms. CBT may
Citalopram 20 mg a day benefit women with PMS by making symptoms more
Escitalopram 20 mg/day
Paroxetine 20 mg/day
manageable. The most rigorous trial48 compared CBT with
Side effects: fluoxetine and found no difference between groups or
Nausea additive effects of CBT and fluoxetine. At follow-up,
Insomnia response to CBT was better maintained than that achieved
Somnolence
Fatigue
with fluoxetine, but attrition was almost as high as 50%. A
Reduced libido meta-analysis of five CBT studies49 showed some benefit,
How to discontinue treatment: although these studies were of poor methodological quality.
Luteal phase regimen – discontinue at any time However, a randomised controlled trial (RCT) evaluating the
Continuous regimen – taper dose over a period of time to avoid
withdrawal symptoms
effect of internet-based CBT (iCBT) on women with probable
diagnosis of PMDD demonstrated a significant and stable
improvement in symptom intensity, disability and a positive
impact on everyday life up to 6 months after treatment.50
reducing the overall symptoms as well as specific symptoms
of PMD. Most of the data related to a moderate dose of SSRI; Complementary therapies including vitex agnus
however, there was consistent evidence that even low doses of castus (VAC)
SSRI were effective. They can be taken either continuously or Data from clinical studies is limited, and studies
in the luteal phase only. They may cause dose-dependent were underpowered.6
adverse effects, the commonest being nausea, asthenia and a
reduction in libido, which can be reduced by cyclical use. Suppression of ovarian hormones
These drugs show a quicker response in women with Combined oral contraception (COC)
PMS/PMDD.44 COC inhibits ovulation. Certain hormonal combinations
in combined pills are suitable for women with no
Block the effect of allopregnanolone contraindications to combined hormonal contraception,
This can be achieved by: based on an assessment using the UK medicial eligibility
Reducing progesterone metabolism by 5-a reductase inhibitor criteria (UKMEC) 2016. A shorter hormone-free interval (24/
A 2016 randomised, double-blind study45 tested the hypothesis 4), tricycling and continuous dosing are considered better
that changes in neurosteroid levels (allopregnanolone) during than standard cyclical (21/7) treatment to control PMD with
the luteal phase of the menstrual cycle were responsible for a reduction in hormonal fluctuations.51 However, a small,
precipitating affective symptoms. Dutasteride (5-a reductase three-arm, RCT failed to demonstrate superior efficacy of
inhibitor) at a daily dose of 2.5 mg, but not placebo, prevented the continuous versus intermittent dosing of oral
luteal phase increase in allopregnanolone and significantly contraceptives.52 A 2011 multicentre phase III trial53 and a
reduced PMDD symptoms. 2012 Cochrane systematic review54 demonstrated significant
Antagonising the effect of allopregnanolone improvement in both physical and emotional symptoms of
(isoallopregnanolone) PMD with newer drospirenone-containing COCs. These pills
An explorative randomised, double-blind, placebo- are available under the trade names Yasmin and Eloine in
controlled study46 tested the effects of a GABAA modulating the UK. Zoely, a combined pill containing estradiol and
steroid antagonist (GAMSA), sepranolone (UC1010), during nomegestrol in a 24/4 regime, may also have a place in
the premenstrual phase in women with PMDD. There was treating women with PMD. Women using Eloine and Zoely
considerable improvement in PMDD symptom severity and can be advised to omit the placebo pills to achieve further
impairment with UC1010 than with placebo (comparable with hormonal stability.
SSRIs and drospirenone-containing oral contraceptives). The Estrogen-containing hormone replacement therapy (HRT)
tolerability and safety of UC1010 were good. Inhibition of ovulation can be achieved using higher doses of
A Phase IIb clinical trial completed in 2020 showed an estrogen (≥100 micrograms) delivered transdermally. Both the
improvement in distress and impairment in women taking cycle-modifying effect of estrogen and the effect on brain

serotonin levels can help control the symptoms of PMD.

Discussion
Endometrial protection is required and can be provided either
by insertion of a levonorgestrel-containing intrauterine PMD can have a considerable adverse effect on the quality of
system, or by micronised progesterone (Utrogestan) life of women, even though the symptoms are cyclical.
delivered for 12 days of each cycle in the dose of 200 Affected women have difficulties with concentration and
milligrams per day. A lower dose of 100 milligrams of social interaction, self-doubt, paranoia, fatigue, tearfulness,
Utrogestan and/or a shorter duration regime (7–10 days) outbursts and increased sensitivity to the environment and
may be used in progesterone-intolerant women. Combining people.58 The symptom-free period is tainted by feelings of
high-dose transdermal estrogen to override any underlying guilt and over compensatory behaviour. Increasing awareness
cyclical activity with micronised progesterone delivered either of PMD could result in destigmatisation of the condition.
orally or per vaginum (out of product license) can be tried as Being better understood by others, especially family, friends
second-line therapy if the standard first-line treatment fails. If a and colleagues, could help to decrease the impairment of
suboptimal progesterone dose is used, women should have PMD.59 There is also a place for information explicitly aimed
regular ultrasound monitoring of endometrial thickness. A at men.60
systematic review55 on the effectiveness and safety of A recent survey by a support group of the International
noncontraceptive estrogen-containing preparations (oral, Association for Premenstrual Disorders (IAPMD), which was
patch, gel or implant) in PMD found very low-quality published on World Suicide Day in 2021, suggests that 86%
evidence and suggests individualisation of dose and regimen of women with PMDD have considered suicide and 30%
as per the women’s choice and response. report at least one attempt during their lifetime. Suicidal
GnRH analogues thoughts, ideation, plans and attempts are strongly associated
By inducing medical menopause, GnRH analogues provide with PMDD, and all premenstrual disorders should be
relief from both physical and psychological symptoms of considered risk categories for suicidality.61,62 It is therefore
PMD. GnRHa therapy is recommended in women with vital that hormonal management of these women is
severe PMS/ PMDD.56 coordinated closely with mental health teams, with plans in
The route of administration can be parental (for example, place for times during which the woman has suicidal ideation
goserelin and leuprorelin) or intranasal (nafarelin). If and intent.
treatment is continued for more than 6 months, add-back Health-related quality of life (HRQoL) is significantly
hormone therapy and regular assessment of bone mineral impacted in women with premenstrual disorders.63 The
density are recommended to reduce the long-term risks of cyclical nature of the disease and the age group affected by
estrogen deficiency. Diagnosis of PMD should be questioned PMS, makes the cumulative lost time of healthy productive
if symptom relief is not achieved after at least 12 weeks of life (as measured by disability-adjusted life years [DALY]), in
GnRHa treatment. the US population comparable to dysthymic disorders and
Removal of both ovaries and the uterus with appropriate only slightly lower than major depressive disorders.5 It is time
estrogen replacement for a new approach for the management of severe PMS.64
This is considered highly effective and is a well-accepted We should also refrain from using the term “just PMS” for
permanent cure for severe PMS/PMDD.57 Surgery is women experiencing devastating symptoms. Further research
beneficial if there are other indications for hysterectomy; into drug therapy for this condition may reduce the need for
for example, fibroid uterus. Hysterectomy is essential along surgical intervention in women of reproductive age.
with bilateral salpingo-oophorectomy (BSO) to allow for
unopposed estrogen to prevent the risk of recurrence of
Conclusion
symptoms with progestogens. Considering the age of affected
women, the decision for BSO and hysterectomy needs careful Extensive research over the last two decades has led to the
assessment, discussion and – ultimately – a clearly inclusion of PMDD as a diagnostic entity in DSM-5 and
documented informed decision, ideally by a ICD-11. DSM-5 has laid down strict diagnostic criteria to
multidisciplinary team where there is any doubt, maintain uniformity of diagnosis, promoting accurate data
particularly in younger women. It is helpful to undertake a collection for future research studies on potential treatments.
GnRHa + estrogen-only add-back test to ensure efficacy and A clear and concise description will ensure that clinicians,
tolerance of estrogen. Despite resultant infertility and risks patients, families and researchers have a common language to
associated with surgery, many women with PMD who communicate diagnosis and increase its legitimacy. It is
undergo hysterectomy report high satisfaction rates. After recommended that clinicians involved in the care of women
surgery, estrogen-only HRT is needed, sometimes with with severe PMS/PMDD build collaborative,
testosterone supplementation. multidisciplinary teams, including psychiatrists and

Goswami et al.
gynaecologists with an interest in PMDD. WHO reinforces Infographic S1. Premenstrual disorders including PMS
the multidisciplinary team approach in ICD-11 by and PMDD
crosslisting PMDD in genitourinary medicine and mental
health, fostering more effective collaboration between
References
these specialties.
In its statement in June 2019, the IAPMD highlighted the 1 Walsh S, Ismaili E, Naheed B, O’Brien S. Diagnosis, pathophysiology and
importance of building multidisciplinary treatment teams for management of premenstrual syndrome. Obstet Gynaecol
2015;17:99–104.
PMDD patients and the crucial role of mental health 2 National Institute for Health and Care Excellence (NICE). Premenstrual
providers with knowledge of PMDD, particularly for syndrome. London: NICE; 2020 [https://cks.nice.org.uk/topics/premenstrual-
women with severe impairment or suicidal risk. syndrome/].
3 Rapkin AJ, Winer SA. Premenstrual syndrome and premenstrual dysphoric
Universities and Royal Colleges should address the training disorder: quality of life and burden of illness. Expert Rev Pharmacoecon
of health care professionals. Psychoeducation can lead to an Outcomes Res 2009;9:157–70.
increased perception of warmth and competence in a woman 4 Mishell DR. Premenstrual disorders: epidemiology and disease burden. Am J
Manag Care 2005;11 Suppl 16:S473–9.
with PMD and help reduce stigmatisation. 5 Halbreich U, Borenstein J, Pearlstein T, Kahn LS. The prevalence, impairment,
WHO states, “Health is a state of complete physical, impact, and burden of premenstrual dysphoric disorder (PMS/PMDD).
mental and social wellbeing and not merely the absence of Psychoneuroendocrinology 2003;28:1–23.
6 Green LJ, O’Brien PMS, Panay N, Craig M. Management of premenstrual
disease or infirmity.” Therefore, we must recognise and syndrome. Green-top guideline 48. BJOG 2016;124:e73–105.
provide appropriate assessment and treatment for women 7 Greene R, Dalton K. The premenstrual syndrome. Br Med J
affected by premenstrual disorders. 1953;1:1007–14.
8 Osborn E, Wittkowski A, Brooks J, Briggs PE, O’Brien PMS. Women’s
experiences of receiving a diagnosis of premenstrual dysphoric disorder: a
Peer support groups (“When ‘I’ is replaced by ‘we,’ qualitative investigation. BMC Womens Health 2020;20:242.
even ‘illness’ becomes ‘wellness’”) 9 Sadler C, Smith H, Hammond J, Bayly R, Borland S, Panay N, et al. Lifestyle
factors, hormonal contraception, and premenstrual symptoms: the United
Support groups provide a platform to share personal Kingdom Southampton women’s survey. J Women’s Health
experiences and feelings, coping strategies and information 2010:19:391–6.
about diseases or treatments. Many PMS support groups 10 Chung SH, Kim TH, Lee HH, Lee A, Jeon DS, Park J, et al. Premenstrual
syndrome and premenstrual dysphoric disorder in perimenopausal women.
are available, including group support, private or public J Menopausal Med 2014;20:69–74.
online support groups, social media, and nonsocial media 11 Rapkin AJ, Winer SA. Premenstrual syndrome and premenstrual dysphoric
support like Inspire. The National Association for disorder: quality of life and burden of illness. Expert Rev Pharmacoecon
Outcomes Res 2009;9:157–70.
Premenstrual Syndromes or NAPS (https://www.pms.org. 12 Cunningham J, Yonkers KA, O’Brien S, Eriksson E. Update on research and
uk)31, Mind (https://www.mind.org.uk) and International treatment of premenstrual dysphoric disorder. Harv Rev Psychiatry
Association for Premenstrual Disorders or IAPMD (https:// 2009;17:120–37.
13 Hantsoo L, Epperson CN. Premenstrual dysphoric disorder: epidemiology
iapmd.org) are the predominant online support and treatment. Curr Psychiatry Rep 2015;17:1–9.
options available. 14 Schmidt PJ, Martinez PE, Nieman LK, Koziol, DE, Thompson KD, Schenkel L,
et al. Premenstrual dysphoric disorder symptoms following ovarian
suppression: triggered by change in ovarian steroid levels but not
Disclosure of interests continuous stable levels. Am J Psychiatry 2017;174:980–9.
There are no conflicts of interest. 15 Huo L, Straub RE, Roca C, Schmidt PJ, Shi K, Vakkalanka R, et al. Risk
for premenstrual dysphoric disorder is associated with genetic variation
in ESR1, the estrogen receptor alpha gene. Biol Psychiatry
Contribution to authorship 2007;62:925–33.
KU proposed the idea. NG wrote the initial draft, which was 16 Dubey N, Hoffman JF, Schuebel K, Yuan Q, Martinez PE, Nieman LK, et al.
further developed with the help of all authors. All authors The ESC/E (Z) complex, an effector of response to ovarian steroids, manifests
an intrinsic difference in cells from women with premenstrual dysphoric
approved the final version.
disorder. Mol Psychiatry 2017;22:1172–84.
17 Steiner M, Pearlstein T. Premenstrual dysphoria and the serotonin system:
Acknowledgements pathophysiology and treatment. J Clin Psychiatry 2000;61 Suppl 12:
17–21.
Nia Morris, chief librarian at John Spalding Library,
18 Bethea CL, Lu NZ, Gundlah C, Streicher JM. Diverse actions of ovarian
Wrexham Maelor for help with literature search. steroids in the serotonin neural system. Front Neuroendocrinol
2002;23:41–100.
19 Studd J, Nappi RE. Reproductive depression. Gynecol Endocrinol 2012;28
Supporting Information Suppl 1:42–5.
20 Studd J, Panay N. Hormones and depression in women. Climacteric
Additional supporting information may be found in the 2004;7:338–46.
21 Timby E, B€ackstr€om T, Nyberg S, Stenlund H, Wihlb€ack AC, Bixo M. Women
online version of this article at http://wileyonlinelibrary.
with premenstrual dysphoric disorder have altered sensitivity to
com/journal/tog allopregnanolone over the menstrual cycle compared to controls: a pilot
study. Psychopharmacology 2016;233:2109–17.

22 Bixo M, Johansson M, Timby E, Michalski L, B€ackstr€ om T. Effects of GABA 45 Martinez PE, Rubinow DR, Nieman LK, Koziol DE, Morrow AL, Schiller CE,
active steroids in the female brain with a focus on the premenstrual et al. 5 a-Reductase inhibition prevents the luteal phase increase in plasma
dysphoric disorder. J Neuroendocrinol 2018;30:e12553. allopregnanolone levels and mitigates symptoms in women with
23 Gulinello M, Smith SS. Anxiogenic effects of neurosteroid exposure: sex premenstrual dysphoric disorder. Neuropsychopharmacology
differences and altered GABAA receptor pharmacology in adult rats. J 2016;41:1093–102.
Pharmacol Exp Ther 2003;305:541–8. 46 Bixo M, Ekberg K, Poromaa IS, Hirschberg AL, Jonasson AF, Andreen L, et al.
24 Shen H, Gong QH, Aoki C, Yuan M, Ruderman Y, Dattilo M, et al. Reversal of Treatment of premenstrual dysphoric disorder with the GABAA receptor
neurosteroid effects at a4b2d GABA A receptors triggers anxiety at puberty. modulating steroid antagonist Sepranolone (UC1010): a randomized
Nat Neurosci 2007;10:469–77. controlled trial. Psychoneuroendocrinology 2017;80:46–55.
25 B€ackstro€m T, Bixo M, Johansson M, Nyberg S, Ossewaarde L, Ragagnin G, 47 B€ackstro
€m T, Ekberg K, Hirschberg AL, Bixo M, Epperson CM, Briggs P, et al.
et al. Allopregnanolone and mood disorders. Prog Neurobiol A randomized, double-blind study on efficacy and safety of sepranolone in
2014;113:88–94. premenstrual dysphoric disorder. Psychoneuroendocrinology
26 Andreen L, Nyberg S, Turkmen S, van Wingen G, Fernandez G, B€ackstr€ om T. 2021;133:105426.
Sex steroid induced negative mood may be explained by the paradoxical 48 Hunter MS, Ussher JM, Browne SJ, Cariss M, Jelley R, Katz M. A randomized
effect mediated by GABAA modulators. Psychoneuroendocrinology comparison of psychological (cognitive behavior therapy), medical
2009;34:1121–32. (fluoxetine) and combined treatment for women with premenstrual
27 Liu B, Wang G, Gao D, Gao F, Zhao B, Qiao M, et al. Alterations of GABA dysphoric disorder. J Psychosom Obstet Gynecol 2002;23:193–9.
and glutamate–glutamine levels in premenstrual dysphoric disorder: a 3T 49 Busse JW, Montori VM, Krasnik C, Patelis-Siotis I, Guyatt GH. Psychological
proton magnetic resonance spectroscopy study. Psychiatry Res intervention for premenstrual syndrome: a meta-analysis of randomized
2015;231:64–70. controlled trials. Psychother Psychosom 2009;78:6–15.
28 Bertone-Johnson ER, Whitcomb BW, Missmer SA, Manson JE, Hankinson 50 Weise C, Kaiser G, Janda C, Kues JN, Andersson G, Strahler J. Internet-based
SE, Rich-Edwards JW. Early life emotional, physical, and sexual abuse and cognitive-behavioural intervention for women with premenstrual dysphoric
the development of premenstrual syndrome: a longitudinal study. J disorder: a randomized controlled trial. Psychother Psychosom
Womens Health 2014;23:729–39. 2019;88:16–29.
29 Girdler SS, Straneva PA, Light KC, Pedersen CA, Morrow AL. 51 Freeman EW, Halbreich U, Grubb GS, Rapkin AJ, Skouby SO, Smith L, et al.
Allopregnanolone levels and reactivity to mental stress in premenstrual An overview of four studies of a continuous oral contraceptive
dysphoric disorder. Biol Psychiatry 2001;49:788–97. (levonorgestrel 90 mcg/ethinyl estradiol 20 mcg) on premenstrual dysphoric
30 Serra M, Pisu MG, Littera M, Papi G, Sanna E, Tuveri F, et al. Social isolation- disorder and premenstrual syndrome. Contraception 2012;85:437–45.
induced decreases in both the abundance of neuroactive steroids and GABA 52 Eisenlohr-Moul TA, Girdler SS, Johnson JL, Schmidt PJ, Rubinow DR.
(A) receptor function in rat brain. J Neurochem 2000;75:732–40. Treatment of premenstrual dysphoria with continuous versus intermittent
31 National Association for Premenstrual syndromes [http://www. https:// dosing of oral contraceptives: Results of a three-arm randomized controlled
www.pms.org.uk/]. trial. Depress Anxiety 2017;34:908–17.
32 Kadian S, O’Brien S. Classification of premenstrual disorders as proposed by 53 Lopez LM, Kaptein AA, Helmerhorst FM. Oral contraceptives containing
the International Society for Premenstrual Disorders. Menopause Int drospirenone for premenstrual syndrome. Cochrane Database Syst Rev
2012;18:43–7. 2012;(2):CD006586.
33 American Psychiatric Association (APA). Diagnostic and Statistical Manual of 54 Marr J, Niknian M, Shulman LP, Lynen R. Premenstrual dysphoric disorder
Mental Disorders. 5th ed. Arlington, VA: APA; 2013. symptom cluster improvement by cycle with the combined oral
34 World Health Organization (WHO). GA34.41 Premenstrual dysphoric contraceptive ethinylestradiol 20 mcg plus drospirenone 3 mg administered
disorder. In: ICD – 11 for mortality and morbidity statistics. Geneva: WHO; in a 24/4 regimen. Contraception 2011;84:81–6.
2021 [https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/ 55 Naheed B, Kuiper JH, Uthman OA, O’Mahony F, O’Brien PM. Non-
1526774088]. contraceptive oestrogen-containing preparations for controlling symptoms
35 Endicott J, Nee J, Harrison W. Daily Record of Severity of Problems (DRSP): of premenstrual syndrome. Cochrane Database Syst Rev 2017;(3):
reliability and validity. Arch Womens Ment Health 2006;9:41–9. CD01050.
36 Reid RL, Soares CN. Premenstrual dysphoric disorder: contemporary 56 Wyatt KM, Dimmock PW, Ismail KM, Jones, PW, O’Brien, PMS. The
diagnosis and management. J Obstet Gynaecol Can 2018;40:215–23. effectiveness of GnRHa with and without ‘add-back’ therapy in treating
37 Reid RL. Premenstrual syndrome. Curr Probl Obstet Gynecol Fertil premenstrual syndrome: a meta analysis. BJOG 2004;111:585–93.
1985;8:43–67. 57 Cronje WH, Vashisht A, Studd JW. Hysterectomy and bilateral
38 Stoddard JL, Dent CW, Shames L, Bernstein L. Exercise training effects on oophorectomy for severe premenstrual syndrome. Hum Reprod 2004;19:
premenstrual distress and ovarian steroid hormones. Eur J Appl Physiol 2152–5.
2007;99:27–37. 58 Hardy C, Hardie J. Exploring premenstrual dysphoric disorder (PMDD) in the
39 Sayegh R, Schiff I, Wurtman J, Spiers P, McDermott J, Wurtman R. The effect work context: A qualitative study. J Psychosom Obstet Gynecol
of a carbohydrate-rich beverage on mood, appetite, and cognitive function 2017;38:292–300.
in women with premenstrual syndrome. Obstet Gynecol 1995;86:520–8. 59 Janda C, Asbrock F, Herget M, Kues JN, Weise C. Changing the perception of
40 Lam RW, Carter D, Misri S, Kuan AJ, Yatham LN, Zis AP. A controlled study premenstrual dysphoric disorder: an online experiment using the stereotype
of light therapy in women with late luteal phase dysphoric disorder. content model. Women Health 2019:59:967–84.
Psychiatry Res 1999;86:185–92. 60 O’Brien S, Briggs P. Her hormones: a book for men. New York: Clink Street
41 Sansone RA, Sansone LA. Sunshine, serotonin, and skin: a partial Publishing; 2020.
explanation for seasonal patterns in psychopathology? Innov Clin Neurosci 61 Saunders KE, Hawton K. Suicidal behaviour and the menstrual cycle. Psychol
2013;10:20. Med 2006;36:901–12.
42 Young SN. How to increase serotonin in the human brain without drugs. J 62 Osborn E, Brooks J, O’Brien PMS, Wittkowski A. Suicidality in women with
Psychiatry Neurosci 2007;32:394. premenstrual dysphoric disorder: a systematic literature review. Arch
43 Marjoribanks J, Brown J, O’Brien PM, Wyatt K. Selective serotonin reuptake Womens Ment Health 2021;24:173–84.
inhibitors for premenstrual syndrome. Cochrane Database Syst Rev 2013; 63 Rapkin AJ, Winer SA. Premenstrual syndrome and premenstrual dysphoric
(6):CD001396. disorder: quality of life and burden of illness. Expert Rev Pharmacoecon
44 Halbreich U, Kahn LS. Treatment of premenstrual dysphoric disorder with Outcomes Res 2009;9:157–70.
luteal phase dosing of sertraline. Expert Opin Pharmacother 64 Panay N, Fenton A. Menopause: natural selection or modern disease?
2003;4:2065–78. Climacteric 2015;18:1–2.

DOI: 10.1111/tog.12855 2023;25:47–58
Review
Human papillomavirus-independent cervical cancer and

its precursor lesions
Ieera Madan Aggarwal MBBS MD FRCOG,a Yen Ching Yeo MBChB FRCPath,
b
Zheng Yuan Ng MBBS MRCOG MMed (O&G) BScc*

a
Senior Consultant, Department of Gynaecological Oncology, KK Women’s and Children’s Hospital, 100 Bukit Timah Rd, Singapore, 229899
b
Senior Consultant, Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, 100 Bukit Timah Rd, Singapore,
229899
c
Consultant, Department of Gynaecological Oncology, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, Singapore, 229899
*Correspondence: Zheng Yuan Ng. Email: ng.zheng.yuan@singhealth.com.sg
Accepted on 15 June 2022.
Key content There is a paucity of evidence-based guidelines tailored to

With the move towards ubiquitous human papillomavirus (HPV) management of HPV-independent adenocarcinomas.
primary screening and increasing coverage with HPV vaccination,
Learning objectives
the prevalence of HPV-associated cervical cancers is predicted To know the various types of HPV-independent cervical cancers,
to decrease.
Clinicians must be aware of HPV-independent adenocarcinomas,
as classified by the WHO 2020 classification of
cervical adenocarcinomas.
which are likely to increase as a To appreciate current understanding of possible precursor lesions
proportion of the total diagnosed cervical
of HPV-independent cervical cancers, especially gastric-
adenocarcinomas.
Advances in histopathology, immunohistochemistry and
type adenocarcinoma.
To be aware of the potential ‘red-flag’ symptoms and findings on
molecular genetics have increased our understanding of the
radiological investigations for early diagnosis, and the current
spectrum of gastric-type and other rare HPV-
evidence available for the management and clinical outcomes of
independent adenocarcinomas.
HPV-independent adenocarcinoma.
Clinical outcome and prognosis of HPV-independent
adenocarcinoma is worse than the HPV- Keywords: carcinoma of the cervix / gastric-type adenocarcinoma /
associated adenocarcinoma. hpv-independent / preinvasive disease of the cervix
Please cite this paper as: Aggarwal IM, Yeo YC, Ng ZY. Human papillomavirus-independent cervical cancer and its precursor lesions. The Obstetrician &
However, there is also the potential for an increase in the

Introduction
proportion of HPV-independent adenocarcinomas,
Cervical cancer is the fourth most frequently diagnosed highlighting the importance of raising awareness of these
cancer and the fourth leading cause of cancer mortality in among clinicians.
women, with an estimated 604 000 new cases and 342 000 Here, we provide a comprehensive review of HPV-
deaths worldwide in 2020.1 Persistent infection with independent cervical cancer, with emphasis on gastric-type
oncogenic human papillomavirus (HPV) is prerequisite in adenocarcinoma (GAC), which forms most of these cases.
most cervical cancers. However, in recent years there has
been increasing recognition of HPV-independent cervical
WHO classification of cervical cancers
cancers, especially adenocarcinoma. In August 2020, the
World Health Organization (WHO) adopted a global The WHO 2020 Classification of Female Genital Tumors
strategy for the elimination of cervical cancer (≤4 per 100 divides squamous and glandular cervical carcinomas based
000 women worldwide), aiming at vaccination of 90% of girls on their association with HPV, rather than the previous
by age 15, screening of 70% of women by a high-performance criteria of morphological cell types (Figure 1).3 The glandular
test and management of 90% of women with preinvasive and precursor lesion, adenocarcinoma in situ (AIS), is similarly
invasive cervical disease.2 These strategies are likely to reduce classified based on HPV association. However, owing to
the prevalence of HPV-associated adenocarcinomas. a lack of definitive evidence of the existence of HPV-

HPV-independent cervical cancer
Cervical
tumours and
precursors
Squamous Glandular
HPV- HPV- HPV- HPV-

associated independent associated independent
LSIL Atypical
SCC SCC AIS AdenoCa LEGH AdenoCa
HSIL
GAIS
Gastric
Clear cell
Mesonephric
NOS
Figure 1. Classification of cervical tumours and precursor lesions. Adapted from WHO 2020 Classification of female genital tumours.3
AdenoCa = adenocarcinoma; AIS = adenocarcinoma in situ; HSIL = high grade squamous intraepithelial lesion; LEGH = lobular endocervical
glandular hyperplasia; LSIL = low-grade squamous intraepithelial lesion; NOS = not otherwise specified; SCC = squamous cell carcinoma.
independent lesions, squamous preinvasive lesions are

Box 1. Causes of human papillomavirus (HPV)-negative
grouped under a single HPV-associated category. The use
tumours5,6
of terms like ‘adenoma malignum’, ‘minimal deviation
adenocarcinoma’ (MDA) and ‘gastric-type variant of HPV-independent (true negative) cervical cancers
mucinous adenocarcinoma’ is no longer encouraged when False negative HPV test results
describing HPV-independent adenocarcinoma. Specific
s Loss of HPV DNA fragments (most HPV tests target L1
region or E6/E7 mRNA) during host genome integration
subtypes described are gastric (showing gastric s Low viral load – latent infection
differentiation), clear cell (with clear eosinophilic cells), s Aetiological agent is non-high-risk HPV
mesonephric (showing wolffian differentiation) and ‘not s Sampling error – necrosis/inflammation at the sampling site
Technical factors associated with various HPV tests –
otherwise specified’ (NOS).3
s
non-nucleic acid signal amplification methods, such as

Hybrid capture 2, have lower sensitivity than DNA
amplification methods like Cobas HPV test, or mRNA
HPV-independent versus HPV-negative amplification assays like APTIMA
cervical cancer Histological misclassification
s
Extension of endometrial cancer to cervix
It is important to appreciate the nuances in differentiating s
Distant metastases from other HPV-negative primary
the terms ‘HPV-independent’ and ‘HPV-negative’. An tumours
estimated 5–11% of cervical cancers worldwide are HPV-
negative.4 Whether these HPV-negative tumours are truly
HPV-independent, or whether the initial trigger was HPV could become HPV-inactive in later stages owing to somatic
that could not be detected for various reasons (Box 1), is the mutations in the cancer driver genes. This would make the
topic of many recent molecular studies aiming to enhance persistence of HPV unnecessary for continued oncogenesis,
our understanding of these aggressive tumours. resulting in a negative HPV test. These HPV-inactive
Most HPV infections are transient, but in cases of tumours also exhibit a global decrease in DNA methylation
persistent infection with high risk HPV, the E6/E7 and increased WNT/b-catenin and Sonic Hedgehog
oncogenes trigger carcinogenesis and integration of the signalling.7 Although classified as HPV-negative, these
HPV genome into the host genome. As elucidated by tumours are not HPV-independent in their initiation. Loss
Banister et al.,7 an HPV-initiated or HPV-active tumour of the L1 fragment during HPV genome integration with the

Aggarwal et al.
host cell can lead to false negative results in tests that target differentiation by showing immunopositivity with
the HPV L1 region only. A second test targeting E6/E7 HIK1083. For a long time, positivity with HIK1083 was
mRNA in these cases can help confirm HPV association. Use considered to be pathognomonic of GAC. However, in 1999,
of nucleic acid signal amplification methods (for example, two separate groups, Nucci et al.13 and Mikami et al.,14
CobasTM HPV DNA or APTIMATM HPV E6/E7 mRNA) are simultaneously described a pseudoproliferative lesion termed
more sensitive, especially where there is low viral load, than ‘lobular endocervical glandular hyperplasia’ (LEGH) and
non-nucleic acid signal amplification methods such as ‘pyloric gland metaplasia’ (PGM), respectively, to highlight a
Hybrid capture2TM or CervistaTM HPV. Careful sample benign lesion with features of gastric metaplasia and a gastric
collection, avoiding necrotic areas and contamination with immunophenotype. Despite positivity with the HIK1083 and
blood, using proper fixation methods and strict quality MUC6 stains, these lesions were morphologically and
control reduce false negative results. In cases of negative clinically benign. Their coexistence with areas showing
results caused by suspected histological misclassification, a atypical change, in situ carcinoma and frank malignancy
systematic immunohistochemical analysis of the tumour and first led to consideration of these lesions as putative
centralised pathology review can help determine its precursors of GAC.
primary origin. Tumours showing gastric differentiation were previously
considered a subset of endocervical-type mucinous
adenocarcinoma with adenoma malignum on the well-
Gastric-type adenocarcinoma and its
differentiated end of the spectrum. In 2007, Kojima and
precursor lesions
colleagues15 identified that some of the mucinous
The lesions described on the spectrum of ‘gastric-type’ adenocarcinomas with gastric phenotype showed marked
glandular tumours of the cervix range from benign (lobular atypia, higher grade and aggressive clinical behaviour,
endocervical glandular hyperplasia, LEGH, or pyloric gland acknowledging the existence of this poorly differentiated
metaplasia, PGM) to premalignant (atypical LEGH or gastric GAC as a distinct entity. In 2018, the International
adenocarcinoma in situ, GAIS) to malignant (gastric Endocervical Adenocarcinoma Criteria and Classification
adenocarcinoma, GAC) based on morphological and (IECC)16 categorised the endocervical adenocarcinomas as
molecular genetic links among these. The historical HPV-associated or non-HPV-associated, taking the HPV
evolution, pathogenesis, clinical presentation, radiological status of the tumour into consideration. Mucinous
findings, pathological assessment, management and carcinomas of the cervix comprised both HPV-associated
prognosis of gastric-type tumours are discussed below. and non-HPV-associated types, of which gastric-type was the
predominant non-HPV-associated type. The previous
Historical evolution distinction into well-differentiated (adenoma malignum)
Most of our knowledge about gastric-type glandular lesions and poorly differentiated adenocarcinoma has been
of the cervix has emerged from studies from Japan. The removed from the current WHO classification owing to
incidence of GAC is higher in Asian countries, particularly in poor prognosis, even in well-differentiated tumours.3
Japan, accounting for 20–25% of all endocervical
adenocarcinoma in contrast to only 10–15% in the western Pathogenesis and molecular mechanisms
population.8 The reason for this disparity is not clear, and Advances in molecular techniques, including next-generation
may reflect the greater awareness and larger volume of sequencing and study of mutational signatures, have
research in Japan than anywhere else in the world. Indeed, enhanced our understanding of gastric-type tumours.
the specific pyloric gland mucin stain HIK1083 is only Similarities in the genetic aberrations of LEGH, GAIS and
commercially available in Japan.8 GAC have lent credence to the extrapolation that these may
The term ‘adenoma malignum’ was first used in 1870 by be the precursor lesions for GAC.
German gynaecologist Gusserow.9 In 1975, Silverberg and The exact aetiopathogenesis of LEGH or PGM is not
Hunt10 suggested substituting it with the term ‘minimal clearly defined, but this process is thought to be a
deviation adenocarcinoma’ to highlight the discrepancy metaplastic gastric differentiation, possibly triggered by
between the innocuous histological appearance of this well- chronic inflammation.17 LEGH by itself is considered a
differentiated adenocarcinoma of the cervix and its aggressive benign lesion, but it can coexist with atypical areas, GAIS or
behaviour. In 1989, Gilks11 published a series of 26 cases of even adenocarcinoma. LEGH may progress to GAC in 1.5%
adenoma malignum, elaborating on their clinicopathological of cases, although in many instances adenocarcinoma arises
and immunohistochemical analysis and highlighting the de novo or from GAIS.18 Comparative genomic
challenges in their diagnosis leading to poor survival hybridisation studies have shown recurrent chromosomal
outcomes. Ishii,12 in 1998, demonstrated for the first imbalances, in the form of gains of chromosome 3q and
time that adenoma malignum exhibited gastric-type loss of 1p in around 20% of LEGH, with these alterations

also being present in adenoma malignum and other cervical On examination, the cervix appears bulky and indurated
mucinous adenocarcinomas.19 without a well-demarcated mass due to the tumour’s location
LEGH and GAC (particularly the well-differentiated and its highly infiltrative pattern of growth. LEGH is typically
adenoma malignum) have been described in patients with situated in the upper endocervix, away from the
Peutz–Jeghers syndrome, an autosomal dominant disorder transformation zone, and is more superficial than deeply
characterised by mutations in the STK11/LKB11 gene on infiltrative GAIS or GAC.24 At presentation, GAC is more
chromosome 19p13.3. STK11 is a tumour suppressor gene likely to involve the parametrium and vaginal tissue than
mediating cell cycle arrest through p21 and affecting the HPV-associated adenocarcinoma.
apoptotic and cell proliferative pathways. In addition to
hamartomatous polyps in the gastrointestinal tract and Radiological assessment
hyperpigmented macules in the oral mucosa, women with Radiologically, HPV-independent glandular tumours of the
Peutz–Jeghers syndrome can develop neoplasms within the cervix appear as multicystic lesions. It can be challenging to
cervix and ovaries, including mucinous tumours and sex-cord distinguish benign lesions like nabothian cysts, tunnel cluster
stromal tumours with annular tubules. Clonality analysis (complex nabothian cyst characterised by multicystic
studies suggest that STK11 gene mutations may be involved in dilatation of the endocervical glands) and LEGH from
the progression of LEGH to well-differentiated GAC.20 invasive GAC. Contrast-enhanced magnetic resonance
In one of the largest studies of its type to date, Selenica and imaging (MRI) can be useful to differentiate these. Coarse
colleagues21 described the genomic alterations in cervical cysts on MRI, with regular, well-defined margins and high
GAC, comparing them with HPV-associated cervical signal intensity on T2-weighted images without invasion into
adenocarcinoma, as well as pancreatic and intestinal-type cervical stroma, suggest a benign lesion.25 LEGH is usually
adenocarcinomas, both of which appear morphologically located at the superior cervix, close to the internal os. The
similar to cervical GAC. The mutations most frequently cysts are small (microcystic) and typically have a floret-like
found in cervical GAC were those affecting genes impacting arrangement, appearing as the ‘cosmos pattern.’23,26 This
cell cycle (TP53, CDKN2A), PI3K-AKT (PIK3CA, STK11) cosmos pattern is considered highly specific for gastric-type
and notch signalling pathways (FBXW7, NOTCH2, CREBBP, mucin-producing lesions, especially if the area exhibiting this
SPEN).21 A heterogenous mutational profile of GAC is pattern is hypointense relative to the surrounding cervical
highlighted by hotspot mutations in other oncogenes as well; stroma.26 Compared with LEGH, GAC is more likely to
for example, GNAS, KRAS, BRAF and SMAD4. Compared exhibit a solid-cystic pattern with inner solid components,
with HPV-associated cervical adenocarcinoma, cervical GAC deep stromal infiltration, indistinct borders and restricted
had more TP53 and CDKN2A mutations and fewer PIK3CA diffusion on MRI (Figure 2). Presence of adnexal or
mutations. Compared with pancreatic and intestinal-type peritoneal metastases and invasion of parametrium or
adenocarcinomas, cervical GAC had fewer TP53 mutations vagina also raises the suspicion of a malignant lesion on
and more STK11 mutations. The coexistence of LEGH and cross-sectional imaging. In comparison, HPV-associated
GAIS in some of these cases, and similar genetic alterations in cervical adenocarcinoma is more often mass-forming or
STK11, TP53 and GNAS, further support the theory that polypoid, less likely to contain intratumoral cysts and usually
LEGH and GAIS could be precursors of cervical GAC.21 situated in the lower endocervix or ectocervix.27
Clinical assessment
Most cases of HPV-independent gastric-type glandular Pathological assessment
tumours present in the older age group than HPV-
associated glandular tumours, with a median age of Cytology
49 years for GAC.15 Clinical manifestations of endocervical Abnormalities on cervical smear in these tumours are quite
glandular tumours with gastric differentiation include watery subtle and can be difficult to diagnose. Often, the smear is
mucoid vaginal discharge, abnormal uterine bleeding and/or reported as ‘atypical glandular cells’ and may be misinterpreted
abdominal pain. The watery discharge can be profuse and be as reactive endocervical cells. Reports of atypical endocervical
mistaken as urinary incontinence. Excessive mucin secretion cells with ‘golden-yellow’ gastric-type mucin have been
from the metaplastic glands in LEGH has presented as rapid described.28 However, this can be challenging to appreciate
accumulation of hydrometra.22 In many cases, however, on liquid-based cytology because the mucin colour becomes
LEGH may not have a specific presenting symptom and is an paler. As described by Schwock et al.,29 commonly noted
incidental histological finding during cervical loop excision architectural, nuclear and cytoplasmic features include
or hysterectomy, with a reported incidence of 0.7%.23 In honeycomb-like sheets, nuclear enlargement (approximately
some cases, GAIS or adenocarcinoma may manifest as twice the size of a neutrophil or a benign endocervical cell) and
atypical glandular cells on a cervical smear. microvesicular cytoplasm (Figure 3). Table 1 elaborates the

Aggarwal et al.
Figure 2. T2-weighted pelvic magnetic resonance imaging (MRI) sagittal view images of gastric-type adenocarcinoma. (a) Fluid-filled endocervical
multicystic mass thought to be multiple nabothian cysts. Initial presentation was for asymptomatic atypical glandular cells on cervical screening.
Final histology was International Federation of Gynecology and Obstetrics (FIGO) Stage 2A2 gastric-type adenocarcinoma (GAC) with adnexal
metastases. (b) Multicystic lesion at superior aspect of anterior cervix with enhancing septae. Knife cone biopsy, endometrial biopsy and
endocervical curettage were inconclusive for malignancy, but hysterectomy specimen showed FIGO Stage 1B2 GAC. (c) Circumferential, infiltrative
tumour causing ectocervical effacement. Radiologically parametria were uninvolved, but radical hysterectomy confirmed FIGO Stage 2B GAC with
right parametrial involvement.
Figure 3. Cervical smears suggestive of gastric-type cervical adenocarcinoma or precursor lesions. (a) Cervical smear showing monolayered and
honeycomb sheets of endocervical cells with enlarged vesicular nuclei with distinct nucleoli (magnification 9200). (b) Pseudostratified endocervical
epithelium with abundant foamy cytoplasm with ‘golden-yellow’ gastric-type mucin and occasional goblet cells (magnification 9400).
comparative cytological features of gastric-type and HPV- and neutral mucins. In contrast, the cells of ‘gastric
associated adenocarcinoma. phenotype’ containing neutral mucin stain predominantly
red (Figure 4).
Histology LEGH is characterised by proliferation of small, round
Normal endocervical cells stain a purple-violet colour with glands lined by mucinous epithelium, basally located bland
Alcian blue/periodic acid Schiff (PAS) owing to a mix of acid nuclei and abundant pale eosinophilic cytoplasm (Figure 5a).

Atypical LEGH shows similar architecture but with four or

Table 1. Cytological differences between human papillomavirus
(HPV)-associated cervical adenocarcinoma and HPV-independent more of the following features: nuclear enlargement, irregular
cervical gastric-type adenocarcinoma30 nuclear contours, distinct nucleoli, coarse chromatin, loss of
polarity, occasional mitotic figures, luminal apoptotic bodies
HPV-independent gastric
HPV-associated adenocarcinoma adenocarcinoma
and infolding of epithelium or papillary projections with fine
fibrovascular stroma.23 GAIS shares many of the features
described for atypical LEGH but lacks the lobular
Crowded hyperchromatic groups Monolayered and honeycomb architecture. The involved glands tend to retain the
with pseudostratified columnar sheets architecture of pre-existing normal endocervical glands,
epithelium with rosette formation
with focal glandular complexity and luminal papillary
Cytoplasmic and nuclear ‘feathering’ Vacuolar and/or foamy infoldings creating a cribriform architecture (Figure 5b).
cytoplasm with GAC can be characterised by varying degrees of
intracytoplasmic golden
differentiation, ranging from well-differentiated to poorly
yellow mucin
differentiated (Figures 6, 7). On the well-differentiated
Enlarged nuclei with coarsely Vesicular nuclei with distinct spectrum, the normal lobular glandular architecture is lost,
granular hyperchromatic chromatin nucleoli and glands may be haphazardly arranged, with claw/crab
and inconspicuous nucleoli
shaped outlines. The glands may be cystic or exhibit papillary
Obvious apoptotic and mitotic Rare apoptotic and mitotic infolding lined by mucinous epithelium with abundant
figures figures eosinophilic apical mucin and minimal or no cytologic
atypia. Deep infiltration into the cervical stroma and focal
Macronucleoli and tumour diathesis Intracytoplasmic neutrophil
seen entrapment
stromal desmoplasia can make it challenging to diagnose this
on a small biopsy specimen. Poorly differentiated tumours
demonstrate a greater degree of cytologic atypia with nuclear
enlargement and hyperchromasia. The glands can be
angulated and dilated with distinct cell borders and marked
stromal desmoplastic reaction. Gland confluence, cribriform
architecture, luminal papillae, signet ring and solid areas can
be seen, unlike the HPV-associated adenocarcinoma. Readily
identifiable apoptosis and ‘floating’ mitoses commonly seen
in HPV-associated adenocarcinoma are not seen in GAC.
Immunohistochemistry
Based on morphology alone, GAC can be difficult
to differentiate from HPV-associated endocervical
adenocarcinoma with mucinous differentiation, metastatic
mucinous adenocarcinoma from the pancreaticobiliary tract
and other nongynaecological sites, and clear cell carcinoma,
necessitating the use of immunohistochemistry to confirm
the diagnosis.21 PAX8 immunopositivity (68–80% in GAC)
favours a primary cervical origin, differentiating it from
pancreaticobiliary and nongynaecological mucinous
adenocarcinomas. Unlike HPV-associated cervical
Figure 4. Alcian blue/ periodic acid Schiff (PAS) stain demonstrates adenocarcinoma, GAC is usually negative or exhibits
red cytoplasmic staining. Staining (indicated with arrows) indicative of mosaic (patchy, non-block pattern) immunoreactivity with
gastric differentiation, in contrast to the purple colour of normal p16, a surrogate marker of HPV infection. A small subset of
endocervical glands (magnification 9100). GAC may show diffuse p16 staining needing further
molecular tests to demonstrate the absence of oncogenic
It is usually limited to the inner half of the cervical wall with HPV. Immunohistochemical stains HIK1083 and MUC6,
no invasion, mitotic figures or stromal desmoplasia. The which highlight gastric mucin, can sometimes aid in the
morphologic clue of ‘lobular arrangement of the acinar diagnosis of GAC. However, these markers are not very
glands’ helps to differentiate this lesion from other benign sensitive or specific, often with focal or negative staining in
mimics like tunnel cluster, deep nabothian cysts and GAC and focal staining in HPV-associated cervical
tuboendometrioid metaplasia.13 adenocarcinoma.23 Approximately 52% of GAC shows

Aggarwal et al.
Figure 5. Histology of lobular endocervical glandular hyperplasia (LEGH) and gastric adenocarcinoma in situ (GAIS). (a) LEGH is a well-
demarcated lesion characterised by proliferation of small round glands surrounding a dilated duct. The glands are lined by cytologically bland
columnar epithelium with pale eosinophilic cytoplasm (magnification 940). (b) Glands involved by GAIS show glandular complexity and luminal
papillary infolding but retention of the architecture of the pre-existing normal endocervical glands. Glands are lined by mildly atypical mucinous
epithelium of gastric phenotype with abundant pale foamy cytoplasm (magnification 940).
Figure 6. Histology of normal endocervix and gastric-type adenocarcinoma (GAC). (a) Normal endocervical glands are situated mainly in the
superficial aspect of the cervical wall with no evidence of infiltrative growth pattern or stromal desmoplasia (magnification 920). (b) GAC is
characterised by a loss of the normal glandular architecture of normal endocervix, with infiltrative and haphazardly arranged glands showing
crab/claw outlines with surrounding stromal desmoplasia (magnification 920).
aberrant mutation-type p53 staining, whereas HPV- association into account. Although LEGH is considered a
associated adenocarcinoma exhibits wild-type p53 staining benign lesion, malignant transformation can occur in 1.4% of
pattern. GAC is generally positive for CK7 and CEA, with cases.18 If diagnosed on a loop excision or cone biopsy of cervix,
CEA immunoreactivity mainly in cytoplasm compared with there is a risk of missing coexistent atypical LEGH, GAIS or
apical CEA positivity in LEGH.23 A proportion of GAC is GAC higher in the endocervical canal. If fertility is not desired, a
also positive for CA-125, CK 20 and CDX2, with the latter completion hysterectomy in such cases should be considered.
two positive in up to 50% of cases. ER, PR, PAX 2, Vimentin, Sectioning of the specimen at multiple levels is necessary for a
p63 and p40 are usually negative. Approximately 90% of thorough histological assessment to rule out a coexistent
GAC is positive for HNF-1, albeit weaker in intensity, and adenocarcinoma. In a longitudinal study by Kobara et al.,18
could lead to a misdiagnosis of clear cell carcinoma.23 Clear women with suspected LEGH who did not undergo
cell carcinoma is negative for CEA, and, despite the clear hysterectomy had periodic surveillance using MRI and
cytoplasm, there is no evidence of mucinous differentiation. cervical smears. An increasing lesion size of >38% on MRI
assessment and worsening cervical cytology was closely
Management associated with onset of malignant transformation in cases of
Currently, there are no defined or separate guidelines for the LEGH.18 Patients with LEGH or in situ lesions who are keen to
management of glandular cervical tumours taking HPV preserve fertility and undergo loop excision, cone biopsy or

Figure 7. Varying degrees of differentiation in gastric-type adenocarcinoma. (a) Low-grade morphology with minimal cytological atypia and
voluminous apical mucin (magnification 9100). (b) High grade neoplastic epithelium demonstrating marked atypia, nuclear enlargement,
hyperchromasia, conspicuous nucleoli and occasional goblet cells (magnification 9100).
simple trachelectomy need careful surveillance with clinical outcome was found in GAC cases subclassified as MDA
review, regular cervical smears and MRI examinations. (>90% of tumour low grade) or non-MDA (at least 10% of
For confirmed cases of GAC, the management principles tumour had high-grade features), corroborating the fact that
are similar to HPV-associated carcinoma. Radical the degree of differentiation does not affect the outcome of
hysterectomy, bilateral salpingo-oophorectomy and pelvic these tumours. In another study of 95 patients with GAC,
lymphadenectomy is recommended in cases amenable to although poorer outcomes were noted in Stage 1A–1B1 disease
surgical resection. In advanced cases, chemoradiation is the than with HPV-associated cervical cancer of the same stage, no
available option. Patients with early stage GAC (Stage 1A1, difference in outcomes were found in Stages 1B2–2, suggesting
1A2) who are keen to conserve fertility are challenging to some influence of the stage on the prognosis in this subtype.32
manage and treatment must be individualised. Due to a Higher recurrence rates were observed in gastric subtype
higher risk of lymphovascular invasion and lymph node tumours (40%) than HPV-associated cancers (14.6%) in this
metsatses, there should be a lower threshold for pelvic lymph study as well.32 Postulated hypotheses for poorer outcomes
node assessment, including the use of sentinel lymph node include an inherent aggressive nature of this neoplasm,
mapping techniques. Ensuring proper assessment of the cone difficulty and delay in diagnosis due to its deep location in
or trachelectomy specimen by an expert pathologist is cervical stroma and resistance to chemoradiotherapy.
extremely important.
Patients known to have Peutz–Jeghers syndrome are at
Clear cell adenocarcinoma
higher risk of developing LEGH as well as GAC of the cervix.
Regular screening with clinical examination, cervical smears Clear cell adenocarcinoma is rare, accounting for
and MRI is advisable in these cases.15 approximately 3–4% of cervical adenocarcinomas.33 In
utero diethylstilbestrol exposure is a known risk factor,
Prognosis resulting in tumours on the ectocervix.34 In contrast,
The prognosis of patients with LEGH and atypical LEGH (5- sporadic clear cell adenocarcinoma usually occurs in the
year survival rate of 100%) is better than with GAC (5-year endocervix. In older women, spread from primary uterine
survival 54%).23 Numerous studies have confirmed the clear cell carcinoma should be excluded before a cervical
aggressive clinical nature of GAC. Kojima et al.15 primary is diagnosed. It may present as an endophytic mass,
demonstrated its higher recurrence and reduced survival, and resulting in diffuse cervical enlargement, or an exophytic
Karamurzin et al.31 demonstrated a 5-year disease specific mass visible on the cervix.35
survival of 42% for GAC versus 91% for HPV-associated Histologically, there are three basic growth patterns:
adenocarcinoma. GAC presented at a higher stage with greater tubulocystic, papillary and solid, which may be admixed to
incidence of metastases to lymph nodes, ovaries and varying degrees.24 Glands, tubules and papillae, with central
abdominal sites.31 However, no difference in survival hyaline fibrous tissue, are lined by polygonal and hobnail cells

Aggarwal et al.
with clear, eosinophilic and granular cytoplasm with minimal this rare entity and only scant evidence of a precursor lesion
stratification and prominent cytoplasmic boundaries. for HPV-independent squamous cell carcinoma.40,41
Occasional cells with cytoplasmic vacuoles may simulate
signet ring morphology, which is commoner in the cervical
Future research directions
clear cell carcinoma than its uterine and ovarian counterparts.
Intracytoplasmic hyaline globules may be observed. There is a Advanced molecular techniques and an expanding genomic
low mitotic count and usually no necrosis and psammoma landscape are opening future avenues for targeted therapy of
bodies. On immunohistochemistry, the carcinoma is usually these aggressive tumours. Various studies have reported
negative or focally positive for p16, with aberrant p53 staining genetic alterations in GAC, mesonephric and squamous cell
in 14%.36 It is usually positive for PAX8 and CK7, and HNF-1b carcinomas (Table 2). There are only a few case reports of
and Napsin A immunoreactivity are demonstrated in 40–70% clear cell carcinoma of the cervix, which show POLE
of cases.37 It is negative for ER, PR, Vimentin, p63, p40, MUC6, mutation or DNA mismatch repair (MMR) deficiency, but
HIK1083 and HER2.37 without loss of the MMR protein or confirmed Lynch
syndrome association.5
GAC harbours mutations in genes affecting various
Mesonephric adenocarcinoma
signalling pathways, with potentially targetable mutations
Mesonephric adenocarcinoma is extremely rare, accounting in ERBB2/3 genes.41 The KRAS, STK11 and BRAF mutations
for <1% of cervical adenocarcinomas.16 It is thought to arise can potentially be targeted by KRAS, AMP kinase/mTOR and
from mesonephric remnants along the course of the BRAF inhibitors, respectively. Studies exploring the role of
embryological mesonephric duct deep in the lateral cervical immune checkpoint inhibitors have shown that the PD-L1
walls, which is where it is usually located. There may be full- (programmed death-ligand 1) pathway may be a therapeutic
thickness invasion, circumferential involvement, ulceration, target in HPV-independent cervical cancers.47 Targeted
and extension into the lower uterine segment.38 It may inhibitors of KRAS and selective inhibitors of mitogen-
present with abnormal vaginal bleeding, abdominal pain, activated protein kinase are also being evaluated in
uterine prolapse or dyspareunia. mesonephric carcinomas enriched with KRAS/NRAS
Mesonephric carcinomas exhibit many histological patterns mutations.48 The development of animal or patient-derived
that vary between cases and even within the same tumour.24 It xenograft models of HPV-independent cancers will enhance
most commonly demonstrates a heterogeneous tubular growth our understanding of their carcinogenesis and provide
pattern, with back-to-back tubules lined by cuboidal cells with opportunities to test therapeutic agents tailored to
lumina filled with dense eosinophilic secretions. The cells are appropriate molecular targets.49
arranged in loosely cohesive clusters with hyperchromatic
nuclei, but smooth nuclear contours characteristic of
Conclusion
mesonephric differentiation. The tumour is positive for
GATA3, PAX8, CD10, and Calretinin, but negative for ER, HPV-associated cervical dysplasia and cancer are more
Napsin A and AMACR. P53 immunostaining is wild type, and prevalent than HPV-independent cervical cancer. Therefore,
p16 and HPV test are negative.37 HPV primary screening remains an effective population
screening method and remains strongly supported. With a
ubiquitous shift towards HPV primary screening, some cases
HPV-independent squamous cell carcinoma
of the clinically aggressive HPV-independent cervical cancer
HPV-independent squamous cell carcinoma of the cervix is may be missed. Hence, it is imperative to be aware of its
rare, accounting for approximately 5–7% of squamous cell presenting features and diagnostic challenges in moving
carcinomas of the cervix.39 The clinical presentation and towards the objective of eliminating cervical cancer. The ‘red-
macroscopic appearance are indistinguishable from HPV- flag’ symptoms of profuse watery mucoid cervicovaginal
associated squamous cell carcinoma, although HPV- discharge, abnormal uterine bleeding and abdominal pain, a
independent carcinomas are more often diagnosed at an bulky cervix on examination, and a multicystic cervical lesion
advanced stage, with a higher rate of lymph node metastasis on MRI should prompt a thorough assessment to rule out
and reduced disease-free and overall survival rates. HPV-independent cervical cancer, even if primary screening
On histology, HPV-independent squamous cell carcinoma with HPV is negative.
may demonstrate abnormal p53 immunostaining. To Consideration should also be given to the possibility of
facilitate classification as HPV-independent squamous cell false negative HPV tests to ensure identification of true HPV-
carcinoma, p16 immunostaining or HPV testing is required, independent tumours. Stratification of cervical
as morphology alone is insufficient for diagnosis. At present, adenocarcinomas based on HPV association may allow
there is limited understanding about the carcinogenesis of tailoring of appropriate targeted therapies in the future.

Table 2. Studies reporting mutational profiles of human papillomavirus (HPV)-independent cervical cancers
Genetic
alterations Oncogenic signalling
Study (proportions) pathways affected Functional implications
Gastric-type adenocarcinoma
Garg et al.42 TP53 (50%) p53 signalling pathway Cell survival, proliferation, apoptosis
MSH6 (43%) MMR DNA repair
CDKN2A/B (36%) p53 signalling pathway Cell survival, proliferation, apoptosis
POLE (36%) MMR, TGF b pathway DNA repair, regulate epithelial–mesenchymal transition
promoting metastasis and invasion
SLX4 (36%) Homology directed repair DNA repair, especially interstrand crosslink repair
ARID1A (29%) PI3K/AKT pathway, p53 Chromatin remodelling, gene transcription, cell cycle arrest
STK11 (29%) PI3K/AKT/mTOR pathway Cell cycle progression and cell survival
BRCA2 (21%) Homology directed repair DNA repair especially inter-strand cross link repair
MSH2 (211%) MMR DNA repair
Hodgson et al.4 TP53 (46%) p53 signalling pathway Cell survival, proliferation, apoptosis
KRAS (36%) RTK-RAS pathway Activation of MAPK, cell proliferation, differentiation
PIK3CA (36%) PI3K/AKT/mTOR pathway Cell cycle progression and cell survival
Lu et al.44 TP53 (53%) p53 signalling pathway Cell survival, proliferation, apoptosis
CDKN2A (27%) p53 signalling pathway Cell survival, proliferation, apoptosis
ARID1A (20%) PI3K/AKT pathway, p53 Chromatin remodelling, gene transcription, cell cycle arrest
PTEN (20%) PI3K/AKT/mTOR pathway Cell cycle progression and cell survival
ERBB2 amplification (13%) RTK-RAS pathway Translation, cell survival, proliferation
Park et al.45 TP53 (52%) p53 signalling pathway Cell survival, proliferation, apoptosis
STK11 PI3K/AKT/mTOR pathway Cell cycle progression and cell survival
PTPRS (19%) Protein tyrosine phosphatases Cell signalling, cell proliferation, migration, invasion
FGFR4 (14%) RTK-RAS, ERK/MAPK pathway Cell proliferation, differentiation, cell migration
Selenica et al.[21] TP53 (41%) p53 signalling pathway Cell survival, proliferation, apoptosis
CDKN2A (18%) p53 signalling pathway Cell survival, proliferation, apoptosis
KRAS (18%) RTK-RAS pathway Activation of MAPK, cell proliferation, differentiation
ERBB2/3 (10%) RTK-RAS pathway Translation, cell survival, proliferation

Aggarwal et al.
Table 2. (Continued)
Genetic
alterations Oncogenic signalling
Study (proportions) pathways affected Functional implications
GNAS (9%) Wnt pathway and ERK/MAPK Cell proliferation

pathway
PIK3CA (6%) PI3K/AKT/mTOR pathway Cell cycle progression and cell survival
BRAF (4%) RTK-RAS pathway Translation, cell survival, proliferation
SMAD4 (4%) TGFb pathway Regulate epithelial-mesenchymal transition promoting

metastasis and invasion
Mesonephric adenocarcinoma
Mirkovic et al.46 KRAS/NRAS (81%) RTK-RAS pathway Activation of MAPK, cell proliferation, differentiation
ARID1A/B and PI3K/AKT pathway, p53 Chromatin remodelling, gene transcription, cell cycle arrest
SMARCA4 (60%)
BCOR/BCORL1 transcriptional corepressor, Cell differentiation

(19%) epigenetic regulator
Squamous cell carcinoma
Regauer et al.40 PIK3CA and STK11 PI3K/AKT/mTOR pathway Cell cycle progression and cell survival
TP53 p53 signalling pathway Cell survival, proliferation, apoptosis
SMARC2B SWI/SNF-like chromatin repair DNA repair
GNAS Wnt pathway and ERK/MAPK Cell proliferation

pathway
Disclosure of interests 3 World Health Organization (WHO) Classification of Tumours Editorial Board.
Female genital Tumours: WHO classification of tumours. 5th ed. Geneva:
There are no conflicts of interest. WHO; 2020.
4 Xing B, Guo J, Sheng Y, Wu G, Zhao Y. Human papillomavirus-vegative
Contribution to authorship cervical cancer: a comprehensive review. Front Oncol 2021;10:606335.
5 Yoshida H, Shiraishi K, Kato T. Molecular pathology of human papilloma
IMA conceived the project. ZYN and IMA performed virus-negative cervical cancers. Cancers (Basel) 2021;13:6351.
literature review and developed the manuscript. YCY 6 Fernandes A, Viveros-Carren
~o D, Hoegl J, Avila M, Pareja R. Human
contributed extensively to the histopathology and papillomavirus-independent cervical cancer. Int J Gynecol Cancer
2022;32:1–7.
immunohistochemistry sections of the manuscript and 7 Banister CE, Liu C, Pirisi L, Creek KE, Buckhaults PJ. Identification and
provided the histological figures. All authors approved the characterization of HPV-independent cervical cancers. Oncotarget
final version. 2017;8:13375–86.
8 Mikami Y. Gastric-type mucinous carcinoma of the cervix and its precursors
– historical overview. Histopathology 2020;76:102–11.
9 Gusserow ALS. Ueber sarcoma des uterus. Arch Gynakol 1870;1:240–51.
References 10 Silverberg SG, Hurt WG. Minimal deviation adenocarcinoma (“adenoma
malignum”) of the cervix: a reappraisal. Am J Obstet Gynecol
1 Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al.
1975;121:971–5.
Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and
11 Gilks CB, Young RH, Aguirre P, DeLellis RA, Scully RE. Adenoma malignum
mortality worldwide for 36 cancers in 185 Countries. CA Cancer J Clin
(minimal deviation adenocarcinoma) of the uterine cervix. A
2021;71:209–49.
clinicopathological and immunohistochemical analysis of 26 cases. Am J
2 Harper DM, Rozek LS. Streamlining the WHO cervical cancer elimination
Surg Pathol 1989;13:717–29.
goal. Lancet Oncol 2021;22:1484–5.

12 Ishii K, Hosaka N, Toki T, Momose M, Hidaka E, Tsuchiya S, et al. A new view 30 Tay A, Gudi M, Lim TYK, Bing Cheng W, Tan JSL, Aw MH, et al. A case study
of the so-called adenoma malignum of the uterine cervix. Virchows Arch of gastric-type adenocarcinoma in situ of the uterine cervix. Cytopathology
1998;432:315–22. 2019;30:265–7.
13 Mikami Y, Hata S, Fujiwara K, Imajo Y, Kohno I, Manabe T. Florid 31 Karamurzin YS, Kiyokawa T, Parkash V, Jotwani AR, Patel P, Pike MC, et al.
endocervical glandular hyperplasia with intestinal and pyloric gland Gastric type endocervical adenocarcinoma: an aggressive tumor with
metaplasia: worrisome benign mimic of “adenoma malignum.” Gynecol unusual metastatic patterns and poor prognosis. Am J Surg Pathol
Oncol 1999;74:504–11. 2015;39:1449–57.
14 Nucci MR, Clement PB, Young RH. Lobular endocervical glandular 32 Nishio S, Mikami Y, Tokunaga H, Yaegashi N, Satoh T, Saito M, et al.
hyperplasia, not otherwise specified: a clinicopathologic analysis of thirteen Analysis of gastric-type mucinous carcinoma of the uterine cervix – an
cases of a distinctive pseudoneoplastic lesion and comparison with fourteen aggressive tumor with a poor prognosis: a multi-institutional study. Gynecol
cases of adenoma malignum. Am J Surg Pathol 1999;23:886–91. Oncol 2019;153:13–9.
15 Kojima A, Mikami Y, Sudo T, Yamaguchi S, Kusanagi Y, Ito M, et al. Gastric 33 Thomas MB, Wright JD, Leiser AL, Chi DS, Mutch DG, Podratz KC, et al. Clear
morphology and immunophenotype predict poor outcome in mucinous cell carcinoma of the cervix: a multi-institutional review in the post-DES era.
adenocarcinoma of the uterine cervix. Am J Surg Pathol 2007;31:664–72. Gynecol Oncol 2008;109:335–9.
16 Stolnicu S, Barsan I, Hoang L, Patel P, Terinte C, Pesci A, et al. International 34 Herbst AL. Behavior of estrogen-associated female genital tract cancer and
Endocervical Adenocarcinoma Criteria and Classification (IECC): a new its relation to neoplasia following intrauterine exposure to diethylstilbestrol
pathogenetic classification for invasive adenocarcinomas of the endocervix. (DES). Gynecol Oncol 2000;76:147–56.
Am J Surg Pathol 2018;42:214–26. 35 Yang L, Zheng A, Zhang X, Fang X, Sun W, Chen Y. Clear cell carcinoma of
17 Mikami Y, Hata S, Melamed J, Fujiwara K, Manabe T. Lobular endocervical the uterine cervix: a clinical and pathological analysis of 47 patients without
glandular hyperplasia is a metaplastic process with a pyloric gland intrauterine diethylstilbestrol exposure. Int J Gynecol Cancer 2017;27:1009–
phenotype. Histopathology 2001;39:364–72. 14.
18 Kobara H, Miyamoto T, Ando H, Asaka R, Takatsu A, Ohya A, et al. Limited 36 Houghton O, Jamison J, Wilson R, Carson J, McCluggage WG. p16
frequency of malignant change in lobular endocervical glandular Immunoreactivity in unusual types of cervical adenocarcinoma does not
hyperplasia. Int J Gynecol Cancer 2020;30:1480–7. reflect human papillomavirus infection. Histopathology 2010;57:342–50.
19 Kawauchi S, Kusuda T, Liu X-P, Suehiro Y, Kaku T, Mikami Y, et al. Is lobular 37 Stolnicu S, Barsan I, Hoang L, Patel P, Chiriboga L, Terinte C, et al. Diagnostic
endocervical glandular hyperplasia a cancerous precursor of minimal Algorithmic Proposal Based on Comprehensive Immunohistochemical
deviation adenocarcinoma? A comparative molecular-genetic and Evaluation of 297 Invasive Endocervical Adenocarcinomas. Am J Surg Pathol
immunohistochemical study. Am J Surg Pathol 2008;32:1807–15. 2018;42:989–1000.
20 Takatsu A, Miyamoto T, Fuseya C, Suzuki A, Kashima H, Horiuchi A, et al. 38 Silver SA, Devouassoux-Shisheboran M, Mezzetti TP, Tavassoli FA.
Clonality analysis suggests that STK11 gene mutations are involved in Mesonephric adenocarcinomas of the uterine cervix: a study of 11 cases
progression of lobular endocervical glandular hyperplasia (LEGH) to minimal with immunohistochemical findings. Am J Surg Pathol 2001;25:379–87.
deviation adenocarcinoma (MDA). Virchows Arch 2013;462:645–51. 39 Rodrıguez-Carunchio L, Soveral I, Steenbergen RDM, Torne A, Martinez S,
21 Selenica P, Alemar B, Matrai C, Talia KL, Veras E, Hussein Y, et al. Massively Fuste P, et al. HPV-negative carcinoma of the uterine cervix: a distinct type of
parallel sequencing analysis of 68 gastric-type cervical adenocarcinomas cervical cancer with poor prognosis. BJOG 2015;122:119–27.
reveals mutations in cell cycle-related genes and potentially targetable 40 Regauer S, Reich O, Kashofer K. HPV-negative squamous cell carcinomas of
mutations. Mod Pathol 2021;34:1213–25. the cervix with special focus on intraepithelial precursor lesions. Am J Surg
22 Takeuchi K, Tsujino T, Sugimoto M, Yoshida S, Kitazawa S. Endocervical Pathol 2022;46:147–58.
adenocarcinoma associated with lobular endocervical glandular hyperplasia 41 Burk RD, Chen Z, Saller C, Tarvin K, Carvalho AL, Scapulatempo-Neto C, et al.
showing rapid reaccumulation of hydrometra. Int J Gynecol Cancer Integrated genomic and molecular characterization of cervical cancer.
2008;18:1285–8. Nature 2017;543:378–84.
23 Mikami Y, McCluggage WG. Endocervical glandular lesions exhibiting 42 Garg S, Nagaria TS, Clarke B, Freedman O, Khan Z, Schwock J, et al.
gastric differentiation: an emerging spectrum of benign, premalignant, and Molecular characterization of gastric-type endocervical adenocarcinoma
malignant Lesions. Adv Anat Pathol 2013;20:227–37. using next-generation sequencing. Mod Pathol 2019;32:1823–33.
24 McCluggage WG. Recent developments in non-HPV-related 43 Hodgson A, Howitt BE, Park KJ, Lindeman N, Nucci MR, Parra-Herran C.
adenocarcinomas of the lower female genital tract and their precursors. Adv Genomic characterization of HPV-related and gastric-type endocervical
Anat Pathol 2016;23:58–69. adenocarcinoma: correlation with subtype and clinical behavior. Int J
25 Park SB, Lee JH, Lee YH, Song MJ, Choi HJ. Multilocular cystic lesions in the Gynecol Pathol 2020;39:578–86.
uterine cervix: broad spectrum of imaging features and pathologic 44 Lu S, Shen D, Zhao Y, Kang N, Wang X. Primary endocervical gastric-type
correlation. Am J Roentgenol 2010;195:517–23. adenocarcinoma: a clinicopathologic and immunohistochemical analysis of
26 Ohya A, Kobara H, Miyamoto T, Komatsu M, Shiozawa T, Fujinaga Y. 23 cases. Diagn Pathol 2019;14:72.
Usefulness of the “cosmos pattern” for differentiating between cervical 45 Park E, Kim SW, Kim S, Kim HS, Lee JY, Kim YT, et al. Genetic characteristics
gastric-type mucin-positive lesions and other benign cervical cystic lesions in of gastric-type mucinous carcinoma of the uterine cervix. Mod Pathol
magnetic resonance images. J Obstet Gynaecol Res 2021;47:745–56. 2021;34:637–46.
27 Kido A, Mikami Y, Koyama T, Kataoka M, Shitano F, Konishi I, et al. 46 Mirkovic J, McFarland M, Garcia E, Sholl LM, Lindeman N, MacConaill L,
Magnetic resonance appearance of gastric-type adenocarcinoma of the et al. Targeted genomic profiling reveals recurrent KRAS mutations in
uterine cervix in comparison with that of usual-type endocervical mesonephric-like adenocarcinomas of the female genital tract. Am J Surg
adenocarcinoma: a pitfall of newly described unusual subtype of Pathol 2018;42:227–33.
endocervical adenocarcinoma. Int J Gynecol Cancer 2014;24:1474–9. 47 Duranti S, Pietragalla A, Daniele G, Nero C, Ciccarone F, Scambia G, et al.
28 Omori M, Kondo T, Nakazawa K, Tagaya H, Ohgi M, Fukasawa H, et al. Role of Immune Checkpoint Inhibitors in Cervical Cancer: From Preclinical to
Interpretation of endocervical cells with gastric-type mucin on Pap Smears: a Clinical Data. Cancers (Basel) 2021;13:2089.
proposal for a cytologic category “atypical endocervical cells with gastric- 48 Mustachio LM, Chelariu-Raicu A, Szekvolgyi L, Roszik J. Targeting KRAS in
type mucin.” Am J Clin Pathol 2018;150:259–66. Cancer: Promising Therapeutic Strategies. Cancers (Basel) 2021;13:1204.
29 Schwock J, Starova B, Khan ZF, Mirkovic J, Parra-Herran C, Ko HM, et al. 49 Larmour LI, Cousins FL, Teague JA, Deane JA, Jobling TW, Gargett CE. A
Cytomorphologic features of gastric-type endocervical adenocarcinoma in patient derived xenograft model of cervical cancer and cervical dysplasia.
liquid-based preparations. Acta Cytol 2021;65:56–66. PLoS One 2018;13:e0206539.

DOI: 10.1111/tog.12849 2023;25:59–71
Review
Thromboprophylaxis in gynaecology: a review of

current evidence
Divya Nambiar MRCOG,a† Jecko Thachil MD FRCPath,b Wai Yoong MD FRCOG,
c
Deepa Balachandran Nair MRCOG Dip Med Edd*†

a
Trust Registrar in Obstetrics and Gynaecology, Buckinghamshire NHS Healthcare Trust, Buckinghamshire HP21 8AL, UK
b
Consultant in Haemostasis and Thrombosis, Manchester Royal Infirmary; Honorary Senior Lecturer, Liverpool School of Tropical Medicine,
Oxford Road, Manchester M13 9WL, UK
c
Consultant Obstetrician and Urogynaecologist, North Middlesex University Hospital, London,N18 1QX, UK
d
Consultant Obstetrician and Gynaecologist, Buckinghamshire NHS Trust, Buckinghamshire HP21 8AL, UK
*Correspondence. Deepa Balachandran Nair. Email: deepa.balachandrannair@nhs.net
†
These authors contributed equally
Accepted on 27 March 2022.
Key content To know the current evidence in key areas relevant to

Thromboembolism is a major cause of preventable morbidity and gynaecological practice: early pregnancy; day case surgery;
mortality. Hospital acquired thrombosis (HAT) accounts for 50– minimally invasive gynaecological surgery; open and complex
60% of all thromboembolic events. benign gynaecology and gynaecological oncology.
As well as effects on patient safety, there are considerable cost To be aware of proposed guidance on risk assessment and
implications to both prophylaxis and treatment. prophylaxis in thrombosis as relevant to the gynaecologist based
While guidance exists on thromboprophylaxis for patients in on current evidence.
obstetrics and those undergoing general surgery, there is a paucity
Ethical issues
of guidance relating to gynaecological practice.
Increasing prevalence of risk factors and multimorbidity is
Problems with thromboprophylaxis in high-risk patients include
noncompliance and refusing animal products/injections.
paralleled by higher risk of thromboembolic events. Clinicians may be reluctant to institute thromboprophylaxis, most
Gynaecological surgery presents some unique risk factors
times because of the possible risks of bleeding.
for thrombosis.
Keywords: benign gynaecology / gynaecological oncology /
Learning objectives

gynaecological surgery / thromboprophylaxis / thrombosis
To understand the basic pathophysiology of thrombosis in relation
to risk factors particularly relevant to gynaecology and
pelvic surgery.
Please cite this paper as: Nambiar D, Thachil J, Yoong W, Balachandran Nair D. Thromboprophylaxis in gynaecology: a review of current evidence. The
Obstetrician & Gynaecologist 2023;25:59–71. https://doi.org/10.1111/tog.12849
the development of National Institute for Health and Care

Introduction
Excellence (NICE) guidance on measures to reduce this risk. A
Venous thromboembolism (VTE) is a major cause of morbidity 95% target for completion of VTE risk assessment for hospital
and mortality. It is a largely preventable complication following inpatients within the National Health Service (NHS) was
surgery. Without thromboprophylaxis, the incidence of mandated by the Commissioning for Quality and Innovation
confirmed deep vein thrombosis (DVT) in major abdominal (CQUIN) payment framework in February 2013.4 By July 2013,
surgery ranges from 17 to 40%.1 The risk of VTE following 96% of adult admissions to NHS-funded acute care hospitals
surgery exists for the first 12 weeks, with the likelihood of were risk-assessed for VTE compared with less than 50% of
admission with VTE being greatest in the first 6 weeks.2 A House patients in July 2010.5
of Commons’ report on prevention of VTE (2004–2005),3 Hospital-acquired, or hospital-associated, thrombosis (HAT)
recognised that deaths associated with pulmonary embolism and is defined as any venous thromboembolic event occurring in
DVT in the UK range between 25 000 and 32 000 per year, with an hospital or within 90 days of hospital admission.5 This accounts
annual cost to the National Health Service (NHS) estimated at for 50–60% of all thromboembolic events.5 HAT accounted for
£640 million per year. The Department of Health commissioned 57.1 VTE-related deaths per 100 000 hospital admissions in

Thromboprophylaxis in gynaecology
2018–2019 within the NHS.6 NICE offers guidance for

thromboprophylaxis in abdominal surgery and pregnancy and
the postpartum period.5
Endothelial injury
Recently, the popularity of outpatient procedures in
gynaecology, as well as ambulatory and day-case surgery, has Surgery, inflammation
increased, including in patients who would have been considered
‘high-risk’ in the past. There is, however, no specific guidance on
thromboprophylaxis regimens for gynaecological procedures,
which results in variation in practice. Increasing prevalence of
patient risk factors (obesity, advancing age, increased
comorbidities), together with added risks from surgery and the Hypercoagulability
underlying gynaecological conditions (pelvic mass, malignancy), Stasis
Cancer, abdominal or pelvic
which may aggravate risk of thrombosis, must be considered. Immobility, venous surgery, underlying
obstruction (pelvic conditions like inflammatory
Furthermore, appropriate preventive measures must be taken to mass, lithotomy) bowel disease, nephrotic
mitigate the morbidity and mortality associated with VTE. syndrome, sepsis, pregnancy
and peripartum
Assessment of the balance between benefits of appropriate
period, thrombophilia,
thromboprophylaxis versus the risks of thromboprophylaxis is estrogen therapy
critical. In addition, thrombosis, its prevention and treatment
have considerable cost implications.
Here, we review existing evidence related to Figure 1. Pathophysiology of thrombosis, Virchow’s triad.
thromboprophylaxis in gynaecology as a starting point to
formulating guidance on this subject. College of Obstetricians and Gynaecologists (RCOG).11
Women with a previous history of VTE (except a single
event related to major surgery), or a total score of ≥4 should
Pathophysiology of thrombosis be started on pharmacological thromboprophylaxis as soon
The basis for thrombosis is explained by the Virchow’s triad: as possible in the first trimester.11
endothelial injury; stasis and hypercoagulability. Risk factors
can be identified in relation to each of these three Risk with hyperemesis and ovarian hyperstimulation
components (see Figure 1). syndrome (OHSS)
Hyperemesis is a recognised risk factor for VTE,
Thromboprophylaxis in early pregnancy primarily associated with dehydration and resulting haemo-
concentration.7,12 Immobility caused by fatigue may further
The problem increase the risk. This, however, is a transient risk existing during
The risk for VTE increases from the first trimester. This is the period of hyperemesis. OHSS also has a clear link to VTE.
attributed to the hypercoagulable state in pregnancy.7,8 Rova et al.13 showed a 100-fold increased risk of VTE in
Thrombin generation increases in women as early as pregnancies achieved by in vitro fertilisation (IVF) and
5 weeks of gestation.9 According to the MBRRACE-UK complicated by OHSS, as opposed to a five-fold increased risk
(Mothers and Babies: Reducing Risk through Audits and in IVF pregnancies without OHSS. Haemoconcentration and
Confidential Enquiries across the UK) 2019 report, VTE was vascular endothelial dysfunction lead to a procoagulant state in
the cause of death in 34 of 209 women who died in 2015– patients with severe OHSS.14 In pregnant women,
2017, making it the second commonest cause of maternal pharmacological thromboprophylaxis in severe OHSS should
death. Thirteen of these women died at fewer than 24 weeks be continued for the duration of the first trimester.11,14 In women
of gestation while still pregnant, or after their pregnancy who do not conceive, thromboprophylaxis can be discontinued
ended at fewer than 24 weeks.10 This indicates that women at the time of withdrawal bleed.15 Thrombosis can occur in
who are already at high thrombotic risk have a higher risk of unusual sites in these women, frequently involving the upper
VTE very early in pregnancy.9 Therefore, they should be limbs and the arterial system. It can present weeks after
started on thromboprophylaxis as early as possible in resolution of the OHSS.14
pregnancy. Ideally, women at high risk of thrombosis
should be identified in primary care, pre-pregnancy, since Risk with miscarriages
their booking visit might only be at the end of the first There is a paucity of evidence regarding thromboprophylaxis in
trimester. A risk assessment should be done as soon as the medical and surgical management of miscarriage. NICE VTE
pregnancy is confirmed, as recommended in guidance on guidance (NG140)16 for women undergoing abortion recognises
VTE risk assessment in pregnancy published by the Royal the lack of evidence to make recommendations in this group.16 It

Nambiar et al.
Table 1. Risk factors for thrombosis5,18–25

Patient-related risk factors
Patient-related risk factors Procedure-related risk factors Risks with underlying malignancy
Cancer is a recognised risk factor for VTE.5,18,24,26 In
gynaecological cancer patients undergoing surgery, there is a
Age > 60 years Increased length of surgery
Raised BMI (>30 kg/m2) (including anaesthetic time)
significantly higher risk of VTE in the postoperative period for
Medical comorbidities Significantly reduced mobility those undergoing laparotomy than laparoscopy. A study by
Previous history of VTE (≥3 days) Kumar et al.27 showed the 30-day prevalence of VTE after
Thrombophilias Laparotomy minimally invasive surgery (MIS) for endometrial and cervical
Cancer Procedural complexity
Pregnancy or postpartum cancer to be low (0.5%; 95% confidence interval [CI], 0.1–
Combined hormonal contraception 1.6%).27 A retrospective cohort study including 1413 patients
Smoking who underwent MIS for endometrial cancer (laparoscopic and
Ethnicity: Black race
robotic) showed no significant difference in the rate of VTE
Acute admission with
inflammatory or among patients who had mechanical thromboprophylaxis alone
intra-abdominal compared with those who received additional pharmacological
condition prophylaxis (0.55% versus 0.23%, p = 0.38).28 These studies
suggest that as the absolute risk of VTE is low with MIS in these
BMI = body mass index; VTE = venous thromboembolism patients, pharmacological thromboprophylaxis may not be
indicated.28 Nick et al. 22 showed that the rate of VTE rises
with increasing complexity of surgery with no cases in the low
complexity group, 0.5% cases in the intermediate complexity
states that the assessment of women undergoing abortion using group and 2.8% in the high complexity cohort, including
risk assessment tools for term pregnancies will overestimate the those who needed lymphadenectomy. Low complexity cases
risk and result in overtreatment. However, women identified at were diagnostic and second-look laparoscopies; intermedi-
high risk of thrombosis need careful assessment and may need to ate complexity cases were unilateral/bilateral salpingo-
start thromboprophylaxis before induced abortion, if there is a oophorectomy, unilateral/bilateral ovarian cystectomy,
considerable delay before the intervention. This requires bilateral tubal ligation, hysterectomy unilateral/bilateral
planning, considering the risks of bleeding from the salpingo-oophorectomy; high complexity cases were radical
intervention, on an individual basis with multidisciplinary hysterectomy, pelvic and/or paraaortic lymphadenectomy,
input, as required. splenectomy, small bowel/colon resection.22 In patients
undergoing surgery for epithelial ovarian cancer, the
Learning from MBRRACE-UK cumulative incidence of DVT was 6.5% (95% CI, 4.4–8.6). In
The MBRRACE-UK report 202017 emphasises the need to risk- the same study, within the subgroup using only mechanical
assess women for VTE following a miscarriage or ectopic prophylaxis, the rate of DVT was 7.4% compared with 5.8% with
pregnancy, citing, as an example, a patient with an ectopic additional pharmacological prophylaxis.19 Dual prophylaxis and
pregnancy who underwent a salpingectomy. She was discharged extended prophylaxis for 4 weeks after pelvic cancer surgery is
home without VTE risk assessment. A week later, she presented effective in reducing VTE.29,30 Most of these data, however, are
with breathlessness and was diagnosed with a pulmonary based on open surgery.
embolism. Her risk factors included age above 35 years and
IVF pregnancy. This gave her a risk score of 2 based on RCOG’s Risks with combined hormonal contraception (CHC)
VTE guidance.11 Furthermore, any surgical procedure in The incidence of VTE is 5–20/10 000 woman-years in pregnancy,
pregnancy or puerperium should be assigned a score of 3. 40–65/10 000 woman-years postpartum, and 3–15/10 000
Thus, appropriate risk assessment in this case would have woman-years for combined hormonal contraceptive users,
indicated 10 days of pharmacological thromboprophylaxis, compared with 1–5/10 000 woman-years outside of
potentially preventing the thromboembolic event.11,17 pregnancy.31 The risk of VTE is greatest among new users in
the first year of use, with highest risk in the first few months.32,33
Following this period, risk reduces and then stabilises; frequent
Thromboprophylaxis for gynaecological
stopping and starting is therefore discouraged.33 The
surgeries
prothrombotic factors with use of CHC last for at least 4–
Various studies have identified factors associated with 6 weeks after stopping CHC, and hence cessation of CHC, is
increased risk of VTE following surgery.18–22 Broadly, these recommended at least 4 weeks before surgery.33-35 There is
can be classified into patient-related and procedure-related reasonable evidence to suggest that CHC users have increased
risk factors (Table 1).5,23–25 risk of VTE, and this is marginally higher in women using CHC

with drospirenone or third-generation progestogens planning surgery for patients currently or recently affected
(desogestrel, gestodene) versus second-generation progestins by COVID-19. The evidence base in relation to this is
(levonorgestrel).31 Norgestimate (third generation) is an rapidly evolving.
exception because the risk is similar to levonorgestrel (second
generation).31 CHC with ethinyl estradiol less than 50 Procedure-related risk factors
micrograms has lower risk of VTE than a higher dosage.31
Most evidence related to VTE risks are from well-designed Effects of anaesthesia and length of surgery
cohort or case-control analytical studies. Unlike with hormone Muscle relaxants used for general anaesthesia, and muscle
therapy, where transdermal preparations are associated with a paralysis secondary to a regional anaesthetic, can cause
lower risk of VTE, the evidence on comparative risks of VTE with venous stasis associated with inadequate pumping by the calf
the different routes of CHC is conflicting. It is unclear whether muscles. Slowing of blood flow can also cause endothelial
there is any significant difference in the risk of VTE with the patch damage. These, in turn, produce a localised
or the ring compared with oral preparations.31 hypercoagulability.44 A 1981 study by Borow et al.45 showed
There is a paucity of clear guidance regarding timing to that the incidence of DVT increased progressively with
restart hormonal contraception following surgery. The increasing duration of surgery. Thromboprophylaxis was not
postoperative period, up to about 3 months after surgery, the standard of care at the time, and DVT was diagnosed by
is recognised as when the risk of VTE is high, and it is highest fibrinogen scanning with venographic confirmation. The
in the first 2 weeks.36 This is combined with the increased study, therefore, included all cases of DVT, including some
risk of VTE that exists when the combined pill is started.32,33 that may not have become symptomatic.45 Several studies
The British National Formulary recommends stopping CHC since have confirmed an association between length of surgery
4 weeks before elective surgery (legs, pelvis, or any surgery and risk of VTE.20,21
involving immobilisation of lower limbs) and restarting CHC There is some evidence that regional anaesthesia is associated
at least 2 weeks after regaining full mobility following with a lower risk of VTE than general anaesthesia. NICE guidance
surgery. A progesterone-only contraceptive may be offered [NG89]5 suggests considering regional anaesthesia in suitable
as an alternative. In emergency surgical situations, when the patients as an additional thromboprophylactic measure. There
patient is on CHC, thromboprophylaxis should take this into were no difference in DVT rates when regional anaesthesia
account as an additional risk factor.33,35 was used along with general anaesthesia versus general
anaesthesia alone.5
Risks with hormone replacement therapy (HRT) However, evidence on DVT and mode of anaesthesia is
A study by Vinogradova et al.37 showed that transdermal HRT is conflicting, and is possibly influenced by rapid advances in
safest in the context of VTE with no increased risk of VTE with the anaesthetic field. A systematic review46 looking at
different regimens.37-40 Estradiol was associated with a lower risk neuraxial versus general anaesthesia in total knee and hip
than conjugated equine estrogen in estrogen-containing replacement showed no statistically significant difference in
preparations when taken orally. When considering venous thromboembolism between the two anaesthetic
combinations, the lowest risk is with estradiol–dydrogesterone routes when thromboprophylaxis was used.46
and the maximum risk is with conjugated equine estrogen–
medroxyprogesterone acetate.37 Conjugated equine estrogen is, Route of surgery: laparotomy versus laparoscopic surgery
however, not commonly used in the UK and has been largely Hysterectomy for benign pathology showed a higher incidence of
replaced by estradiol-based compounds, which carry a lower risk VTE with laparotomy (0.24–0.6%) than laparoscopy (0.13–
of VTE. The risk was also less in estrogen-only (OR = 1.2; 95% CI 0.2%).20,47 Similar results were shown when analysing
0.6–2.6) than in combined estrogen–progesterone treatment hysterectomy for endometrial cancer, with increased VTE rates
(OR = 2.7; 95% CI 1.4–5.1).38 with laparotomy (1.1–2.2%) than laparoscopic and vaginal
The overall risk of VTE is not increased by continuing routes of surgery (0.13–0.7%).21,48,49 In the context of surgeries
HRT in the perioperative period.38,41 The Society of other than hysterectomy, a prospective cohort study looking at
Obstetricians and Gynaecologists of Canada (SOGC) laparoscopic surgery for benign conditions such as adnexal
guidelines42 on prevention of venous thromboembolic pathology, ovarian cyst, endometriosis and infertility found no
disease in gynaecological surgery recommend no cessation increased risks of VTE in these patients.50 However, the sample
of HRT before surgery. Instead, HRT should be considered size for this study was small (n = 266). A systematic review by
within the VTE risk-assessment for surgery.42 Jorgensen et al.,51 which assessed VTE in minimally invasive
gynaecological surgery, showed that the risk of VTE is reduced
Thromboembolic risk with COVID-19 with MIS, and this is largely attributable to early ambulation,
COVID-19 has been identified as a risk factor for VTE.43 The faster postoperative recovery and early discharge from hospital.
associated hypercoagulability must be considered when Despite the reduced risk with laparoscopic surgery, these

Nambiar et al.
procedures still carry a risk of thrombosis and an individual risk women during a 12-week period without surgery. Procedures
assessment should be made.44 identified as highest risk were hip and knee replacement and
cancer surgery.2
Route of surgery: vaginal versus abdominal Based on the evidence above, reduced hospital stay in day
Vaginal surgery is associated with very low rates of VTE of surgery seems to lower the risk of VTE. In these patients,
0.16–0.17%.52,53 This is supported further by Chong et al.,54 a however, other risk factors (person or procedure related)
large retrospective cohort study involving 63 108 patients must be considered when assessing individual risk for VTE.
who underwent pelvic organ prolapse surgery from 2011– European guidelines for thromboprophylaxis in day case and
2017. Most (68.6%) patients had vaginal surgery, 16 518 fast-track surgery (defined as surgery after which patients are
(26.2%) had laparoscopic surgery and 3311 (5.2%) had mobilised within hours postoperatively and fully mobilised
abdominal surgery. Among these patients, the vaginal route no later than on the day after surgery, with discharge no later
had lower incidence of VTE (0.16%) versus abdominal than the fifth day) published in 2017, recommend assessing
(0.72%) or laparoscopic route (0.25%) when followed up for patients based on procedural and patient risk.56
a 30-day postoperative period.54 In patients undergoing
urogynaecological surgery by all routes, laparotomy was
Modes of thromboprophylaxis
associated with an increased thrombotic risk than other
routes (vaginal and laparoscopic).54,55 Further review to Several measures have been suggested for thromboprophylaxis.
assess the role of concurrent hysterectomy in women These include ambulation, mechanical thromboprophylaxis
undergoing pelvic organ prolapse (POP) repair showed no and pharmacological thromboprophylaxis.
significant difference in VTE associated with concurrent
hysterectomy.52 This is supported by Chong et al.,54 wherein, Early ambulation
after adjusting for confounders, concurrent procedures Early ambulation is accepted as a method of VTE prevention.
(hysterectomy, incontinence procedures and mesh repairs) A systematic review58 exploring the effectiveness of
did not increase the rate of VTE. ambulation to prevent VTE concluded that ambulation
alone should not be considered as adequate prophylaxis for
Duration of hospital stay and risks for thrombosis VTE or reason enough to discontinue pharmacological
Day surgery is defined as a surgical procedure wherein the prophylaxis in patients. Aggressive ambulation is suggested
patient is discharged on the same day of surgery or admitted for low-risk procedures by the American College of
and discharged within 24 hours.56 There is a paucity of data Obstetricians and Gynaecologists (ACOG)23 and, for very
for procedures specific to gynaecological surgery. Pannucci low-risk procedures by the American College of Chest
et al.57 conducted a large prospective observational cohort Physicians (ACCP).24
study to explore predictors of VTE developing over 30 days
postoperatively in patients undergoing outpatient surgery Mechanical: anti-embolic stockings/graduated
(defined as surgery where the length of stay was 0 days, i.e. compression stockings (GCS)
patients who were discharged on the day of surgery or had Anti-embolic stockings (thromboembolus deterrent, or TED,
less than a 23-hour observation period). This study included stockings) work by exerting compression, with the greatest
all outpatient procedures across specialties and found the pressure at the ankle and the level of compression decreasing
incidence of VTE, over the period studied, to be low (0.15%). upwards. This prevents peripheral pooling of blood and
Significant risk factors identified were current pregnancy, endothelial injury occurring because of stasis. The
active cancer, age >40 years, body mass index (BMI) ≥40, recommended ankle pressure for primary prophylaxis is
operation time ≥120 minutes, arthroscopic surgery and 18 mm Hg.5
saphenofemoral junction surgery.57 Data from the UK’s A 2018 Cochrane review examining GCS for prevention of
Million Women Study,2 with 947 454 women recruited VTE found a 9% incidence of DVT in the GCS group,
between 1996 and 2001 and followed by record-linkage to compared with 21% in the control group. An overall effect in
their NHS data on hospital admissions and deaths, showed reduction of VTE was shown favouring GCS use (Peto OR
that 239 614 women were admitted for surgery. Among these 0.35; 95%CI 0.28–0.43, p < 0.001). The review concluded
women 5419 were admitted with VTE and a further 270 died that there is high quality evidence that use of GCS reduces the
of VTE. This study found that in the first 6 weeks risk of DVT in hospitalised patients who have undergone
postoperatively, women were 70 times more likely to be general and orthopaedic surgery, with or without other
admitted with VTE following inpatient surgery and 10-fold methods of background prophylaxis.59 The incidence of
more likely after day case surgery. In 12 weeks following pulmonary embolism (PE) had also dropped from 5% to 2%;
surgery, the risk of VTE with inpatient surgery was 1 in 140, however, this evidence was categorised as low quality.59 A
compared with 1 in 815 after day case surgery, and 1 in 6200 2012 Cochrane review looked at knee-length versus thigh-

length GCS in preventing DVT in postoperative surgical A systematic review and meta-analysis68 evaluating the efficacy of
patients. This review identified no difference between the two preoperative pharmacoprophylaxis (unfractionated heparin
in reducing postoperative DVT and concluded that there is and/or LMWH) on incidence of VTE following major
insufficient high-quality evidence to determine any difference gynaecologic and gynaecology oncological procedures, found a
in their effectiveness.60 Proper fit of the stockings is 40% reduction in the odds of VTE when preoperative
important because a tourniquet effect could promote pharmacoprophylaxis is given versus no preoperative
venous stasis if they are too tight or rolled down. Patient pharmacoprophylaxis. This benefit was most pronounced
adherence was noted to be better with knee-length stockings when the preoperative pharmacoprophylaxis was used in
than thigh-high stockings.61 conjunction with intraoperative and postoperative mechanical
prophylaxis. However, there was insufficient evidence to suggest
Mechanical: intermittent pneumatic compression benefit in minor and benign procedures. The review included
(IPC) papers in major gynaecological surgery, comparing preoperative
Intermittent pneumatic compression (IPC) devices work by pharmacological prophylaxis to no prophylaxis, mechanical
preventing peripheral pooling of blood in the legs. Evidence prophylaxis, or only postoperative prophylaxis. Further,
shows that use of IPC reduced the incidence of DVT assessment of bleeding complications showed no significant
(including asymptomatic and distal DVT) by 60%.24 In a increase in the risk of perioperative bleeding with preoperative
meta-analysis by Feng et al.,62 use of IPC for 5 days or until pharmacoprophylaxis. Optimal timing preoperatively for
full ambulation lowered the risk of DVT; however, use for administration of pharmacoprophylaxis, however, could not
only 24 hours did not prevent DVT. Adherence for IPC is be established.68
low (58%).24 A study by Gao et al.63 found a combination of
IPC and GCS reduced the occurrence of DVT. This study, Low-dose unfractionated heparin (LDUH)
however, had a small sample size of 108 patients. In another LDUH significantly reduces the risk of DVT than no
prospective multicentre randomised controlled trial (RCT), prophylaxis. LDUH was associated with a 47% reduction in
625 women were randomised into four groups: GCS alone; the odds of fatal PE and 41% reduction in odds of nonfatal
GCS and IPC; GCS and low-molecular-weight heparin PE, with a 57% increase in the odds of nonfatal bleeding.24
(LMWH); and GCS, IPC and LMWH. This study showed Renal impairment does not need dose adjustment because it
the incidence of DVT to be 5.2% in the GCS with IPC does not affect LDUH clearance. LDUH is not a commonly
group, compared with 8.8% in the GCS alone group. This used method for thromboprophylaxis because other options
was further reduced to 3.8% in the GCS with LMWH group, are available.
and lowest at 2.6% when all three were combined. This
study showed that combination prophylaxis, especially Fondaparinux
LMWH-containing regimes, are better than a single A systematic review and meta-analysis comparing
modality.64 An RCT with a relatively small sample size fondaparinux with LMWH showed a significant reduction
looked at GCS alone and in combination with IPC in in incidence of VTE with fondaparinux, compared with
prevention of VTE in patients with acute cerebral LMWH for perioperative thromboprophylaxis. Bleeding
haemorrhage.65 It found the incidence of DVT in the complications were, however, higher with fondaparinux.69
combination group was 4.7%, compared with 15.9% in the Similar reduction of VTE was shown in a study by Turpie
GCS alone group. et al.70 in an orthopaedic population; reduction in VTE was by
more than 50% with fondaparinux, without increasing the risk
Pharmacological thromboprophylaxis of significant bleeding. NICE guidance (NG89)5 recommends
fondaparinux as an alternative to LMWH. It is also excreted
Low-molecular-weight heparin (LMWH) through the kidneys. The disadvantages of fondaparinux are
LMWH was shown to be as effective as unfractionated its longer duration of action and lack of a reversal agent.
heparin in the reduction of VTE.66 ACCP guidance24
recommends both as acceptable for prophylaxis, with Direct oral anticoagulants (DOAC)
similar efficacy. LMWH is excreted by the kidneys and, These have a rapid onset of action and are short acting, with
owing to its long half-life, requires dose adjustment in low bleeding risks (compared with warfarin). They have good
patients with renal failure. LMWH is the preferred agent of safety profiles and, unlike warfarin, do not require regular
choice in many countries, including the UK, because it has blood monitoring. DOACs currently available are apixaban,
more predictable pharmacokinetics, reduced complications dabigatran, rivaroxaban and edoxaban.
like heparin-induced thrombocytopaenia (HIT), and once- A 2020 multicentre RCT compared postoperative prophylaxis
daily dosing.23 It is also more cost-effective than with apixaban and enoxaparin in gynaecological oncology
unfractionated heparin.67 patients undergoing surgery. The primary outcome was major

Nambiar et al.
bleeding and clinically significant nonmajor bleeding. No

Box 1. Risk factors for bleeding to be considered before
statistically significant difference was observed between these pharmacological thromboprohylaxis25
two groups in terms of major or nonmajor bleeding. There was
also no difference in venous thromboembolic events. However, Patient-related risk factors
the study was underpowered for the prevention of VTE. Patient Active bleeding
Acquired bleeding disorders
satisfaction was significantly higher in the apixaban group, with Concurrent use of other anticoagulants
patients finding this easier to take (OR 0.06; 95% CI 0.01–0.25; Acute stroke
P < 0.001) and less painful (OR 9.20; 95% CI 2.67– Platelet count <75 9 109/L
31.82;P < 0.001).71 Uncontrolled blood pressure (≥230/120 mmHg)
Untreated inherited bleeding disorders
There are no studies evaluating the use of rivaroxaban in
gynaecological surgery. A study comparing rivaroxaban with Procedure-related risk factors
Procedures with high risk of bleeding
enoxaparin for thromboprophylaxis in trauma patients72 Risks related to anaesthesia: within 12 hours of an anticipated
showed no statistical difference in VTE between the two lumbar puncture/epidural/spinal anaesthesia and within 4 hours
groups. Incidence of bleeding was comparable. Rivaroxaban after lumbar puncture/epidural/spinal anaesthesia
had a similar safety profile to LMWH, while being more
effective in reducing VTE in the orthopaedic
subset studied.73,74 after a diagnosis of DVT. This presents with leg swelling,
There are studies evaluating the use of dabigatran in pain, hyperpigmentation and thickening of the skin, leg
orthopaedic surgery, but not specifically in ulcers and venous gangrene.77
gynaecological patients.75
A key consideration with the use of DOAC is reversal of
Contraindications and complications of
anticoagulant effects in the event of bleeding. Two specific
thromboprophylactic measures
agents have been approved for use: idarucizumab for
dabigatran reversal and andexanet alfa for apixaban and Mechanical thromboprophylaxis
rivaroxaban. Nonspecific prohaemostatic agents such as Anti-embolic stockings are contraindicated in the presence of
prothrombin complex concentrate (PCC) and activated PCC peripheral arterial disease, peripheral arterial bypass grafting,
have also been used to treat bleeding associated with DOAC.76 peripheral neuropathy, skin conditions like dermatitis, or
conditions where the stocking may further damage the skin
like leg oedema, known allergy to the material or severe limb
Assessment of risk of bleeding deformity preventing a correct fit.5 Intermittent pneumatic
Patients should be assessed for bleeding risk before compression is contraindicated in patients with known
commencing pharmacological thromboprophylaxis. The allergy to the material of the compression sleeve, localised
Department of Health VTE Risk Assessment Tool25 leg problems like cellulitis, wound infection, oedema from
identifies conditions to be considered when assessing the congestive heart failure, venous problems like active phlebitis
risk of bleeding. These include patient-related and or DVT or significant arterial insufficiency.5,78 Common
admission-related factors (Box 1). Patient-related adverse events reported with the use of mechanical
conditions are active bleeding, acquired bleeding disorders, compression therapy are skin irritation, discomfort and
concurrent use of anticoagulants, acute stroke, platelet count pain. Forefoot oedema and lymphoedema is rare. Very rare
of less than 75 9 109/L, uncontrolled blood pressure (230/ adverse events reported were allergic skin reaction, bacterial
120 mmHg or higher) and untreated inherited bleeding and fungal infections, soft tissue damage or necrosis, arterial
disorders. Any increased risks of bleeding specific to the insufficiency, nerve damage, venous thromboembolism
procedure need to be considered. Pharmacological (mostly superficial thrombophlebitis associated with
thromboprophylaxis should be avoided if a lumbar improper application) and cardiac decompensation.79
puncture, epidural or spinal anaesthesia is expected in the
next 12 hours, or if the patient has had a lumbar puncture, Pharmacological thromboprophylaxis
epidural or spinal anaesthesia within the previous 4 hours.25 Pharmacological thromboprophylaxis is contraindicated in
the presence of active bleeding, or any condition where there
is an increased risk of bleeding.
Complications of VTE Bleeding is the commonest adverse effect. Reported rates
The most serious complication of VTE is death caused by of nonfatal bleeding vary between 2.9 and 6.0%, with no fatal
pulmonary embolism. Another common but under bleeding recorded in a systematic review by Johnson et al.46
recognised complication is post-thrombotic syndrome, The other less common adverse effects of unfractionated
which can affect up to 50% of patients in the first 2 years heparin (UFH) and LMWH are injection site reaction,

heparin-induced thrombocytopaenia (HIT), and considers multiple risk factors, including age, pregnancy, oral
osteoporosis.80 The latter two are less common with LMWH. contraceptive or HRT, type of surgery, recent events like major
surgery, pneumonia and other conditions, venous disease or
Well leg compartment syndrome (WLCS) clotting disorder, mobility, BMI, malignancy and other risk
Compartment syndrome is a condition in which compartment factors. Each risk factor is given a score and, based on the total
pressure exceeds perfusion pressure, causing tissue ischaemia score, patients are risk stratified. Thromboprophylaxis is
and necrosis.81 WLCS is defined as an acute lower leg prescribed as appropriate for the risk group.26
compartment syndrome occurring in the absence of trauma
and may occur without pre-existing vascular disease.81
Ethical issues and barriers to
Prolonged abdominopelvic surgeries, often lasting more than 4
implementation
hours, with patients in the lithotomy position, with or without
head down, have been identified as risk factors for the Some patients may hold personal beliefs objecting to the use
development of this condition. Complex laparoscopic of certain animal products. Patients should be informed that
endometriosis and gynaecological oncology surgical LMWH is porcine-derived, where this may be of significance
procedures fall in this category. Other risk factors include age to them, and alternative therapy (fondaparinux or DOAC)
younger than 35 years, BMI more than 25, presence of vascular should be offered.
disease and intraoperative hypotension. Wide variation is noted Noncompliance with thromboprophylaxis is a
in the incidence of the condition.81 The role of mechanical contributory factor in cases of VTE. Patient education and
compression devices (stockings and foot pumps) have been appropriate counselling may help to reduce the risks. Large
evaluated as contributory factors.81 The authors acknowledge the international studies have shown that thromboprophylaxis is
paucity of randomised trials or observational studies looking at not consistently applied by clinicians in hospital practice. To
the occurrence of WLCS in relation to mechanical counsel patients appropriately, clinicians must be convinced
thromboprophylaxis. They suggest that the theoretical risk of to accept evidence-based practice. Clinician hesitance to
WLCS with the use of anti-embolic stockings and/or IPC must be instituting thromboprophylaxis as routine practice following
weighed against the risk of developing VTE. They, therefore, surgery can pose a considerable constraint to
consider it inappropriate to avoid carefully applied stockings implementation. While compliance will improve once
and/or IPC for prevention of VTE in patients undergoing clinicians are convinced it adds value to patient care, only a
prolonged pelvic surgery purely because of risk of WLCS, and multilevel approach at the individual, cultural and
suggest alternative measures like positional change every 4 hours organisational levels will lead to sustained change.83–86
to reduce occurrence of WLCS.
A systematic review of mechanical thromboprophylaxis and
Recommendations
lithotomy position82 identified the lack of conclusive evidence to
show that mechanical thromboprophylaxis causes compartment Pregnant women at high risk of thrombosis (previous
syndrome in the lithotomy position. The authors acknowledge personal history of VTE not related to major surgery or a
that evidence is limited. However, they suggest that IPC may be total score of ≥4) should be identified in primary care,
considered safe if other measures to reduce compartment prepregnancy, and should be risk-assessed as soon as
syndrome, like periodic lowering of the legs to horizontal pregnancy is confirmed. These women may already
position, reducing intraoperative hypotension and adequate develop thrombosis by the time of their booking visit.
padding, are adhered to. High-risk women should be started on pharmacological
thromboprophylaxis as soon as possible in the first
trimester. This should be continued throughout
Stratifying risks for thromboprophylaxis
pregnancy and for 6 weeks postnatally.
Scoring systems have been developed with the intention of Pharmacological thromboprophylaxis in severe OHSS
identifying patients who need thromboprophylaxis. One such should be commenced at diagnosis after assessing the
system is the Caprini score, which has been extensively risks of bleeding and continued for the duration of the first
validated in both medical and general surgery patients.51 VTE trimester in women who are pregnant. In women who do
guidelines by the ACCP and the European guidelines on not conceive, thromboprophylaxis can be discontinued at
perioperative venous thromboembolism prophylaxis are the time of withdrawal bleed.
based on the Caprini scoring system. All pregnant women, irrespective of pregnancy outcome,
should be risk-assessed, and any surgical procedure in
Caprini score pregnancy or puerperium should be assigned a score of 3,
First published in 1991, the Caprini score assigns points to each based on RCOG guidance, mandating a minimum of
risk factor and then categorises them into groups. This system 10 days thromboprophylaxis (see Figure 2).

Nambiar et al.
Early pregnancy
(Risk assessment based on RCOG guidance)
Miscarriage
Need for
Personal history of VTE (surgical/
OHSS hospitalisation, Ectopic pregnancy
or total score ≥4 medical
e.g. hyperemesis
management)
Conservative/
Surgical
medical
management
management
Pharmacological thromboprophylaxis if no contraindications

(if contraindicated, GCS + IPC)
Personal history of VTE or
total score ≥4
Continue thromboprophylaxis as recommended for the specific condition and review prior to stopping
Give contact details if bleeding issues develop
Figure 2. VTE risk assessment in early pregnancy. GCS = graduated compression stockings; IPC = intermittent pneumatic compression;
VTE = venous thromboembolism; RCOG = Royal College of Obstetricians and Gynaecologists; OHSS = ovarian hyperstimulation syndrome.
Patient requiring gynaecological surgery
Stop CHC as per

guidelines.
HRT can be
Personal history of thrombosis No continued (HRT to
or Assess VTE risk be considered as a
underlying malignancy factor for risk
assessment)
Yes High/highest Low/moderate
No
Pharmacological thromboprophylaxis if no contraindications anticoagulation
(if contraindicated, GCS + IPC) (to consider
GCS/IPC)
Continue thromboprophylaxis for specified time period and review prior to stopping
Give contact details if bleeding issues develop
If CHC has been discontinued, consider recommencing 2 weeks after regaining full mobility
Figure 3. VTE risk assessment pathways for patients undergoing gynaecological surgeries. VTE = venous thromboembolism; CHC = combined
hormonal contraception; HRT = hormone replacement therapy; GCS = graduated compression stockings; IPC = intermittent pneumatic
compression.

Table 2. VTE risk scores for patients undergoing gynaecological surgeries5,11,23–26
Patient-related risk factors Score Procedure-related risk factors Score
Age Duration of surgery (total anaesthetic and surgical time)

≤40 years 0 <60 minutes +1
41–60 years +1 >60 minutes +2
61–74 years +2
≥75 years +3
BMI
≥30 +1
≥40 +2
CHC/oral HRT +1
Pregnancy or 6 weeks following delivery (any gestation) +3

or miscarriage*
Varicose veins +1
Pelvic mass of significant sizea +1
Personal history of VTE +3
Family history of unprovoked VTE +3
Known high-risk inherited thrombophiliab +3
Mobility
Currently on bed restc +1
Patient confined to bed >72 hours +2
Medical conditions (acute MI, COPD, inflammatory bowel +1

disease, heart failure, sepsis, pneumonia, diabetes
requiring insulin)
Major surgery in the past month +1
Hip, pelvis or leg fracture; stroke; multiple trauma; acute +5

spinal cord injury causing paralysis
Active cancer/cancer treatment** +2
Smoking +1
Immobilising plaster cast +2
Blood transfusion +1
a
Pelvic mass is defined as any pelvic mass significant enough to cause pelvic venous compression; for example, fibroid >12 weeks in size
b
Antithrombin deficiency, Protein C deficiency and Protein S deficiency. Other thrombophilias to be discussed with haematology
c
Bed rest is defined as an inability to walk 10 metres at one time. Going to the bathroom or walking in the room are not considered ambulation
*Any surgical procedure in pregnancy or within 6 weeks of birth should be scored 3 and requires a minimum of 10 days LMWH (+IPC), unless
contraindicated
**LMWH (+IPC) should be given for 28 days if there is current diagnosis of cancer, unless contraindicated
BMI = body mass index; CHC = combined hormonal contraception; COPD = chronic obstructive pulmonary disease; HRT = hormone replacement
therapy; IPC = intermittent pneumatic compression; LMWH = low-molecular-weight heparin; MI = myocardial infarction; VTE = venous
thromboembolism

Nambiar et al.
intervention. Large-scale studies to provide robust evidence

Table 3. Thromboprophylaxis based on VTE score (adapted from the
Caprini score)26 on risk of VTE in patients undergoing MIS for early-stage
gynaecological malignancy will be beneficial in avoiding
Risk score Risk strata Thromboprophylaxis potentially unnecessary prolonged thromboprophylaxis in
this group.
0 Low risk Ambulation alone or IPC or GCS
during hospitalisation
Disclosure of Interests
JT has received honoraria from Bayer, BMS Pfizer, Boehringer,
1–4 Moderate risk IPC +/- GCS during hospitalisation Daichii, Octapharma, Shire, Takeda, Grifols, Sobi,
NovoNordisk, Roche, Shionogi, Amgen, and Novartis. WY is a
5–8 High risk IPC + LMWH or LMWH alone for 7-
10 days
trustee of the Haemorrhage after Childbirth Foundation, a
member of RCOG Joint Standing Committee on Patient Safety
≥9 Highest risk IPC + LMWH or LMWH alone for and an Associate Editor of The Obstetrician and Gynaecologist; he
30 days was excluded from editorial discussions and had no involvement
in the decision to publish. The remaining authors have no
GCS = graduated compression stockings; IPC = intermittent conflict of interests.
pneumatic compression; LMWH = low-molecular-weight heparin;
VTE = venous thromboembolism Contribution to authorship
DN and DBN designed and drafted the article and performed
the literature review. All authors made critical revisions to the
manuscript and approved the final version.
CHC should be stopped 4 weeks before elective surgery and
only restarted at least 2 weeks after regaining full mobility Acknowledgements
following surgery. A progesterone-only contraceptive may The authors would like to thank Gill Rose, Clinical Outreach
be offered as an alternative. In emergency surgical situations, Librarian for Women, Children and Sexual Health Services,
when the patient is on CHC, thromboprophylaxis should Buckinghamshire NHS Trust, and the library services at
take this into account as an additional risk factor. Buckinghamshire NHS Trust for their contribution to the
HRT does not need to be stopped prior to surgery. It literature search.
should be considered as a factor while risk-assessing
for VTE.
Reduced hospital stay in day surgery is associated with
References
lower risk of VTE. In these patients, other risk factors 1 Rahn DD, Mamik MM, Sanses TVD, Matteson KA, Aschkenazi SO,
(patient-related or procedure-related) must be considered Washington BB, et al. Venous thromboembolism prophylaxis in gynecologic
surgery: a systematic review. Obstet Gynecol 2011;118:1111–25.
on VTE risk assessment. Patients attending for procedures 2 Sweetland S, Green J, Liu B, Berrington de Gonzalez A, Canonico M, Reeves
like hysteroscopy do not need to be routinely given G, et al. Duration and magnitude of the postoperative risk of venous
pharmacological thromboprophylaxis in the absence of thromboembolism in middle aged women: prospective cohort study. BMJ
2009;339:b4583.
other risk factors if the total duration of procedure is less 3 House of Commons Health Committee. The prevention of venous
than 60 minutes and no significant reduction in mobility thromboembolism in hospitalised patients: second report of session 2004–
relative to their normal is anticipated (see Figure 3). 2005. London: Stationery Office; 2005 [https://publications.parliament.uk/
pa/cm200405/cmselect/cmhealth/99/99.pdf].
We propose risk assessment (Table 2) and management 4 National Health Service (NHS) Commissioning Board. Commissioning for
guidance based on risk scoring (Table 3) for gynaecological quality and innovation (CQUIN): 2013/14 guidance. London: NHS; 2013
patients undergoing surgery, taking into consideration the [https://www.england.nhs.uk/wp-content/uploads/2012/12/cquin-
guidance.pdf].
evidence reviewed, the Caprini score, and guidelines 5 National Institute for Health and Care Excellence (NICE). Venous
published by NICE, RCOG, ACOG and ACCP. 5,11,23,24,26 thromboembolism in over 16s: reducing the risk of hospital-acquired deep
A score of 3 has been arbitrarily assigned for pregnancy vein thrombosis or pulmonary embolism. NICE guideline [NG89]. London:
NICE; 2018 [https://www.nice.org.uk/guidance/ng89/chapter/Context].
and within 6 weeks of delivery/termination, and 1 to large 6 National Health Service (NHS) Digital. NHS Outcomes Framework 2019/20.
pelvic masses likely to contribute to pelvic venous stasis. A Indicator and domain summary tables. London: NHS; 2020 [https://files.
pragmatic approach has been followed in these two digital.nhs.uk/43/6B7A4F/nhs-out-fram-feb-20-dash.pdf].
7 James AH, Tapson VF, Goldhaber SZ. Thrombosis during pregnancy and the
situations based on case reports. postpartum period. Am J Obstet Gynecol 2005;193:216–9.
We hope that standardisation will decrease variation in 8 Ray JG, Chan WS. Deep vein thrombosis during pregnancy and the
practice and allow review of the scoring and validation of puerperium: a meta-analysis of the period of risk and the leg of
presentation. Obstet Gynecol Surv 1999;54:265–71.
thromboprophylaxis protocols in gynaecological practice. In 9 Bagot CN, Leishman E, Onyiaodike CC, Jordan F, Freeman DJ. Normal
turn, this will reduce mortality and morbidity from this pregnancy is associated with an increase in thrombin generation from the
preventable condition, while avoiding unnecessary very early stages of the first trimester. Thromb Res 2017;157:49–54.

10 Knight M, Bunch K, Tuffnell D, Shakespeare J, Kotnis R, Kenyon S, et al. 29 Einstein MH, Kushner DM, Connor JP, Bohl AA, Best TJ, Evans MD, et al. A
Saving lives, improving mothers’ care: Lessons learned to inform maternity protocol of dual prophylaxis for venous thromboembolism prevention in
care from the UK and Ireland confidential enquiries into maternal deaths gynecologic cancer patients. Obstet Gynecol 2008;112:1091.
and morbidity 2015–17. Mothers and Babies: Reducing Risk through Audits 30 Bergqvist D, Agnelli G, Cohen AT, Eldor A, Nilsson PE, Le Moigne-
and Confidential Enquiries across the UK (MBRRACE-UK). Oxford: National Amrani A, et al. Duration of prophylaxis against venous
Perinatal Epidemiology Unit, University of Oxford 2019. thromboembolism with enoxaparin after surgery for cancer. N Engl J
11 Royal College of Obstetricians and Gynaecologists (RCOG). Reducing the risk Med 2002;346:975–80.
of venous thromboembolism in pregnancy and the puerperium. Green-top 31 Practice Committee of the American Society for Reproductive Medicine.
guideline no. 37a. London: RCOG; 2015 [https://www.rcog.org.uk/media/ Combined hormonal contraception and the risk of venous
qejfhcaj/gtg-37a.pdf]. thromboembolism: a guideline. Fertil Steril 2017;107:43–51.
12 Virkus RA, Løkkegaard E, Lidegaard Ø, Langhoff-Roos J, Nielsen AK, 32 Suissa S, Blais L, Spitzer WO, Cusson J, Lewis M, Heinemann L. First-time use
Rothman KJ, et al. Risk factors for venous thromboembolism in 1.3 million of newer oral contraceptives and the risk of venous thromboembolism.
pregnancies: a nationwide prospective cohort. PLoS One 2014;9:e96495. Contraception 1997;56:141–6.
13 Rova K, Passmark H, Lindqvist PG. Venous thromboembolism in relation to 33 Faculty of Sexual and Reproductive Health (FSRH) Clinical Effectiveness Unit.
in vitro fertilization: an approach to determining the incidence and increase Faculty of Sexual and Reproductive Health guideline: combined hormonal
in risk in successful cycles. Fertil Steril 2012;97:95–100. contraception. London: FSRH; 2019 [https://www.fsrh.org/standards-and-
14 Royal College of Obstetricians and Gynaecologists (RCOG). The guidance/documents/combined-hormonal-contraception/].
management of ovarian hyperstimulation syndrome. Green-top guideline 34 Robinson G, Burren T, Mackie I, Bounds W, Walshe K, Faint R, et al. Changes
no.5. London: RCOG; 2016 [https://www.rcog.org.uk/media/or1jqxbf/gtg_ in haemostasis after stopping the combined contraceptive pill: implications
5_ohss.pdf]. for major surgery. BMJ 1991;302:269–71.
15 Prakash A, Mathur R. Ovarian hyperstimulation syndrome. Obstet Gynaecol. 35 Contraceptives, hormonal ¦ Treatment summaries ¦ BNF ¦ NICE; https://bnf.
2013;15:31–5. nice.l/org.uk/treatment-summaries/contraceptives-hormonal/
16 National Institute for Health and Care Excellence (NICE). Abortion care: VTE 36 Kearon C. Duration of venous thromboembolism prophylaxis after surgery.
prophylaxis for women having abortion. NICE guideline NG140. London: Chest 2003;124 6 Suppl:386S–92S.
NICE; 2019 [https://www.nice.org.uk/guidance/ng140/evidence/e-vte- 37 Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement
prophylaxis-for-women-having-abortion-pdf-6905052977]. therapy and risk of breast cancer: nested case-control studies using the
17 Knight M, Bunch K, Tuffnell D, Shakespeare J, Kotnis R, Kenyon S, et al. QResearch and CPRD databases. BMJ 2020;371:m3873.
Saving lives, improving mothers’ care: Lessons learned to inform maternity 38 Douketis J. Hormone replacement therapy and risk for venous
care from the UK and Ireland confidential enquiries into maternal deaths thromboembolism: what’s new and how do these findings influence clinical
and morbidity 2016-18. Mothers and Babies: Reducing Risk through Audits practice? Curr Opin Hematol 2005;12:395–400.
and Confidential Enquiries across the UK (MBRRACE-UK). Oxford: National 39 National Institute for Health and Care Excellence (NICE). Menopause:
Perinatal Epidemiology Unit, University of Oxford; 2020. diagnosis and management. NICE guideline NG23. London: NICE; 2015
18 Ritch JMB, Kim JH, Lewin SN, Burke WM, Sun X, Herzog TJ, et al. Venous [https://www.nice.org.uk/guidance/ng23].
thromboembolism and use of prophylaxis among women undergoing 40 Chalhoub V, Edelman P, Staiti G, Benhamou D. Oral contraception and
laparoscopic hysterectomy. Obstet Gynecol 2011;117:1367–74. hormone replacement therapy: management of their thromboembolic risk
19 Mokri B, Mariani A, Heit JA, Weaver AL, McGree ME, Martin JR, et al. in the perioperative period. Ann Fr Anesth Reanim 2008;27:405–15.
Incidence and predictors of venous thromboembolism after debulking 41 Hurbanek JG, Jaffer AK, Morra N, Karafa M, Brotman DJ. Postmenopausal
surgery for epithelial ovarian cancer. Int J Gynecol Cancer hormone replacement and venous thromboembolism following hip and
2013;23:1684–91. knee arthroplasty. Thromb Haemost 2004;92:337–43.
20 Barber EL, Neubauer NL, Gossett DR. Risk of venous thromboembolism in 42 Tafler K, Kuriya A, Gervais N, Leyland N. (2021). Guideline no. 417:
abdominal versus minimally invasive hysterectomy for benign conditions. prevention of venous thromboembolic disease in gynaecological surgery. J
Am J Obstet Gynecol 2015;212:609.e1–7. Obstet Gynaecol Can 2022;44:82–96.e1.
21 Barber EL, Gehrig PA, Clarke-Pearson DL. Venous thromboembolism in 43 Nopp S, Moik F, Jilma B, Pabinger I, Ay C. Risk of venous thromboembolism
minimally invasive compared with open hysterectomy for endometrial in patients with COVID-19: A systematic review and meta-analysis. Res Pract
cancer. Obstet Gynecol 2016;128:121–6. Thromb Haemost 2020;4:1178–91.
22 Nick AM, Schmeler KM, Frumovitz MM, Soliman PT, Spannuth WA, 44 Golemi I, Salazar Adum JP, Tafur A, Caprini J. Venous thromboembolism
Burzawa JK, et al. Risk of thromboembolic disease in patients undergoing prophylaxis using the Caprini score. Dis Mon 2019;65:249–98.
laparoscopic gynecologic surgery. Obstet Gynecol 2010;116:956–61. 45 Borow M, Goldson H. Postoperative venous thrombosis. Evaluation of five
23 Committee on Practice Bulletins – Gynaecology, American College of methods of treatment. Am J Surg 1981;141:245–51.
Obstetricians and Gynecologists. ACOG Practice Bulletin No. 84: Prevention 46 Johnson RL, Kopp SL, Burkle CM, Duncan CM, Jacob AK, Erwin PJ, et al.
of deep vein thrombosis and pulmonary embolism. Obstet Gynecol Neuraxial vs general anaesthesia for total hip and total knee arthroplasty: a
2007;110:429–40. systematic review of comparative-effectiveness research. Br J Anaesth
24 Gould MK, Garcia DA, Wren SM, Karanicolas PJ, Arcelus JI, Heit JA, et al. 2016;116:163–76.
Prevention of VTE in non orthopedic surgical patients: antithrombotic 47 Kahr HS, Thorlacius-Ussing O, Christiansen OB, Skals RK, Torp-Pedersen C,
therapy and prevention of thrombosis, 9th ed: American College of Chest Knudsen A. Venous thromboembolic complications to hysterectomy for
Physicians evidence-based clinical practice guidelines. Chest 2012;141: benign disease: a nationwide cohort study. J Minim Invasive Gynecol
e227S. 2018;25:715–23.e2.
25 Department of Health (DOH). Risk assessment for venous 48 Swenson CW, Berger MB, Kamdar NS, Campbell DA Jr, Morgan DM. Risk
thromboembolism (VTE). London: DOH; 2010 [https://www.nice.org.uk/ factors for venous thromboembolism after hysterectomy. Obstet Gynecol
guidance/ng89/resources/department-of-health-vte-risk-assessment-tool- 2015;125:1139–44.
pdf-4787149213]. 49 Fader AN, Weise RM, Sinno AK, Tanner EJ 3rd, Borah BJ, Moriarty JP, et al.
26 MDCalc. Caprini score for venous thromboembolism. 2019 [https://www. Utilization of minimally invasive surgery in endometrial cancer care: a quality
mdcalc.com/caprini-score-venous-thromboembolism-2005]. and cost disparity. Obstet Gynecol 2016;127:91–100.
27 Kumar S, Al-Wahab Z, Sarangi S, Woelk J, Morris R, Munkarah A, et al. Risk 50 Ageno W, Manfredi E, Dentali F, Silingardi M, Ghezzi F, Camporese G, et al.
of postoperative venous thromboembolism after minimally invasive surgery The incidence of venous thromboembolism following gynecologic
for endometrial and cervical cancer is low: a multi-institutional study. laparoscopy: a multicenter, prospective cohort study. J Thromb Haemost
Gynecol Oncol 2013;130:207–12. 2007;5:503–6.
28 Freeman AH, Barrie A, Lyon L, Littell RD, Garcia C, Conell C, et al. Venous 51 Jorgensen EM, Hur HC. Venous thromboembolism in minimally invasive
thromboembolism following minimally invasive surgery among women with gynecologic surgery: a systematic review. J Minim Invasive Gynecol
endometrial cancer. Gynecol Oncol 2016;142:267–72. 2019;26:186–196.

Nambiar et al.
52 Escobar CM, Gomez-Viso A, Agrawal S, Smilen S, Rosenblum N, Brucker 69 Kumar A, Talwar A, Farley JF, Muzumdar J, Schommer JC, Balkrishnan R,
BM, et al. Venous thromboembolism prophylaxis in vaginal surgery for et al. Fondaparinux sodium compared with low-molecular-weight heparins
pelvic organ prolapse: Predictors of high risk in a low-risk population. for perioperative surgical thromboprophylaxis: a systematic review and
Neurourol Urodyn 2021;40:176–82. meta-analysis. J Am Heart Assoc 2019;8:e012184.
53 Hokenstad ED, Habermann EB, Glasgow AE, Occhino JA. Risk of venous 70 Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Fondaparinux vs enoxaparin
thromboembolism in patients undergoing surgery for pelvic organ prolapse. for the prevention of venous thromboembolism in major orthopedic
Int Urogynecol J 2016;27:1525–8. surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern
54 Chong W, Bui AH, Menhaji K. Incidence and risk factors for venous Med 2002;162:1833–40.
thromboembolism events after different routes of pelvic organ prolapse 71 Guntupalli SR, Brennecke A, Behbakht K, Tayebnejad A, Breed CA, Babayan
repairs. Am J Obstet Gynecol 2020;223:268.e1–268.e26. LM, et al. Safety and efficacy of apixaban vs enoxaparin for preventing
55 Montoya TI, Leclaire EL, Oakley SH, Crane AK, Mcpencow A, Cichowski S, postoperative venous thromboembolism in women undergoing surgery for
et al. Venous thromboembolism in women undergoing pelvic reconstructive gynecologic malignant neoplasm: a randomized clinical trial. JAMA Netw
surgery with mechanical prophylaxis alone. Int Urogynecol J Open 2020;3:e207410.
2014;25:921–6. 72 Kingdon LK, Miller EM, Savage SA. The utility of rivaroxaban as primary
56 Venclauskas L, Llau JV, Jenny JY, Kjaersgaard-Andersen P, Jans Ø, ESA VTE venous thromboprophylaxis in an adult trauma population. J Surg Res
Guidelines Task Force. European guidelines on perioperative venous 2019;244:509–15.
thromboembolism prophylaxis: day surgery and fast-track surgery. Eur J 73 Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, et al.
Anaesthesiol 2018;35:134–8. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip
57 Pannucci CJ, Shanks A, Moote MJ, Bahl V, Cederna PS, Naughton NN, et al. arthroplasty. N Engl J Med 2008;358:2765–75.
Identifying patients at high risk for venous thromboembolism requiring 74 Cao YB, Zhang JD, Shen H, Jiang YY. Rivaroxaban versus enoxaparin for
treatment after outpatient surgery. Ann Surg 2012;255:1093–9. thromboprophylaxis after total hip or knee arthroplasty: a meta-analysis
58 Lau BD, Murphy P, Nastasi AJ, Seal S, Kraus PS, Hobson DB, et al. Effectiveness of of randomized controlled trials. Eur J Clin Pharmacol
ambulation to prevent venous thromboembolism in patients admitted to 2010;66:1099–108.
hospital: a systematic review. CMAJ Open 2020;8:E832–43. 75 Rosencher N, Samama CM, Feuring M, Brueckmann M, Kleine E,
59 Sachdeva A, Dalton M, Lees T. Graduated compression stockings for Clemens A, et al. Dabigatran etexilate for thromboprophylaxis in over
prevention of deep vein thrombosis. Cochrane Database Syst Rev 2018;11 5000 hip or knee replacement patients in a real-world clinical setting.
(11):CD001484. Thromb J 2016;14:8.
60 Sajid MS, Desai M, Morris RW, Hamilton G. Knee length versus thigh length 76 Cuker A, Burnett A, Triller D, Crowther M, Ansell J, Van Cott EM, et al.
graduated compression stockings for prevention of deep vein thrombosis in Reversal of direct oral anticoagulants: guidance from the Anticoagulation
postoperative surgical patients. Cochrane Database Syst Rev 2012;(5): Forum. Am J Hematol 2019;94:697–709.
CD007162. 77 National Institute for Health and Care Excellence (NICE). Deep vein
61 Wade R, Sideris E, Paton F, Rice S, Palmer S, Fox D, et al. Graduated thrombosis: what are the complications? London; NICE; 2022 [https://cks.
compression stockings for the prevention of deep-vein thrombosis in nice.org.uk/topics/deep-vein-thrombosis/background-information/
postoperative surgical patients: a systematic review and economic model complications/].
with a value of information analysis. Health Technol Assess 2015;19:1–220. 78 Berliner E, Ozbilgin B, Zarin DA. A systematic review of pneumatic
62 Feng JP, Xiong YT, Fan ZQ, Yan LJ, Wang JY, Gu ZJ. Efficacy of intermittent compression for treatment of chronic venous insufficiency and venous
pneumatic compression for venous thromboembolism prophylaxis in ulcers. J Vasc Surg 2003;37:539–44.
patients undergoing gynecologic surgery: a systematic review and meta- 79 Rabe E, Partsch H, Morrison N, Meissner MH, Mosti G, Lattimer CR, et al.
analysis. Oncotarget 2017;8:20371–9. Risks and contraindications of medical compression treatment – a critical
63 Gao J, Zhang ZY, Li Z, Liu CD, Zhan YX, Qiao BL, et al. Two mechanical reappraisal. An international consensus statement. Phlebology
methods for thromboembolism prophylaxis after gynaecological pelvic 2020;35:447–60.
surgery: a prospective, randomised study. Chin Med J (Engl) 80 Solari F, Varacallo M. Low molecular weight heparin (LMWH). In: StatPearls
2012;125:4259–63. [Internet]. Treasure Island (FL): StatPearls; 2022 [https://www.ncbi.nlm.nih.
64 Sang CQ, Zhao N, Zhang J, Wang SZ, Guo SL, Li SH, et al. Different gov/books/NBK525957/].
combination strategies for prophylaxis of venous thromboembolism in 81 Gill M, Fligelstone L, Keating J, Jayne DG, Renton S, Shearman CP, et al.
patients: A prospective multicenter randomized controlled study. Sci Rep Avoiding, diagnosing and treating well leg compartment syndrome after
2018;8:8277. pelvic surgery. Br J Surg 2019;106:1156–66.
65 Lacut K, Bressollette L, Le Gal G, Etienne E, De Tinteniac A, Renault A, et al. 82 Gelder C, McCallum AL, Macfarlane AJR, Anderson JH. A systematic review
Prevention of venous thrombosis in patients with acute intracerebral of mechanical thromboprophylaxis in the lithotomy position. Surgeon
hemorrhage. Neurology 2005;65:865–9. 2018;16:365–71.
66 Mismetti P, Laporte S, Darmon JY, Buchm€ uller A, Decousus H. Meta-analysis 83 Grol R. Successes and failures in the implementation of evidence-based
of low molecular weight heparin in the prevention of venous guidelines for clinical practice. Med Care 2001;39 8 Suppl 2:II46–54.
thromboembolism in general surgery. Br J Surg 2001;88:913–30. 84 Cabana MD, Rand CS, Powe NR, Wu AW, Wilson MH, Abboud PA, et al.
67 Wade WE, Spruill WJ. Cost-effectiveness of dalteparin versus unfractionated Why don’t physicians follow clinical practice guidelines? A framework for
heparin as venous thromboembolism prophylaxis in malignant gynecologic improvement. JAMA 1999;282:1458–65.
surgery. Am J Ther 2008;15:512–5. 85 Grimshaw JM, Thomas RE, MacLennan G, Fraser C, Ramsay CP, Vale L, et al.
68 Bisch S, Findley R, Ince C, Nardell M, Nelson G. Efficacy of pre-operative Effectiveness and efficiency of guideline dissemination and implementation
pharmacologic thromboprophylaxis on incidence of venous strategies. Health Technol Assess 2004;8:iii–72.
thromboembolism following major gynecologic and gynecologic oncology 86 Chapman NH, Lazar SP, Fry M, Lassere MN, Chong BH. Clinicians adopting
surgery: a systematic review and meta-analysis. Int J Gynecol Cancer evidence based guidelines: a case study with thromboprophylaxis. BMC
2021;31:257–64. Health Serv Res 2011;11:240.

DOI: 10.1111/tog.12847 2023;25:72–7
Tips and Techniques
Articles in the Tips and Techniques

Management of Bartholin’s cyst and section are personal views from
experts in their field on how to
carry out procedures in obstetrics
abscess and gynaecology.
a b
Ayesha Bati-Paracha BSc Hons MBBS MRCOG,* Mona Sharma MBBS MD MRCOG
a
Specialty Registrar/ST5, Women’s Health Department, Queen’s Hospital, Barking, Havering and Redbridge NHS Trust, London RM7 0AG, UK
b
Consultant Obstetrician and Gynaecologist, Women’s Health Department, Queen’s Hospital, Barking, Havering and Redbridge NHS Trust,
London RM7 0AG, UK
*Correspondence: Ayesha Bati-Paracha. Email: ayesha.bati-paracha@nhs.net
Accepted on 27 August 2021. Published online 27 November 2022.
Please cite this paper as: Bati-Paracha A, Sharma M. Management of Bartholin’s cyst and abscess. The Obstetrician & Gynaecologist 2023;25:72–7. https://doi.org/
10.1111/tog.12847
Introduction Box 1. Differential diagnoses of cystic vulvular lesions2,3
A Bartholin’s duct cyst or abscess is a common condition Bartholin’s duct cyst – usually unilateral and can be asymptomatic. It
affecting approximately 2% of women. Trainees working in the is vestibular in location and is soft and nontender.
acute gynaecology setting see this on a regular basis and they Bartholin’s gland abscess – unilateral and vestibular in location. It
should be familiar with the different treatments available.1 presents as a painful, erythematous and fluctuant lump.
Cyst of the canal of Nuck – a soft cyst found on the labia majora and
mons pubis. It is caused by the entrapment of peritoneum in round
ligament.
Anatomy and pathophysiology Epidermal inclusion cyst – found on the labia majora and are mobile
and non-tender. It is caused by the obstruction of pilosebaceous cyst.
The Bartholin’s or vestibular glands were first described by
Hydradenoma papilliforum – small nodules arising from apocrine
the 17th century Danish anatomist Casper Bartholin. These sweat glands and are 0.2–3.0 cm in diameter.
glands are pea sized (0.5–1.0 cm) and are lined with Mucous cyst of the vestibule – small, superficial cysts <2 cm found
columnar epithelium. The duct length is 1.5–2 cm and is on the labia minora and vestibule.
Skene duct cyst – found proximal to urethral meatus in vestibule and
lined with squamous epithelium. The glands are located
can present in neonates.
bilaterally at 4 and 8 ‘o clock positions at the base of the labia
minora. The embryological origin is derived from the
urogenital sinus; hence, the blood supply and nerve
innervation is via the external pudendal artery and medially. The presentation is that of localised unilateral
pudendal nerve, respectively. The superficial inguinal and swelling leading to pain and discomfort. There can also be
pelvic nodes provide the lymphatic drainage.2 associated fever with an abscess. Differentiation from other
The gland secretes mucus and provides vulval and vaginal vulvar cystic lesions is important because management can
lubrication. Blockage of the duct can be caused by trauma, vary (see Box 1).
infection and oedema. This leads to a build-up of mucus,
which causes dilatation of the duct, leading to cyst or
abscess development.
Management
Risk factors3 associated with the development of a Management is determined by the symptoms, size, recurrence
Bartholin’s cyst and abscess include nulliparity, sexually history and age of the patient and their preference. Bartholin’s
active women under the age of 40 and previous history of abscess can be managed conservatively or surgically. Surgical
vulval surgery or trauma, such as female genital mutilation. management can be done in the outpatient setting if appropriate
Abscesses are commonly caused by polymicrobial organisms, equipment and expertise are available. By offering outpatient
such as Escherichia coli and Staphylococcus aureus, although management, the patient can avoid undergoing general
sexually transmitted organisms such as Gonorrhoeae may be anaesthesia and may be spared a prolonged stay while awaiting
involved in some cases.2 a slot on theatre emergency list. However, in recurrent cases (or if
Bartholin’s duct cysts or abscesses2,3 are vestibular in the patient is systemically unwell), surgical management under
location and present with an increase in size and swelling anaesthesia would be recommended.

Bati-Paracha and Sharma
The two commonest forms of management in UK practice

are under local anaesthesia (in the ambulatory setting) via the
use of the balloon catheter, which achieves fistualisation by
draining the abscess or cyst, or marsupialisation done under
general anaesthesia or sedation.4 Both procedures have similar
recurrence rates, as shown in the WoMan trial,5 a randomised
trial carried out in the Netherlands. This study randomly
allocated 160 women to treatment by ‘Word’ balloon catheter
or marsupialisation. Recurrence occurred in 12% women with
the Word balloon catheter, compared with 10% in the
marsupialisation group. After the Word catheter procedure,
women recorded pain scores of 33% compared with 74% who
underwent marsupialisation. Figure 1. Balloon catheter equipment. Inflated silicone catheter
An Austrian study of 30 women showed that balloon attached to a syringe. A small incision is made along the most fluctuant
part of the cyst and an uninflated catheter is placed. A total of 2–3 ml of
catheter treatment was successful in 87% of cases, with a saline is injected to inflate the balloon. The syringe is removed and the
recurrence rate of 3.8%. The cost of balloon catheter open end of the catheter can be left exposed. Photograph of ‘Word’
treatment per patient was €216 compared with €1584 for balloon catheter provided by Medical Photography department at
surgical marsupialisation (the higher cost being potentially Queens Hospital, Barking and Havering NHS Trust.
associated with the need for an overnight stay).6 A 2019
systematic review evaluating different treatments for
Bartholin’s cyst or abscess concluded that current
randomised trial evidence did not support a particular
treatment, but it did recommend use of balloon catheter over
marsupialisation because it has a low recurrence rate and can
be inserted easily under local anaesthesia.7
Management in the outpatient setting

Outpatient management is a good option when there are
reduced theatre services due to bed pressures in winter.
Outpatient management also reduces the risk of contracting
hospital acquired infections. The acute gynaecology unit
should be equipped to allow this procedure, and trainees
should be able to carry it out independently.
Figure 2. Silicone catheter and syringe. Photograph provided by
Conservative management Medical Photography department at Queens Hospital, Barking and
Conservative management of symptomatic cysts or abscesses Havering NHS Trust.
may include sitz baths, compresses, analgesics and antibiotics
when appropriate. Antibiotics can be given if the patient is (12% at 12 months) and is well tolerated. Disadvantages are
pyrexial with or without cellulitis and if there is a risk of a that there is a 23% risk of premature expulsion, insertion can
sexually transmitted infection.2 If the cyst or abscess does not be painful, and it is contraindicated in patients with a
improve with such measures, then surgical options should latex allergy.2,4
be considered. The cyst/abscess and surrounding area should be cleaned
with a suitable cleaning solution and the area infiltrated with
Outpatient surgical management 5-10 ml of 1% lignocaine. A 5-mm stab incision can be made
A balloon Word catheter (Figure 1 and 2) or ‘Jacobi’ ring with a blade on the mucosal surface of the abscess or cyst.
catheter prevents reclosure of the wound and induces a The cyst/abscess should be drained and swabbed to
reaction leading to the formation of an epithelised fistula. determine the organism. A swab stick can be used to clean
They are both inexpensive and result in fewer complications the cavity and break locules, and the balloon catheter
with low recurrence rates. inserted. The balloon can be inflated with 2–3 ml of
normal saline with the provided syringe and needle
Balloon Word catheter (Figure 3) and end placed in the vagina. A suture can be
This is a 5-cm silicon-based uninflated tube with a maximum applied to prevent the balloon from falling out if it
3-ml inflation capacity. It is cheap, has a low recurrence rate appears loose.

Management of Bartholin’s cyst and abscess
differences in recurrence rates were observed. However,

reported patient satisfaction was better with the Jacobi ring.
In this procedure, an incision is made into the mucosal
surface of the abscess, which is then drained. A Kelly’s forcep
is inserted into the incision into the abscess/cyst cavity, where
a second incision is made. The Kelly’s forcep is then used to
grasp one end of a 7-cm 8 French T-tube or 5 cm tubing
from a butterfly venipuncture set with an absorbable suture
in the lumen through the cavity. Both ends of the suture are
tied forming a ring (Figures 3 and 4). Unlike the balloon
catheter, it does not risk premature expulsion and can be left
in place for 4–6 weeks. It is removed by cutting the suture
and removing the tube.3,8
Use of the Jacobi ring catheter has a low recurrence rate
(4% in 12 months), is inexpensive, presents no risk of
premature expulsion, and is an easy procedure to perform.
However, it requires two incisions and can be painful.9
Figure 3. Jacobi ring catheter. Ring made from the tubing of a
butterfly venipuncture set. Photograph of Jacobi ring provided by Sclerotherapy
Medical Photography department at Queens Hospital, Barking and Alcohol or silver nitrate can also be used to chemically
Havering NHS Trust.
destruct the epithelial lining of a Bartholin’s duct cyst or
abscess; however, this is not common practice in the UK.3,8
The catheter remains in place for 4–6 weeks until the tract is In alcohol sclerotherapy, an 18- to 20-gauge needle is
re-epithelialised; a minimum of 4 weeks is recommended for a inserted into the cyst at the point of maximal fluctuation and
good result. A 4-week follow-up appointment should be the contents are aspirated. Alcohol (70%) is injected into the
organised for balloon removal (though in some instances it cyst and left for 5 minutes, then re-aspirated. This procedure
may fall out before this). If the patient has significant pain at the heals within a week and causes less tissue damage than silver
site, removing 1 ml fluid to deflate the balloon may improve nitrate sclerotherapy.3 However, recurrence occurs in 8–10%
their symptoms.2,3 The patient should be provided with leaflets within 6–7 months, and there is a risk of tissue necrosis,
and contact details of the emergency gynaecology unit. haematoma and dyspareunia associated with destruction of
the gland surface.3,7
Ring catheter or Jacobi ring In silver nitrate sclerotherapy,3,5 the area is infiltrated with
This is an uncommon procedure in the UK, but may be local anaesthetic and the contents drained. A 5-mm-diameter
useful in a resource-poor setting. In a randomised study,8 silver nitrate stick is inserted into the cavity with a suture
Word catheter and the Jacobi ring were compared, and no applied at the site to maintain the position of the stick in the
Figure 4. Insertion of Jacobi ring catheter. Two incisions are made on the cyst, the tube is inserted and pulled out with an Allis forceps and
the suture then tied. Illustration of Ring catheter insertion provided by Mr S Naqvi.

Figure 5. Illustration of marsupialisation. A superficial incision is made over the most fluctuant part of the cyst and the mucosa separated
exposing the cyst wall. An incision is made along the cyst and the contents drained. The cyst wall and mucosa can be sutured with interrupted
absorbable sutures around the gland opening. Illustration provided by Miss M Sharma.
cavity. The stick is removed after 3 days and should have Inpatient/day-case surgical management
necrotised tissue attached.
This procedure is quick to perform, equipment is easy to Marsupialisation
source, and it has a 2-week healing time.1,3 However, This procedure should be done under general anaesthesia
scarring, chemical burns, labial oedema and pain can occur, because it can be uncomfortable for the patient. The operator
and the recurrence rate is 3.8% at 2 months.1,3 requires a sterile environment with appropriate lighting. It is
recommended for the treatment of recurrent cysts and
Needle aspiration abscesses. In a sterile setting, an incision is made along the
Needle aspiration is a simple procedure but has a 13% entire length of the cyst on the mucosal surface. Small
recurrence rate and is not recommended in current practice.13 incisions are better avoided, as the opening will shrink by

Management of Bartholin’s cyst and abscess
50% while healing, thereby increasing the risk of recurrence. for retraction, which allows dissection and identification of
Once the cyst is opened, it can be drained and irrigated with the blood supply. After removal of the gland, the dead space
saline.3,4 Locules in the cavity can be broken using an Allis should be closed with absorbable sutures and a small drain
forcep or small blunt curettage. If there is bleeding, it can be can be placed to prevent haematoma formation.12
packed with ribbon gauze. The cyst wall and mucosa can be
sutured with interrupted absorbable sutures (2.0 or 3.0
Conclusion
Vicryl) all around the gland opening (Figure 5).
This procedure has low recurrence rates (0% at 6 months Bartholin’s duct abscess or cyst is a common condition that
and 10% at 12 months) and high patient satisfaction.5 presents in acute gynaecology and can be managed in the
However, there is a risk of secondary infection and scarring, outpatient setting with the use of a balloon Word catheter.
and risks associated with general anaesthesia. It is also more This is less painful, has a low recurrence rate, and allows
expensive and healing is prolonged. patients early resumption of sexual activity. Marsupialisation
in theatre should be reserved for recurrent cases and for
women who are unable to tolerate balloon catheter insertion.
Postprocedure care
Women need to be aware of risks and complications of both
Patients are advised to: procedures and have written information provided.12
Keep the perineum clean and dry
Wear and change sanitary towels regularly Disclosure of interests
Use simple analgesia, such as paracetamol, or NSAIDs such There are no conflicts of interest.
as ibuprofen, for pain relief
Avoid intercourse for 5 days if marsupialisation is Contribution to authorship
undertaken (but intercourse is fine if a balloon catheter MS instigated and edited the article. ABP researched and
is in place) wrote the article. Both authors approved the final version.
Wear loose fitting clothing and underwear.
Patients should be provided with information leaflets and
Acknowledgements
contact details of the emergency gynaecology unit.
Many thanks to Queen’s Hospital Medical Photography
department for providing us with photos of the equipment,
Cancer risk and to Mr S. Naqvi and Mr Y. Shivkar who provided us with
The risk of malignancy in the Bartholin’s gland is rare and sketches of the procedure.
makes up 5% of vulval cancers. The commonest type of
carcinoma found is squamous cell carcinoma associated with
References
human papillomavirus type 16, and adenocarcinoma. This is
commoner in women over the age of 40 and can present as a 1 Lee MY, Dalpiaz A, Schwamb R, Miao Y, Waltzer W, Khan A. Clinical
pathology of Bartholin’s glands: a review of the literature. Curr Urol
firm, fixed or irregularly shaped swelling. In these patients,
2015;8:22–5.
biopsy with or without excision is recommended.10 Early 2 Omole F, Simmons BJ, Hacker Y. Management of Bartholin’s duct cyst and
recognition of this condition is important because of the risk gland abscess. Am Fam Physician 2003;68:135–40.
3 Omole F, Kelsey RC, Phillips K, Cunningham K. Bartholin duct cyst and
of local invasion and metastasis.1,3
gland abscess: office management. Am Fam Physician 2019;99:760–6.
4 National Institute for Health and Care Excellence (NICE). Balloon catheter
insertion for the Bartholin’s cyst or abscess. Interventional procedures
Recurrent Bartholin’s cyst guidance [IPG323]. London: NICE; 2009 [https://www.nice.org.uk/guidance/
ipg323].
Excision of the gland can be considered under general 5 Kroese JA, van der Velde M, Morssink LP, Zafarmand MH, Geomini P, van
anaesthesia in cases that reoccur despite marsupialisation or Kesteren P, et al. Word catheter and marsupialisation in women with a cyst
or abscess of the Bartholin gland (WoMan-trial): a randomised clinical trial.
Word catheter. There is a high chance of blood loss due to the
BJOG 2017;124:243–9.
blood supply from the pudendal artery and the overlying 6 Reif P, Ulrich D, Bjelic-Radisic V, H€ausler M, Schnedl-Lamprecht E, Tamussino
venous plexus of the vestibular bulb. Postoperatively, there is a K. Management of Bartholin’s cyst and abscess using the Word catheter:
implementation, recurrence rates and costs. Eur J Obstet Gynecol Reprod
risk of haematoma formation, cellulitis and dyspareunia.1,3,12
Biol 2015;190:81–4.
Excision of the cyst involves using Allis clamps to retract 7 Illingworth B, Stocking K, Showell M, Kirk E, Duffy J. Evaluation of
the labia and an incision is made on the vaginal mucosa treatments for Bartholin’s cyst or abscess: a systematic review. BJOG
2020;127:671–8.
above the gland. Retracting the mucosa exposes the gland
8 Gennis P, Li SF, Provataris J. Randomized pilot study comparing a rubber ring
and a small scissor can be used to separate the cyst wall from catheter to the word catheter in the treatment of Bartholin abscesses. Acad
the vaginal mucosa. Forceps can be applied to the cyst wall Emerg Med 2004;11:527.

9 Gennis P, Li SF, Provataris J, Shahabuddin S, Schachtel A, Lee E, et al. Jacobi 11 Speck NM, Boechat KP, Santos GM, Ribalta JCL. Treatment of Bartholin
ring catheter treatment of Bartholin’s abscesses. Am J Emerg Med gland cyst with CO2 laser. Einstein (Sao Paulo) 2016;14:25–9.
2005;23:414–5. 12 Lopes T, Spirtos N, Naik R, Monaghan J. Bonney’s Gynaecological surgery.
10 Huvila J, Blake Gilks C. Vulva, vagina and female urethra. Other 11th edition. Wiley-Blackwell; 2011.
carcinomas. Bartholin gland carcinoma. Bingham Farms: Pathology 13 Wechter ME, Wu JM, Marzano D, Haefner H. Management of Bartholin
Outlines; 2020 [https://www.pathologyoutlines.com/topic/ duct cysts and abscesses: a systematic review. Obstet Gynecol Surv
vulvabartholinglandcarc.html]. 2009;64:395–404.

DOI: 10.1111/tog.12858 2023;25:78–81
CPD
CPD questions for volume 25 issue 1
CPD credits can be claimed for the following questions With regard to strategies aimed at reducing the incidence
online via the TOG CPD submission system in the RCOG of term breech presentation,
CPD ePortfolio. You must be a registered CPD participant of
10. moxibustion involves the burning of dried
the RCOG CPD programme (available in the UK and
Mugwort over an acupuncture point on the
worldwide) in order to submit your answers.
great toe. ThFh
Completion of TOG true/false questions can be claimed as a
11. the number needed to treat for routine 36-
Specific Learning Event. Participants can claim two credits per
week ultrasound scanning in the prevention of
set of questions if at least 70% of questions have been answered
undiagnosed term breech is 40. ThFh
correctly. CPD participants are advised to consider whether the
articles are still relevant for their CPD, in particular if there are Physiological breech birth,
more recent articles on the same topic available and if clinical
12. is associated with a statistically significant
guidelines have been updated since publication.
reduction in perineal injury. ThFh
Please direct all questions or problems to the CPD Office.
13. requires prompt intervention at any stage
Tel: +44 (0)20 7772 6307 or email: cpd@rcog.org.uk.
should there be a delay of 90 seconds. ThFh
The blue symbol denotes which source the questions refer to
including the RCOG journals, TOG and BJOG, and RCOG Women planning vaginal breech birth at term should be
guidance, such as Green-top Guidelines (GTGs) and Scientific informed that,
Impact Papers (SIPs). All of the above sources are available to
RCOG Members and Fellows via the RCOG website. RCOG 14. RCOG guidance advises against vaginal breech
Members, Fellows and Associates have full access to TOG content birth in fetuses with an estimated fetal weight
via the Wiley Online Library app (available for iOS and Android). <10th centile. ThFh
15. pelvimetry is a recommended investigation. ThFh
16. an estimated fetal weight of >4 kg is associated
TOG Management of term breech
with a greater risk of failure. ThFh
presentation
Regarding intrapartum care for women planning vaginal
Risk factors for breech presentation at term include,
birth with a breech-presenting fetus,
1. Caucasian ethnicity. ThFh
17. the fetal torso most commonly delivers in a
2. low body mass index. ThFh
sacro-anterior position. ThFh
3. oligohydramnios. ThFh
18. use of a fetal electrode for continuous
4. bicornuate uterus. ThFh
fetal heart rate monitoring is
5. multiparity. ThFh
not contraindicated. ThFh
With regard to external cephalic version, 19. epidural analgesia is contraindicated. ThFh
20. where the use of forceps is required for the
6. pre-procedure tocolysis has not been shown to
aftercoming head, Wrigley’s forceps are
increase success rate. ThFh
preferable to Neville-Barnes or
7. performing at 35/40 has been shown to be
Kiellands forceps. ThFh
associated with higher rates of cephalic
presentation at delivery when compared with
performing at term. ThFh TOG Valvular heart disease in pregnancy
8. routine post-procedural Kleihauer testing is
With regard to cardiac disease in pregnancy,
advised in Rhesus D negative women. ThFh
9. the likelihood of reversion to breech 1. women with a root dilatation classified as
presentation following successful external WHO III are actively counselled
cephalic version is around 3%. ThFh against pregnancy. ThFh

CPD
2. Marfan syndrome is the most common cause of Concerning labour,

aortic root dilatation in women of child-
20. ergometrine should be avoided for the
bearing age. ThFh
management of the third stage of labour in
3. atenolol is the beta-blocker of choice for the
women with arrhythmia. ThFh
treatment of pulmonary hypertension. ThFh
4. the risk of fetal cardiac defects in those with
left-ventricular outflow tract pathology is TOG Pitfalls of prenatal diagnosis associated
approximately 10%. ThFh with mosaicism
With regard to aortic stenosis,
Reasons for a false positive noninvasive prenatal testing
5. it is the most common cause of left ventricular (NIPT) result include,
outflow tract obstruction. ThFh
1. raised maternal body mass index. ThFh
6. an increase in the echocardiographic gradient
2. maternal malignancy. ThFh
across the aortic valve in women with this
3. vanishing twin. ThFh
pathology is suggestive of narrowing of
4. early gestational age of sample. ThFh
the valve. ThFh
5. fetal placental mosaicism. ThFh
7. Rheumatic fever is the most common cause in
women of child-bearing age. ThFh Regarding first trimester screening,
Regarding mitral stenosis in pregnancy, 6. a high risk result is deemed as being >1:200. ThFh
8. the overall mortality is ~10%. ThFh 7. true fetal mosaicism is the most common type
9. up to 30% of infants born to affected mothers of mosaicism. ThFh
are delivered preterm. ThFh Regarding confined placental mosaicism,
With regard to heart valve disease, 8. it occurs in >10% of chorionic villous sample. ThFh
10. anticoagulation throughout pregnancy is 9. type 1 is associated with a false negative
recommended for those who have undergone NIPT result. ThFh
replacement surgery. ThFh 10. it is associated with an increased risk of fetal
11. regurgitant disease is better tolerated in growth restriction. ThFh
pregnancy than stenotic disease. ThFh Regarding true fetal mosaicism,
12. intrapartum antibiotic prophylaxis against
infective endocarditis is recommended for 11. type 5 is associated with a false negative
women with prosthetic valves. ThFh NIPT result. ThFh
13. surgery in pregnancy is associated with a fetal When analysing a chorionic villous sample,
mortality of up to 30%. ThFh
12. cytotrophoblast is typically more
Regarding anticoagulation and valvular heart disease
representative of the fetal karyotype than
in pregnancy,
the mesenchyme. ThFh
14. it is recommended that 24 hours elapse between
Regarding NIPT screening,
the last dose of therapeutic anticoagulation and
the siting of regional analgesia. ThFh 13. its specificity for T13, T18 and T21 is >99%. ThFh
15. breastfeeding is safe for women on warfarin. ThFh 14. the risk of mosaicism for Monosomy X in a
16. for those on warfarin in the third trimester, it is chorionic villous sample following a high-risk
advised that this is stopped 48 hours prior to test result is >50%. ThFh
delivery, otherwise a caesarean section is indicated. ThFh 15. the risk of mosaicism for Trisomy 21 in a
17. newer, direct oral anticoagulants are an option chorionic villous sample after a high-risk test
for women with mechanical valves postnatally, result is >10%. ThFh
providing they are not breastfeeding. ThFh 16. in the case of an abnormal test result suggestive
18. facial cleft is the predominant abnormality of Trisomy 21, if there are no identifiable
associated with warfarin embryopathy. ThFh structural fetal anomalies, chorionic villous
19. it is recommended that women with sampling is an appropriate next step. ThFh
mechanical heart valves take low-molecular- 17. inadequate fetal fraction (<4%) is associated
weight heparin twice daily. ThFh with an increased risk of Trisomy 13 and 18. ThFh

CPD
18. QF-PCR suggestive of a biallelic trisomy in the 16. the efficacy of continuous combined oral
absence of structural fetal abnormality on contraceptives (COCs) is similar to that of
ultrasound is sufficient to be acted upon. ThFh cyclical COCs. ThFh
19. if a structural fetal anomaly is identified and 17. dutasteride reduces luteal phase increase in
the QF-PCR analysis from amniocentesis or allopregnanolone levels. ThFh
chorionic villous sampling is normal, a 18. there are no trials on the benefit of exposure to
chromosomal microarray should sunlight as a treatment option. ThFh
be conducted. ThFh
With regard to investigations for premenstrual disorders,
20. sex chromosome aneuploidies are screened for
in the NHS Fetal Anomaly Screening first 19. a prospective recording of symptoms over 2
trimester screening programme. ThFh cycles using a symptom diary is essential. ThFh
20. demonstrating fluctuations in progesterone
levels during the menstrual cycle supports
TOGPremenstrual disorders including
the diagnosis. ThFh
premenstrual syndrome and premenstrual
dysphoric disorder
TOG Human papillomavirus-independent
With regard to premenstrual disorders,
cervical cancer and its precursor lesions
1. they are reported to also occur in women
With regard to cervical cancers,
after menopause. ThFh
2. they include cyclical symptoms which worsen 1. the WHO 2020 classification is based on HPV
just after menstruation. ThFh association rather than
3. a recent survey suggest that about 30% of women morphological appearance ThFh
with PMDD have had at least one suicidal attempt. T h F h 2. there is strong evidence of an HPV-
independent squamous cell cervical
Considering PMS/PMDD pathophysiology,
precursor lesion. ThFh
4. progesterone increases serotonin levels by 3. there is strong evidence of an HPV-
decreasing MAO activity. ThFh independent gastric-type cervical
5. allopregnanolone causes negative mood effect precursor lesion. ThFh
by action on GABA receptors. ThFh 4. the HPV-independent type presents in the older
age group compared with the HPV-
With regard to diagnosing PMS/PMDD,
associated type. ThFh
6. there is no relation of symptoms to the luteal 5. the prognosis of both the HPV-independent
phase of the menstrual cycle. ThFh and HPV-associated types is the same. ThFh
7. a symptom-free period after ovulation is a
Regarding the aetiopathogenesis of cervical cancer,
diagnostic criterion. ThFh
8. DSM-5 defines the diagnostic criteria for PMDD. ThFh 6. worldwide approximately 0.5–1.1% are
9. GnRH analogues have both diagnostic and HPV negative. ThFh
therapeutic roles. ThFh 7. both the HPV-independent and HPV-
10. it is a diagnosis of exclusion after other associated types have identical clinical course
underlying medical and psychiatric illnesses and presentation. ThFh
have been ruled out. ThFh 8. the presence of ‘red-flag symptoms’ (such as
11. failure after 3 months’ treatment with GnRHa profuse watery mucoid cervicovaginal
to alleviate symptoms rules out the diagnosis discharge, abnormal uterine bleeding and
in most cases. ThFh abdominal pain, a bulky cervix on
examination) is an indication for a thorough
Regarding the management of PMS/ PMDD,
assessment to rule out an HPV-
12. cognitive behavioural therapy has no role. ThFh independent disease. ThFh
13. continuous SSRIs have a better side effect
Regarding gastric-type adenocarcinoma of the cervix,
profile compared to luteal phase SSRIs. ThFh
14. progesterone-only pills reduce the symptoms. ThFh 9. it is the most common subtype of HPV-
15. hysterectomy with removal of both ovaries independent cervical cancer. ThFh
offers a permanent cure. ThFh 10. it is typically situated in the lower endocervix. ThFh

CPD
11. patients with Peutz-Jeghers syndrome are at 6. anaesthesia (general and regional) increases risk
an increased risk of lobular endocervical of VTE by causing venous stasis due to
glandular hyperplasia. ThFh inadequate pumping of blood by the
12. clinical manifestations include watery vaginal calf muscles. ThFh
discharge, abnormal uterine bleeding and 7. the incidence of VTE is lowest with the
abdominal pain. ThFh laparoscopic route. ThFh
13. the ‘cosmos pattern’ is pathognomonic. ThFh 8. increasing surgical complexity increases the risk
14. unlike HPV-associated cervical factor of VTE. ThFh
adenocarcinoma, it is usually negative or
With regard to combined hormonal contraception (CHC)
exhibits mosaic (patchy, non-block pattern)
and hormone replacement therapy,
immunoreactivity with p16. ThFh
15. prognosis is strongly influenced by grade of 9. first generation progestogens like
the disease. ThFh norethisterone pose a greater risk of VTE
16. most cases (>70%) show aberrant mutation- compared to third generations like desogestrel. ThFh
type p53 staining. ThFh 10. the risk of VTE is lower with transdermal than
Regarding lobular endocervical glandular hyperplasia, with oral preparations. ThFh
11. the British National Formulary recommends
17. it is considered a benign condition. ThFh restarting CHC after a minimum of 2 weeks
18. malignant transformation occurs in following surgery subsequent to regaining
approximately 2–5% of cases. ThFh full mobility. ThFh
19. if it is diagnosed on a loop excision or cone biopsy 12. estradiol has a lower risk of VTE than
of cervix, a completion hysterectomy should be conjugated equine estrogen hormone
considered if fertility is no longer desired. ThFh replacement therapy. ThFh
20. the five-year survival is approximately 100%. ThFh
Regarding thromboprophylactic measures,
TOG Thromboprophylaxis in gynaecology: a 13. compression stockings work by exerting

review of current evidence greater pressure at the ankle and lower
pressures at the calf. ThFh
Regarding venous thromboembolism (VTE) in 14. in the UK, low-molecular-weight heparin is
early pregnancy, the agent of choice for thromboprophylaxis. ThFh
1. it was the second most common cause of 15. dose adjustment of unfractionated heparin
maternal death in 2015–2017 as reported in the is recommended for patients with renal
2019 MBRRACE-UK report. ThFh failure. ThFh
2. the risk is increased from as early as 16. specific reversal agents are not available for
5 weeks’ gestation. ThFh direct oral anticoagulants. ThFh
Regarding thromboprophylaxis in early pregnancy, Regarding complications of VTE and prophylaxis,
3. it is advisable for women with hyperemesis to 17. post-thrombotic syndrome is uncommon. ThFh
continue low-molecular-weight heparin for the 18. complex gynaecological surgeries are
duration of pregnancy. ThFh considered at risk for the development of well
4. there is a paucity of evidence to make leg compartment syndrome. ThFh
recommendations for women undergoing 19. mechanical thromboprophylaxis has been
surgical management of miscarriage. ThFh proven to cause well leg compartment
syndrome in the lithotomy position. ThFh
Concerning surgery,
20. measures suggested to reduce well leg
5. increased operating time is a recognised risk compartment syndrome include periodic
factor for VTE. ThFh lowering of the legs to horizontal position. ThFh

DOI: 10.1111/tog.12853 2023;25:82–4
MBRRACE-UK update
Key messages from the UK and Ireland Confidential

Enquiries into Maternal Death and Morbidity 2022
The latest report from the UK and Ireland Confidential Psychiatric disorders and cardiovascular disorders are now
Enquiries into Maternal Deaths and morbidity, the ninth in responsible for the same number of maternal deaths in the
the now annual report format, includes surveillance and UK; together these two causes represent 30% of maternal
Confidential Enquiries covering the period 2018–2020.1 The deaths. During 2020, maternal mortality directly attributable
report also includes reviews into the care of women who died to COVID-19 was at a rate comparable with that due to
during or after pregnancy in the Republic of Ireland as well as psychiatric and cardiovascular disorders.
the UK. Following the annual topic-specific format, this There was a statistically significant increase in maternal
report includes topic-specific reviews into the care of women death rates from direct causes between 2015–17 and 2018–20.
who died from cardiovascular causes, hypertensive disorders Thrombosis and thromboembolism remains the leading
and early pregnancy disorders and the care of women who cause of direct maternal death during or up to 6 weeks
died from mental health-related causes and accidents in 2020. after the end of pregnancy. Deaths from mental health-
The report also includes a Morbidity Confidential Enquiry related causes as a whole (suicide and substance abuse)
into the care of women with diabetic ketoacidosis in account for nearly 40% of deaths occurring within a year
pregnancy. Messages for improving the care of women with after the end of pregnancy, with maternal suicide remaining
hypertensive disorders were also identified from reviews of the leading cause of direct deaths in this period.
babies who died or had brain injury conducted by the
Healthcare Safety Investigation Branch (HSIB).
Key messages for care
Care of women with mental health problems and
Key facts and figures
multiple adversity
There was a statistically non-significant increase in the overall Mental ill health remains one of the leading causes of
maternal death rate in the UK between 2015–17 and 2018–20 maternal death in pregnancy and the first postnatal year.
(risk ratio [RR] 1.19, 95% confidence interval [CI] 0.98– Reviews of the care of women who died from mental health-
1.44), which is now 10.90 per 100 000 maternities (95% CI related causes in 2020 were expedited for inclusion in the
9.53–12.40). 2022 report. There has been a statistically significant increase
Nine of the deaths which occurred between March and in the rate of suicide during pregnancy and up to six weeks
December 2020 were directly attributable to COVID-19 after pregnancy in the UK, comparing 2017–19 with 2020
infection. If these nine deaths are excluded, the maternal (0.46 per 100 000 in 2017–19 compared with 1.48 per 100 000
mortality rate for 2018–20 would be 10.47 (95% CI 9.13–11.95). in 2020; RR 3.22, 95% CI 1.20–8.63, p = 0.012). Of particular
There remains a close to four-fold difference in maternal concern is a further increase in teenage suicides.
mortality rates among women from Black ethnic At least half of the women who died by suicide and the majority
backgrounds and an almost two-fold difference among of women who died from substance misuse had multiple
women from Asian ethnic backgrounds compared with adversity. Many of the younger women who died were care
white women. Women who live in the 20% most deprived leavers. Presentations could be complex with mental illness,
areas have two-and-a-half times the maternal mortality rate substance misuse and physical health symptoms, such as chronic
of women who live in the 20% most affluent areas. pain. There were several instances where services did not become
Eleven percent of the women who died during or up to a involved soon enough during pregnancy. Earlier involvement
year after pregnancy in the UK in 2018–20 were at severe and may have given more time to develop a therapeutic
multiple disadvantage. The main elements of multiple professional relationship.
disadvantage were a mental health diagnosis, substance use A history of childhood and/or adult trauma were very
and domestic abuse. frequent. It is important that all services recognise the

MBRRACE-UK update
importance of a trauma history. Specialist Perinatal Mental sudden intrauterine death in pregnancy, especially after
Health Teams should be involved where there is a significant 36 weeks, and women should therefore be advised about
history of involvement with secondary mental health services highly effective contraception pre-pregnancy until their
or risk, particularly if it is a woman’s first pregnancy. control is as good as possible.
Several women had unusually severe insomnia, despite Women with diabetes should receive the same advice
medical intervention to address this. Sleep disturbance is very about awareness of fetal movements as all other women, and
common in relation to mental illness and a broader range of this should be discussed at every visit.
psychological difficulties. However, in these women the DKA was precipitated in several women by steroid
severity of insomnia was very marked and persisted despite administration. Antenatal corticosteroids reduce admission
the use of hypnotic medication. Severe sleep disturbance to the neonatal unit for babies born before 36+6 weeks’
should lead clinicians to consider further assessment for gestation. From 37+0 to 38+6 weeks, they may not reduce
underlying severe mental illness. admission and they may cause harm including
A pattern of multiple adversity remained extremely hypoglycaemia and potential developmental delay to a
common in women who died through suicide, substance neonate. Given that pregnant women with diabetes will
misuse, homicide and accidental death. The importance of require extra insulin when receiving antenatal steroids, the
thorough, over-arching assessments which do not simply risk of neonatal hypoglycaemia and DKA in the mother,
consider the woman’s presentation ‘in the moment’ are as antenatal steroids should only be given after 36+6 weeks after
important in these women as they are in women with a full discussion of the risks and benefits.
psychosis who may not have such a background history.
Professional sensitive enquiry about underlying factors such Lessons on cardiovascular care
as substance misuse and domestic abuse remains an Six of the women who eventually died from myocardial
important part of the risk assessment and clinicians need to causes had complained about cough, wheeze and/or
be mindful as to reasons why such information may not shortness of breath. Two further women were treated for
be disclosed. suspected lower respiratory tract infection. Wheeze can be a
manifestation of pulmonary oedema. Consider wheeze which
Caring for women with diabetic ketoacidosis does not respond to standard asthma management and
Many women with diabetic ketoacidosis (DKA) had multiple, exertional syncope as red flag symptoms of cardiovascular
complex and interacting medical and social conditions. disease in addition to orthopnoea and chest pain.
Several women were so complex that their care teams There were several women with a persistent tachycardia
clearly felt overwhelmed. There were many occasions when which was not investigated. Palpitations are common in
women fell through the gaps, impacting on aspects of pregnancy; while they are frequently benign, some will
diabetes care as well as care for their other morbidities. represent a significant arrhythmia. Pregnant women
Women with complex problems should be identified early in presenting with palpitations require a careful assessment to
pregnancy and need a multidisciplinary team approach that determine whether their symptoms can be attributed to
can respond to changes through pregnancy, birth and normal physiology or require further investigation
postpartum and plan for (or avoid with adequate for pathology.
contraception) the next pregnancy. Several women presented repeatedly before the diagnosis
A number of women were admitted with DKA that was of cardiac disease was made. The common symptoms
not promptly recognised or treated appropriately, which associated with ischemic heart disease can develop over a
contributed to poor fetal and neonatal outcomes. DKA in short time frame and necessitate immediate attention.
pregnancy is associated with a high maternal and perinatal Women with young babies and other children do not have
death rate and should be treated as an obstetric emergency time to present repeatedly to the emergency department
and requires a multidisciplinary approach. DKA can occur unless there is something wrong. A repeat presentation
with lower glucose levels in the presence of raised ketones. should prompt senior, multidisciplinary review.
Pregnant women with diabetes who present with signs and
symptoms associated with DKA should have DKA excluded, Prevention and treatment of hypertensive disorders
noting that occasionally DKA may be the first presentation of Despite the knowledge that low-dose aspirin (75–150 mg)
diabetes in pregnancy. reduces the risk of pre-eclampsia having been widespread for
Several women with pre-existing diabetes became pregnant many years, a number of women were not receiving low-dose
with a raised HbA1c at booking and later went on to have aspirin or received it later in pregnancy than advised. A
sudden intrauterine deaths in the third trimester. All medical national Patient Group Direction was released in February
staff should be aware that both a raised HbA1c at booking 2022, and it is now essential that this is widely implemented.
and poor glucose control in pregnancy increase the risk of This will enable both midwives and pharmacists to prescribe

MBRRACE-UK update
aspirin for pregnant women with recognised risk factors and Assessment with Sonography for Trauma (FAST) scan should
hence ensure all women can access aspirin as early as possible be carried out before thrombolysis in all women of
to benefit from its preventive effect. reproductive age. All collapsed or shocked pregnant women
Several compromised babies were born after prolonged do not have a pulmonary embolism. Treatment should not
induction of labour. Staff did not recognise the prolonged be given until a FAST scan has excluded intra-abdominal
induction of labour as a change in the mothers’ risk status. pathology or bleeding.
Bedside reviews by the obstetric teams did not occur until
multiple cycles of prostaglandin had been given over several
Conclusions
days. Earlier input from the multidisciplinary team to
facilitate communication with the mothers about their This report included the surveillance information for women
preferences with broader insight into their cumulative risk who died during and after pregnancy for 2018–20, which
factors may have led to different care pathways. included the first year of the COVID-19 pandemic, when
Co-existence of diabetes and pre-eclampsia adds there were many service-related changes. The clearest impact
complexity to women’s management because requirements on maternal mortality rates has been an increase in mental
for management of the two conditions may be conflicting. health-related deaths, principally women who have died by
Similarly, the tendency of diabetes to lead to larger babies and suicide. Assessors identified important messages concerning
that of hypertensive disorders of pregnancy to lead to smaller the care of women with multiple adversity and multiple
babies, in combination, may lead to a baby being born on a morbidities, who were once again over-represented. Impacts
birth centile within the expected range who has unrecognised of pandemic-related service changes were noted in several
fetal growth restriction. This may impact on the baby’s ability women who died from conditions other than COVID-19.
to cope with the demands of labour and on the accuracy of The majority of women who died from COVID-19 in 2020
the clinical team’s intrapartum risk assessment. It is were from ethnic minority groups, however the disparity in
important to be aware that it is not only babies predicted maternal mortality rates between women from Black, Asian
to be small for gestational age who may be at risk of and Mixed ethnic groups and white women has continued to
compromise during labour when a woman’s pregnancy is decrease slightly. Nevertheless, the maternal mortality rate
complicated by both hypertension and diabetes. amongst women who live in the most deprived areas is
increasing and addressing these disparities must remain an
Lessons on caring for women with early pregnancy important focus.
disorders
Vulnerable and young women remain disproportionately Marian Knight MA DPhil FFPH FRCP Edin FRCOG FMedSci
represented among those who died from ectopic pregnancy. MBRRACE-UK Maternal Programme Lead, NIHR Professor of Maternal
They need additional safety measures incorporated into their and Child Population Health, National Perinatal Epidemiology Unit,
Nuffield Department of Population Health, University of Oxford, Old Rd
care, for example, enhanced follow-up pathways. Each Campus, Oxford, OX3 7LF, UK
contact with girls or women of childbearing age following Email: marian.knight@npeu.ox.ac.uk
miscarriage, prescribing contraception, at sexually
transmitted infection screening and at smear tests is an
opportunity to educate regarding red flag symptoms Reference
associated with ectopic pregnancy. The awareness of 1 Knight M, Bunch K, Patel R, Shakespeare J, Kotnis R, Kenyon S, Kurinczuk JJ
symptoms may reduce deaths amongst vulnerable women (Eds.) on behalf of MBRRACE-UK. Saving Lives, Improving Mothers’ Care -
Lessons learned to inform maternity care from the UK and Ireland
and teenage girls. Confidential Enquiries into Maternal Deaths and Morbidity 2018-20. Oxford:
Three women died from ruptured ectopic pregnancies National Perinatal Epidemiology Unit, University of Oxford 2022. Available at:
after receiving thrombolysis. A pregnancy test and a Focussed www.npeu.ox.ac.uk/mbrrace-uk

DOI: 10.1111/tog.12854
2023;25:85
And finally. . .
Medicine and the media

James Drife MD FRCOG FRCPED FRCSEd FCOGSA FFSRH
Emeritus Professor of Obstetrics and Gynaecology, Leeds, UK
Every weekday morning my inbox pings with the RCOG Daily diagnosis now comes from the National Institute for Health
Press Monitoring. It’s circulated to the College’s team of media and Care Excellence (NICE), not the RCOG, and is a
spokespersons, of which I was once a member. Back in the BZ depressing example of bureaucratic obfuscation aimed at
(Before Zoom) era, we spent a lot of time dashing into TV and “stakeholders” but not the practitioner in the consulting
radio studios. It was stressful work and I mused about it in an room. Get a grip, NICE, and hire some marketing professionals.
early edition of TOG (2000;2:56). O&G was constantly on the
defensive, blamed for the rising caesarean section rate, doing
Writing to The Times
too many hysterectomies, medicalising the menopause and
failing to show enough enthusiasm for birth under water. If you’re looking for clearly expressed common sense, go to the
The landscape has changed since then. Today, the media’s letters page of The Times. It puts everything into perspective,
guns are trained on the NHS. The RCOG is respected for with wisdom in the top left-hand corner and wit in the bottom
setting the standards which the maternity services keep failing right. Last October, a retired obstetrician, John Davies-
to meet. Our Press Office is doing a good job but is still Humphreys of Chester, made the top spot with a succinct
under pressure. The President is expected to issue a statement summary of how the most experienced midwives were turned
whenever anyone complains about anything, and it has to into managers, setting the scene for our present troubles. I added
strike the right note – not an easy task when the media are a supporting letter because, like him, I believe the page is read by
looking for scapegoats. top politicians. I like to imagine them opening The Times while
being chauffeured to their photocalls, but I suspect that in reality
they’re on their mobiles reading tweets from their minders.
That’s infotainment
Do obstetricians feature in the bottom right-hand corner?
As I write, the latest email has arrived, highlighting today’s No, but their witty wives do. Suzie Marwood’s incisive
important issues. A former Made in Chelsea star has opened up comments are always a joy.
on Instagram about feeling anxious during her pregnancy.
Michele Obama (aged 58) has put on weight and blames it on the
The birth of IVF
menopause. MBRRACE-UK’s latest report has been issued,
showing a 19% rise in Britain’s maternal mortality rate. All these It’s good that we now have a better relationship with the press
summaries are listed in the same font and format, and I try to than in the bad old days when most College spokespersons were
guess which story – if any – has made the front page of the men. But go further back and things were much worse. Doctors
tabloids or gained lots of sympathetic emojis on social media. used to be taught that courting publicity was unethical, and
Today the women’s health agenda is driven partly by they avoided the media completely. I was reminded of this
activists and partly by press releases from universities and while proof-checking a book about landmark historical events
wellness gurus, all of whom employ marketing professionals. in the College’s old home in Sussex Place. In 1979 Steptoe and
But the most powerful driver is celebrity. The rich and Edwards gave their first lecture about successful IVF there, and
famous need little persuasion to “open up” with details of the forty years later we held a reminiscence meeting. The book,
journey they’ve shared with their reproductive organs. Presenting the First Test-Tube Baby, has transcripts of both.
Today’s lead feature in the quality papers is Jennifer One chapter is by Janice Barker, formerly a journalist at the
Aniston’s account of her unsuccessful IVF treatment. Oldham Chronicle. She describes how reporters besieged the
Telling the world about it has brought her inner peace. hospital, and Steptoe organised the caesarean section in
Specialists generally emerge with credit from such case secret. Their cat-and-mouse relationship would have today’s
histories, but GPs don’t. The papers regularly quote women public relations teams tearing their hair but the story had a
who have been devastated by the failure of their primary care happy ending for everyone – including Janice. She and her
physician to detect endometriosis. I’ve checked the current colleagues were named “Provincial Journalists of the Year”
guideline and I can sympathise with those doctors. Advice on for being first to break the news to the public.

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17444667, 2023, 1, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/tog.12810 by Cochrane Saudi Arabia, Wiley Online Library on [15/01/2023].

TOG The Obstetrician & Gynaecologist

ISSN 1467-2561/221–302 (online) onlinetog.org

ISSN 1467-2561/1744-4667 (online)

TOG_v25_i1_cover.indd 1 1/10/2023 4:33:40 PM

Volume 25 Issue 1 2023

Editorial 47 Human papillomavirus-independent cervical cancer and its

Tips and Techniques

38 Premenstrual disorders including premenstrual syndrome and

Subscription rates 2023

ª 2023 Royal College of Obstetricians and Gynaecologists. 3

Spotlight on. . . maternal medicine

4 ª 2023 Royal College of Obstetricians and Gynaecologists.

ª 2023 Royal College of Obstetricians and Gynaecologists. 5

Facilitating HIV testing in colposcopy clinics to improve

Accepted on 19 July 2022. Published online 10 December 2022

6 ª 2022 Royal College of Obstetricians and Gynaecologists.

ª 2022 Royal College of Obstetricians and Gynaecologists. 7

Management of term breech presentation

Djavid Alleemudder MBChB MRCS (Ed) MRCOG BScd

Accepted on 6 March 2022. Published online 24 November 2022

Key content  To understand the principles of physiological breech

a few women will continue to deliver breech babies vaginally.

8 ª 2022 Royal College of Obstetricians and Gynaecologists.

 Extended or frank breech accounts for two-thirds of all

Figure 3. Breech presentation: semi-ﬂexed/incomplete.

No discussion of breech birth in the modern era could

ª 2022 Royal College of Obstetricians and Gynaecologists. 9

Figure 4. Breech presentation: standing. Figure 6. Breech presentation: kneeling.

Box 1. Risk factors for breech presentation2–4

attitude and practice around the management of term breech

10 ª 2022 Royal College of Obstetricians and Gynaecologists.

differences in combined outcomes for fetal/neonatal

Box 2. Procedural criticisms of the Term Breech Trial (TBT)3,6–8

 A lack of adherence to inclusion criteria.

 Over-representation of macrosomia in the vaginal birth group.

 Signiﬁcant interinstitutional variance in standards of care.

 Relationship between mode of birth and cause of death.

 Deﬁnition and implications of ‘morbidity’.

ª 2022 Royal College of Obstetricians and Gynaecologists. 11

External cephalic version

Maternal factors Guideline Fetal factors Guideline

History of abruption NVOG Abnormal cardiotocography NVOG, RANZCOG, RCOG

Cardiac disease ACOG Major congenital anomaly ACOG, RANZCOG, RCOG

Obesity ACOG Hyperextension of the neck ACOG

Previous caesarean section ACOG Macrosomia (>4 kg) ACOG

Restrictive nuchal cord RANZCOG

12 ª 2022 Royal College of Obstetricians and Gynaecologists.

ª 2022 Royal College of Obstetricians and Gynaecologists. 13

supine positioning. A nonsignificant reduction in serious

Figure 7. Physiological breech algorithm41

14 ª 2022 Royal College of Obstetricians and Gynaecologists.

ª 2022 Royal College of Obstetricians and Gynaecologists. 15

16 ª 2022 Royal College of Obstetricians and Gynaecologists.

There is ample evidence that elective caesarean section is safer References

ª 2022 Royal College of Obstetricians and Gynaecologists. 17

18 ª 2022 Royal College of Obstetricians and Gynaecologists.

Valvular heart disease in pregnancy

Accepted on 15 June 2022.

interplay between severity of disease, prepregnancy

ª 2022 Royal College of Obstetricians and Gynaecologists. 19

20 ª 2022 Royal College of Obstetricians and Gynaecologists.

Class Risk of pregnancy Examples of conditions

Key content To understand the principles of physiological breech

Extended or frank breech accounts for two-thirds of all

A lack of adherence to inclusion criteria.

Over-representation of macrosomia in the vaginal birth group.

Signiﬁcant interinstitutional variance in standards of care.

Relationship between mode of birth and cause of death.

Deﬁnition and implications of ‘morbidity’.

Key content To appreciate underlying principles in NIPT and genomic testing

Relief of symptoms following the onset of menstruation

Key content There is a paucity of evidence-based guidelines tailored to