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The Obstetrician & Gynaecologist

The Obstetrician & Gynaecologist

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Volume 23 2021 1
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 TOG
The Obstetrician & Gynaecologist
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 23 Issue 1 2021

Contents

Editorial Education
3 Editorial 60 Developing situational awareness (‘helicopter view’)
Jo Morrison Wai Yoong, Sayantana Patra-Das, Neil Jeffers, Maud Nauta,
Wasim Lodhi

Editor’s Pick
CPD
4 Spotlight on… contraception
Nicola Mullin 67 CPD questions for volume 23 issue 1

Letters and emails

Commentary 72 Re: Laparoscopic cornual resection of interstitial pregnancy using
6 Bridging justice and health: reparations for conflict-related the Endo GIATM Universal Stapler
sexual violence Maximilian Brincat, Tom K Holland, Joel Naftalin, Davor Jurkovic
Sunneva Gilmore, Kieran McEvoy (includes authors’ reply)

Reviews 76 TOG ratings

9 Lynch syndrome for the gynaecologist
SBA
Neil AJ Ryan, Raymond FT McMahon, Neal C Ramchander,
Mourad W Seif, D Gareth Evans, Emma J Crosbie 78 UKOSS update
21 Raised CA125 – what we actually know…
SBA Tamara Howe, Nava Sokolovsky, Ahmad Sayasneh, Kazal Omar, And finally…
Farshad Tahmasebi 80 And now for something completely different
28 Does ovarian cystectomy pose a risk to ovarian reserve and James Drife
SBA fertility?
Neerujah Balachandren, Ephia Yasmin, Dimitrios Mavrelos,
Ertan Saridogan
38 Very advanced maternal age
SBA Alice Howell, Margaret Blott
48 Care in pregnancies subsequent to stillbirth or perinatal death
SBA Nicole Graham, Louise Stephens, Alexander EP Heazell
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The Obstetrician & Gynaecologist 10.1111/tog.12711 http://onlinetog.org Editorial

Editorial
I am delighted to deputise for Kate Harding and Graham et al. discuss care of women in pregnancies
welcome you to the January 2021 edition of The subsequent to a stillbirth or perinatal death. They focus Editorial Board
UK
Obstetrician & Gynaecologist (TOG). Writing this on a on the need to understand the cause of the previous Kate Harding FRCOG
drizzly November afternoon in second lockdown, pregnancy loss, especially if there are maternal, genetic Guy’s and St Thomas’ NHS Foundation
Trust, London (Editor-in-Chief)
looking forwards to 2021, it is difficult to know what to or placental causes. In addition, parents are likely to Jo Morrison BM BCh MA FRCOG DPhil (Oxon)
expect. None of us anticipated how different life would require significant psychological support, and the Musgrove Park Hospital, Taunton
(Deputy Editor-in-Chief)
be this time last year. Although it has been a year of authors emphasise the need for multidisciplinary care. George Attilakos MD MRCOG
many losses, it has also been one of discovering how This article has links with another on very advanced University College London Hospitals NHS
Foundation Trust, London
adaptive we are and how we can learn from maternal age. With advances in reproductive techniques, Shagaf Bakour MD FRCOG
City Hospital, Birmingham
current circumstances. these pregnancies are increasingly common, but come
Evelyn Ferguson
TOG is a quarterly journal, with articles proposed
MBChB MRCP DFFP MRCOG RCOG/RCR
with significant maternal and fetal risks which Howell Dip Adv Obs US PGCertMedEd
NHS Lanarkshire
many months in advance. As before, we have decided and Blott discuss and suggest an evidence-based
Kannamannadiar Jayaprakasan MBBS MD DNB MRCOG
not to focus on management of COVID-19 in management approach. PhD
Royal Derby Hospital, Derby
pregnancy, as it would be likely that any articles would Moving onto gynaecological topics, Balachandren
Swati Jha MD FRCOG
be out of date by the time of publication, with the et al. examine the effect of ovarian cystectomy on Sheffield Teaching Hospitals NHS Foundation Trust,
Sheffield
rapidly evolving evidence base. However, in these ovarian reserve and future fertility. They recommend
Justin Konje FMCOG (Nig) FWACS MRCOG
challenging times, this TOG edition focusses on other maintaining a holistic view of the patient and her University of Leicester, Leicester
(Lead CPD Editor)
difficult issues including conflict-related sexual violence, situation to guide decision-making, especially in Bid Kumar FRCOG
death of mothers and their babies, the effect of ovarian children, adolescents and women who have not finished Wrexham Maelor Hospital, Wrexham
Mohamed Mehasseb
cysts and their treatment on fertility, and management their families. MD PhD MRCOG
Liverpool Women’s Hospital, Liverpool
of raised CA125 levels and women with Lynch Two articles have an oncological perspective. The Aarthi Mohan MRCOG

mutations. In the Spotlight on. . . contraception, TOG article by Ryan et al. on Lynch syndrome is extremely University Hospitals Bristol NHS Foundation
Trust, Bristol
Associate Editor Nicola Mullin looks back at recent timely, following the recent National Institute for Health Nicola Mullin MFFP FRCOG
Countess of Chester Hospital NHS
TOG articles in this area. and Care Excellence recommendations for Lynch testing Foundation Trust, Chester

Sadly, the COVID-19 pandemic has put many in women with endometrial cancer. They discuss Surabhi Nanda MRCOG
Guy’s and St Thomas’ NHS Foundation Trust,
women at increased risk, not from a virus, but from the management of women with known Lynch variants and London

people they live with. Worldwide, women are frequent the lack of evidence for screening, which risks giving Kate Navaratnam
PhD
MBChB (hons) MRCOG DRCOG DFSRH

casualties of violence, especially at times of war and
unrest. In their Commentary, Gilmore and McEvoy
discuss moves toward better resolving physical,
false reassurance and may delay risk-reducing surgery. A
diagnosis of Lynch syndrome has implications for a
women’s future health and that of her family, and the
Institute of Translational Medicine, University of Liverpool,
Liverpool (Trainee Representative)
Nikoletta Panagiotopoulou MD MRCOG
Royal Victoria Hospital, Belfast

psychological and socio-economic harms of conflict- authors emphasise the need for collaboration with Asha Shetty MD FRCOG
Aberdeen Maternity Hospital, Aberdeen
related sexual violence on women, children and genetic counselling services. In their article on CA125, Chantal Simon
their communities. Howe et al. explain how interpretation of a raised level GP, Bournemouth
Thomas Tang MD MRCOG
We include a UKOSS update from Marian Knight on should be made in the context of the clinical situation, Regional Fertility Centre, Royal Maternity
outcomes of pregnancies in women with cystic fibrosis given the wide range of conditions associated with an Hospital, Belfast
Philip Toozs-Hobson MBBS MRCOG MFFP BSCCP MD
and consequences of single intrauterine fetal death in elevation in CA125 levels, in order to avoid unnecessary FRCOG
monochorionic twins. The next MBRRACE-UK report intervention, harm and concern. Birmingham Women’s and Children’s NHS Foundation
Trust, Birmingham
will be published just after this TOG edition, and we Many of us have seen plans for social events Ephia Yasmin MRCOG
look forward to a summary in the next TOG issue; cancelled or curtailed and have sorely missed family, University College London Hospitals NHS
Foundation Trust, London
however, as these data cover those collected between friends and social contacts. In his regular end piece, Wai Yoong MD FRCOG
2016 and 2018, we will need to wait for the 2023 report James Drife laments the loss of formal dinners, especially North Middlesex University Hospital, London

to understand the impact of COVID-19, both direct after-dinner speeches, and anticipates his first virtual International

and indirect. ‘end of conference’ speech. We wish him luck (and a Richard Brown MBBS DFSRH FRCOG FACOG
McGill University Health Centre, Montreal, Canada
Learning points from MBRRACE-UK usually good broadband connection!). Amr El-Shalakany MSc MD FRCOG
include the importance of maintaining situational January can be a bleak month. Hopefully, January Ain Shams University Maternity Hospital,
Cairo, Egypt
awareness in emergencies. In their educational article, 2021 will offer a glimmer of light with the recent news of Sebastian Gidlöf MD PhD
Yoong et al. emphasise the need to notice, understand effective vaccines, an administration in the White House Stockholm South Hospital, Sweden

and think ahead in difficult situations. They outline working with experts on public health and climate Carman Lai MRCOG FHKCOG FHKAM (O&G) Cert RCOG
(Maternal and Fetal Medicine)
human factors and how other team members have a role emergencies, as well as lengthening days and the promise Queen Mary Hospital, University of Hong
Kong, Hong Kong
in recognising when situational awareness has broken of Spring. Whatever the new year may bring, the
Henry Murray MRCOG
down or may be delegated to others at times when the (extended and often virtual) TOG ‘family’ wish you all Australia
surgeon is required to focus on a task. health and happiness for 2021. N Rajamaheswari MD DGO MCh (Urology)
Director, Urogynaecology Research Center
Pvt Ltd, India
Duru Shah MD FCPS FICS FICOG DGO DFP FICMCH
Jaslok Hospital, Sir Hurkinsondas Hospital
Deputy Editor-in-Chief and Breach Candy Research Centers, India

David Shaker FRCSEd FRCOG FRANZCOG

University of Queensland, Rockhampton

Jo Morrison
Base Hospital and Mater Private Hospital,
Australia
Jason Waugh MRCOG (Emeritus Editor)
Auckland, New Zealand

ª 2021 Royal College of Obstetricians and Gynaecologists 3

 DOI: 10.1111/tog.12712
The Obstetrician & Gynaecologist
http://onlinetog.org
Spotlight on. . . contraception
Nicola Mullin FRCOG FFSRH
Consultant in Sexual and Reproductive Health, Virgin Care, Chester, UK
Correspondence: Nicola Mullin. Email: nicolamullin@nhs.net
During the COVID-19 pandemic there has been much
discussion about the pressures on health services in primary
and secondary care in the UK and other countries. The Royal
College of Obstetrics and Gynaecologists (RCOG) quickly
produced guidance on how obstetric and gynaecological care
should be provided, including access to contraception and
abortion care. The RCOG, the Faculty of Sexual and
Reproductive Healthcare (FSRH) and the Royal College of
Midwives (RCM) emphasised the advantages of providing
immediate postpartum contraception during the pandemic. In
an article on postpartum contraception previously published
in The Obstetrician & Gynaecologist (TOG), Cooper and
Cameron provided method-specific guidance on hormonal
contraception, as well as on how to insert intrauterine
contraception at the time of caesarean section and after
vaginal delivery (TOG 2018;20:159–66). It was with access and
choice in mind that I had the pleasure of revisiting other articles
published in TOG on contraception and the noncontraceptive
uses of contraceptive methods in obstetrics and gynaecology.
Prepregnancy planning
Obstetricians and gynaecologists know the importance of
planning pregnancy in women with medical conditions,
such as multiple sclerosis (TOG 2019;21:177–84), and after
treatment for malignancy (TOG 2016;18:283–9). Correct
information about the most effective and suitable methods
of contraception should be provided; in particular,
knowledge that all long-acting reversible contraception
(LARC) methods are immediately reversible will allow for
prepregnancy counselling and the opportunity for women
to conceive while in remission to avoid disease-modifying
therapies. Pregnancy prevention plans are critical for
women taking sodium valporate and for women with
cardiac disease for whom a pregnancy may be extremely
dangerous (TOG 2018;20:21–9). An article on reproductive
health in survivors of childhood cancer discussed the
balance between addressing the challenges of premature
ovarian insufficiency/subfertility and the need for
contraception, since fertility can recover years later
(TOG 2016;18:315–22).
4 ª 2020 Royal College of Obstetricians and Gynaecologists
2021;23:4–5
Editor's Pick
Benign gynaecology
An excellent overview of the noncontraceptive uses and
benefits of combined oral contraception (COC) was
presented by Carey and Allen (TOG 2012;14:223–8). Our
patients may have misinformation about hormonal
contraception and know little about the many benefits.
Some past TOG articles still have relevance today. Wylie and
Gebbie addressed concerns on the impact of contraception
on subsequent fertility (TOG 2002;4:151–5); they reminded
us that 70% of women ovulate in the first month after
discontinuing COC and 98% by their third cycle. More detail
has been published on the use of the drosperinone-containing
COC and the use of estrogen alongside the levonorgestrel-
containing system (LNG-IUS) for treating premenstrual
syndrome (TOG 2015;17;99–104). Ovarian suppression may
be beneficial for women suffering from pelvic congestion
syndrome (TOG 2013;15:151–7). Hoo et al. presented the
relative merits of COC, progestogen-only contraception and
the LNG-IUS in treating endometriosis-related pelvic pain
(TOG 2017;19;131–8). Dysmenorrhoea is also effectively
treated with hormonal contraception (TOG 2010;12:149–54).
An evidence-based review of management of uterine fibroids
also covered all the different types of hormonal options,
including depo-medroxyprogesterone acetate, LNG-IUS,
mifepristone and ulipristal acetate (TOG 2016;18:33–42).
During the perimenopause, women may also need treatment
for heavy menstrual bleeding and effective contraception until
12 months after the last menstrual period, and this may
overlap with a time when hormone replacement theory (HRT)
is necessary (TOG 2017;19:289–97). Hormonal contraception
may be used in preference to HRT for women with Turner
syndrome (TOG 2019;21:43–50).
Contraception for specific groups
TOG has published articles on the contraceptive challenges
for women with additional needs. In the middle of the UK
Government’s 10-year Teenage Pregnancy Strategy, clinicians
were given information to confidently address the
contraceptive needs of young people under 16 by Vanhegan

(TOG 2008;10:22–6), wherein the legal aspects of treating
young people and the importance of confidentiality were
clearly explained. The 2013 article on the management of
menstrual problems in adolescents with learning and physical
disabilities remains a useful summary (TOG 2013;15:106–
12). A multidisciplinary team approach is recommended for
treatment decisions and to address the relevant ethical issues
– for example, parental distress versus the young person’s
own distress and her ability to cope with bleeding. Women
with addictions may need particularly targeted assistance and
encouragement to help them access effective contraception
(TOG 2014;16;269–71).
Global health
Postpartum contraception is one of the three elements of the
RCOG Leading Safe Choices programme (https://www.rcog.
org.uk/leadingsafechoices). The programme also encompasses
the training and raising the professional standing of healthcare
professionals working in sexual and reproductive health in
Tanzania and South Africa. Access to family planning is essential
if the Millennium Development Goals are to be achieved,
ª 2020 Royal College of Obstetricians and Gynaecologists
Editor’s Pick
especially numbers 3, 4 and 5 (promote gender equality and
empower women, reduce child mortality and improve maternal
health) (TOG 2014;16:1–5). Reproductive health suffers during
times of conflict and population displacement. Black et al.
outline the minimum reproductive health package required
during a humanitarian crisis, and access to contraception is very
important (TOG 2014;16:153–60).
Litigation
Common areas of litigation in gynaecology were presented by
Jha and Rowland (TOG 2014;16:51–7), and sterilisation and
laparoscopy were listed. The causes of post-sterilisation
conception were considered. TOG articles have covered
both laparoscopic sterilisation, written by Filshie in the first
edition (TOG 1999;1:26–32), and more recently
hysteroscopic sterilisation by Murthy et al. (TOG 2017;19:
227–35). The authors were clear on the lack of data on long-
term outcomes and potential complications after using the
Essure device.
A virtual issue of all TOG article on contraception is
available at http://onlinetog.org.
5
 DOI: 10.1111/tog.12707 2021;23:6–8
The Obstetrician & Gynaecologist
Commentary
http://onlinetog.org

Bridging justice and health: reparations for conflict-related

sexual violence
Sunneva Gilmore
MB BCh BAO MRCOG,
a
* Kieran McEvoy LLB MSc PhD FASS MRIA
b

a
PhD Candidate in Law and Obstetrics and Gynaecology Specialist Trainee Year 4 (Out of Programme Research Leave), School of Law, Queen’s
University Belfast, Main Site Tower, University Square, Belfast BT7 1NN, UK
b
Professor of Law and Transitional Justice, School of Law, Queen’s University Belfast, Main Site Tower, University Square, Belfast BT7 1NN, UK
*Correspondence: Sunneva Gilmore. Email: sgilmore08@qub.ac.uk

Accepted on 15 May 2020. Published online 7 December 2020.

Please cite this paper as: Gilmore S, McEvoy K. Bridging justice and health: reparations for conflict-related sexual violence. The Obstetrician & Gynaecologist 2021;
23:6–8. https://doi.org/10.1111/tog.12707

to more effectively articulate and provide meaningful

Introduction
Conflict-related sexual violence (CRSV) is a key challenge in
health care and conflict today. In international law, sexual
violence can amount to a war crime, genocide or crime
against humanity.1 While much legal and scholarly attention
has historically focused on the investigation and prosecution
of perpetrators, in recent decades there has been an
increasing focus upon victims and their needs. This has
been particularly evident in the field of reparations, which
has seen the evolution of ever more sophisticated engagement
with gender-based harms. Reparations for CRSV are intended
to address various physical, mental and socio-economic
harms that impact the health and quality of life of those
directly and indirectly affected by such violations; for
example, children born out of rape, or entire communities
where abuses have been normalised.
Although gender-based violence is a prominent issue in
settled democracies, there is significant evidence that such
violations are often exacerbated during conflict.2 In response,
medical actors and professional associations have become
progressively engaged in this arena. The Royal College of
Obstetricians and Gynaecologists has committed to
supporting the United Nations’ (UN) Sustainable
Development Goals (SDGs) on promoting peace and
prosperity through action on good health and wellbeing
(SDG 3) and gender equality (SDG 5).3 However, beyond
SDGs 3 and 5, reparations also provide specialist
rehabilitative medical care (such as fistula surgery or
psychosexual medicine) to harms arising from sexual
violence, which intersects with SDG 16, on peace, justice
and institutions, including health and social care.
This article outlines how clinicians in obstetrics and
gynaecology are in a unique position to help narrow the
‘justice gap’ by illuminating implications for health, but also
outcomes to enhance victims’ quality of life. We outline
the normative and legal basis of reparations, explore some of
the key challenges in delivering reparations for victims of
conflict-related sexual violence, and offer some specific
suggestions on the ‘value added’ benefits of a medical lens
in navigating some of the tensions concerning the
reparations/CRSV intersection.
Reparations for conflict-related
sexual violence
Reparations are the variety of efforts used to acknowledge
and repair human rights violations, crime, abuse or other
injury by a responsible actor. A state, nonstate actor or
individual with responsibility for addressing the wrong in
question may deliver reparations. In international law,
various obligations exist requiring an effective remedy for
those affected by sexual violence.4 CRSV encompasses
violations directly or indirectly related to conflict and can
occur alongside other violations or patterns of violence. The
UN Secretary-General (UNSG) defines CRSV as including
‘rape, sexual slavery, forced prostitution, forced pregnancy,
forced abortion, enforced sterilization, forced marriage and
any other form of sexual violence of comparable gravity
perpetrated against women, men, girls or boys that is directly
or indirectly linked to a conflict’.5 For activists and victims in
the field, this was idly viewed as an overly restrictive
definition. As a result, in 2019, over 50 civil society
organisations, together with victims and independent
experts, created a ‘Civil Society Declaration on Sexual
Violence’, which articulated a more complex array of sexual
violence violations.6
In the legal realm, reparations have evolved from concepts
in private law and international human rights law,

6 ª 2020 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-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

concerning notions such as remedy, compensation and
restitution. A minimalist understanding of reparations
requires some form of acknowledgement of the victims’
harm, as well as a system to provide them with compensation
(usually financial) for the harm suffered. However, more
imaginative understanding is evolving in international law
and practice.7,8 For example, the 2005 UN publication, ‘Basic
Principles and Guidance on the Right to an Effective Remedy
and Reparation’ outlines three complementary and
overlapping variants of reparations: satisfaction,
rehabilitation and guarantees of non-repetition.4 Others
have argued for the importance of considering symbolic
forms of reparations, including truth recovery,
memorialisation and carefully choreographed apologies.9
Despite these advances, the field remains underdeveloped
with regards to the specific contribution of healthcare to
those who have suffered CRSV.
Challenges in implementing reparations
Providing reparations to victims of gross violations of human
rights often faces three main challenges: 1) Who will benefit?
2) How will it be funded? 3) Does the state in question have
the capacity and political will to deliver the
required measures?
After years of conflict, determining who is a victim is often
contested and complex. Monochromatic notions of who is a
perpetrator and who is a victim do not always match the
messy realities of conflict-affected societies.10 With regard to
both funding and capacity, conflict often devastates
infrastructure, housing, education, employment and so on,
resulting in such services sometimes being prioritised over
the needs of victims. It may also be difficult to prioritise
specialist rehabilitative services for sexual violence, when
basic healthcare needs for the whole population are not being
met. In some circumstances, addressing the needs of victims
of sexual violence may not be prioritised because it draws
attention to the past actions of the state, or other powerful
actors, which were responsible for such abuses in the first
place, sapping political will to deliver reparations.
With these challenges in mind, the medical profession –
and obstetricians and gynaecologists, in particular – can offer
a unique added value to these debates. According to the
International Federation of Gynaecology and Obstetrics,
healthcare professionals in sexual and reproductive health
have a duty to enunciate concerns when legislative, policy or
regulatory measures obstruct access to medical care.11 This
includes after sexual violence, or when they deprive persons
of their choice regarding their right to a private and family
life,12,13 whether through identifying and caring for victims of
sexual violence in a sensitive and empathetic manner,
documenting the scale and medical consequences of such
abuses or performing rehabilitative medical or surgical
ª 2020 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists
Gilmore and McEvoy
interventions to improve the sexual, urological, or
reproductive functions of victims after sexual violence.14,15
These are all key contributions, albeit rarely conceptualised as
a form of reparations. Indeed, clinicians can provide
invaluable insight to reparations and their effectiveness,
given that they holistically understand the patient.
Conclusion
A professional commitment to women’s healthcare is at the
ethical core of obstetrics and gynaecology. Therefore, as a
specialty, we can enhance the legal practice of reparations and
take a victim-sensitive approach in the care and treatment of
sexual and gender-based violence, while also ensuring that
patriarchal norms do not spill into reparations delivering
vital healthcare.11 Treating the individuals violated as
patients, rather than as eligible victims, we can also provide
reparative benefits through caring for them with dignity and
respect, mediating tensions on appropriate reparations, as
well as contributing to concepts of restoration. Our
continuing work is to develop a framework for improving
the effectiveness of reparations, including the involvement of
healthcare professionals.
Disclosure of interests
There are no conflicts of interest.
Contribution to authorship
SG conceived, designed and drafted the article. KM
contributed to drafting and revising the article. Both
authors approved the final version.
References
1 Grey R. Prosecuting sexual and gender-based crimes at the international
criminal court: practice, progress and potential. Cambridge: Cambridge
University Press; 2019.
2 Davies SE, True J. Reframing conflict-related sexual and gender-based
violence: bringing gender analysis back in. Security Dialogue
2015;46:495–512.
3 Royal College of Obstetricians and Gynaecologists (RCOG). RCOG Strategy.
London: RCOG; 2017 [https://www.rcog.org.uk/en/about-us/what-we-do/
rcog-strategy/].
4 United Nations (UN) Human Rights Office of the High Commissioner. Basic
principles and guidelines on the right to a remedy and reparation for victims
of gross violations of International human Rights Law and serious violations
of International Humanitarian Law. A/RES/60/147. Geneva: UN; 2005.
5 United Nations Secretary-General. Conflict related sexual violence. Report of
the United Nations Secretary-General. S/2019/280. Geneva: UN; 2019
[https://www.un.org/sexualviolenceinconflict/wp-content/uploads/2019/04/
report/s-2019-280/Annual-report-2018.pdf].
6 Women’s Initiatives for Gender Justice (WIGJ). Civil society declaration on
sexual violence. The Hague: WIGJ; 2019 [https://4genderjustice.org/wp-
content/uploads/2019/09/Civil-Society-Declaration-on-Sexual-Violence.pdf].
7 Rubio-Marın R. The gender of reparations in transitional societies. In: Rubio-
Marın R, editor. Unsettling sexual hierarchies while redressing human rights
violations. Cambridge: Cambridge University Press; 2009. pp. 63–120.
8 Coalition for Women’s Human Rights in Conflict Situations, Urgent Action
Fund –Africa (Kenya), Rights and Democracy (Canada), Alianza de Mujeres
7
 Bridging justice and health
Rurales por la Vida, Tierra y Dignidad (Guatemala), Association Africaine de
Defense des Droits de l’Homme, section, Katanga (Democratic Republic of
Congo), Asociacion Reflexi on de Inocentes Liberados (Peru), et al. Nairobi
Declaration on Women’s and Girls’ Right to Remedy and Reparation. 2007
[https://www.fidh.org/IMG/pdf/NAIROBI_DECLARATIONeng.pdf].
9 Dudai R. Closing the gap: symbolic reparations and armed groups. Int Rev
Red Cross 2001;93:783–808.
10 Moffett L. Reparations for “guilty victims”: navigating complex identities of
victim-perpetrators in reparation mechanisms. Int J Transition Justice
2016;10:146–67.
11 International Federation of Gynecology and Obstetrics (FIGO) Committee for
the Study of Ethical Aspects of Human Reproduction and Women’s Health.
Issues in contraception and abortion. In: Ethical issues in obstetrics and
gynecology. London: FIGO; 2015 [https://www.figo.org/sites/default/files/
2020-08/FIGO%20ETHICAL%20ISSUES%20-%20OCTOBER%202015%20%
28003%29.pdf].
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12 United Nations (UN) Human Rights Office of the General Commissioner.
Article 16. In: Convention on the Elimination of All Forms of Discrimination
against Women. New York: UN; 1979 [https://www.ohchr.org/en/profe
ssionalinterest/pages/cedaw.aspx].
13 Gilmore S, Guillerot J, Sandoval C. Beyond silence and stigma: crafting a
gender-sensitive approach for victims of sexual violence in domestic
reparation programmes. Belfast: Reparations, Responsibility and Victimhood
in Transitional Societies; 2020.
14 Ribeiro FS, van der Straten Ponthoz D. International protocol on the
documentation and investigation of sexual violence in conflict: best practice
on the documentation of sexual violence as a crime or violation of
international law. 2nd ed. London: UK Foreign and Commonwealth Office;
2017.
15 Gilmore S, Moffett L. Redressing forced sterilisation: the role of the medical
profession. BJOG 127:923–6.
 DOI: 10.1111/tog.12706 2021;23:9–20
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Lynch syndrome for the gynaecologist

Neil AJ Ryan PhD MRCS(Eng),a Raymond FT McMahon MD FRCPath,b Neal C Ramchander MBChB,
c

Mourad W Seif PhD FRCOG,d D Gareth Evans MD FRCP,e Emma J Crosbie PhD FRCOG*f
a
Obstetrics and Gynaecology Specialty Registrar and Honorary Clinical Lecturer, Centre for Academic Women’s Health, University of Bristol,
Bristol, UK
b
Consultant Histopathologist and Emeritus Professor of Medical Education, Department of Histopathology, Manchester University NHS
Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
c
Foundation Programme Doctor, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary’s
Hospital, Manchester, UK
d
Consultant Gynaecologist and Honorary Senior Lecturer, Division of Gynaecology, St Mary’s Hospital, Manchester University NHS Foundation
Trust, Manchester Academic Health Science Centre, Manchester, UK
e
Professor of Medical Genetics and Cancer Epidemiology and Honorary Consultant in Medical Genetics, Division of Evolution and Genomic
Medicine, University of Manchester, St Mary’s Hospital, Manchester, UK
f
Professor of Gynaecology Oncology and Honorary Consultant Gynaecological Oncologist, Division of Cancer Sciences, Faculty of Biology,
Medicine and Health, University of Manchester, St Mary’s Hospital, Manchester, UK
*Correspondence: Emma J Crosbie. Email: emma.crosbie@manchester.ac.uk

Accepted on 20 April 2020.

Key content

Lynch syndrome is an autosomal dominant condition closely
associated with colorectal, endometrial and ovarian cancer.

Women with Lynch syndrome are at increased risk of both
endometrial and ovarian cancer and should be offered personalised
counselling regarding family planning, red flag symptoms and risk-
reducing strategies.

Surveillance for gynaecological cancer in women with Lynch
syndrome remains controversial; more robust data are needed to
determine its effectiveness.

Universal testing for Lynch syndrome in endometrial cancer is

To understand the testing strategies for Lynch syndrome in women
with gynaecological cancer.

To learn how best to counsel women with Lynch syndrome
regarding gynaecological cancer and risk-reducing strategies to
enable informed decision-making.
Ethical issues

Offering gynaecological surveillance despite a lack of robust
evidence for its clinical effectiveness may falsely reassure women
and delay risk-reducing hysterectomy.

Genetic testing may yield variants of unknown significance with ill-

being adopted by centres across Europe and is now recommended defined clinical implications, which can lead to confusion
by the National Institute for Health and Care Excellence; thus, and anxiety.

Genetic testing has implications not only for the individual, but
gynaecologists must become familiar with testing strategies and
their results. also for the whole family, so expert counselling is crucial.

Testing strategies involve risk stratification of cancers based on
Keywords: endometrial cancer / genetic predisposition / Lynch
phenotypical features and definitive germline testing. syndrome / mismatch repair / ovarian cancer
Learning objectives

To define the pathogenesis of Lynch syndrome and its associated
gynaecological cancers.

Please cite this paper as: Ryan NAJ, McMahon RFT, Ramchander NC, Seif MW, Evans DG, Crosbie EJ. Lynch syndrome for the gynaecologist. The Obstetrician &
Gynaecologist 2021;23:9–20. https://doi.org/10.1111/tog.12706

genomic test directory1 and will be encouraged to order

Introduction
Genetics has become an integral part of our specialty,
informing prenatal diagnosis, fertility investigations, the
management of gynaecological cancers and many other
aspects of women’s health care. Genomics England has now
completed its sequencing of 100 000 genomes and has
established a workable infrastructure for continuing gene
and genome sequencing within the UK’s National Health
Service (NHS). Soon, clinicians will have access to a national
genetic testing for their patients. In parallel, ever-increasing
numbers of people are taking private genetic tests and
looking to their doctors to explain the results. With the
integration of genomic medicine into routine clinical
practice, obstetricians and gynaecologists must become
familiar with common genetic conditions. One such
condition is Lynch syndrome.
Lynch syndrome is an autosomal dominant inherited
condition that predisposes an individual to a constellation of

ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists. 9
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.
 Lynch syndrome for the gynaecologist
cancers, including colorectal, endometrial and ovarian
cancer. It is thought to be the most common high
penetrance inherited predisposition to cancer, with most
affected people unaware of their risk.2 Gynaecological cancer
is often the first cancer diagnosis in women with Lynch
syndrome.3 This provides an opportunity to diagnose Lynch
syndrome before they or their family are affected by further
oncological sequelae. Early diagnosis allows women to be
enrolled in cancer surveillance programmes and enables
cascade testing for their at-risk family members. There is a
well-documented survival advantage for those with Lynch
syndrome who are compliant with colonoscopic surveillance
for bowel polyps.4 In addition, early identification of Lynch
syndrome can enable the uptake of cancer risk-reducing
strategies, including taking aspirin and lifestyle modification.
The gynaecologist, therefore, has a crucial role in diagnosing
Lynch syndrome and advising women of its implications.
Lynch syndrome
Lynch syndrome was first described by Aldred Warthin in
1913 and was further delineated by Henry Lynch in 1966,
after whom the condition is named.5 In these seminal
pedigrees, it was endometrial cancer that predominated. The
cancers associated with Lynch syndrome are shown
in Figure 1.
Lynch syndrome arises from inherited mutations, known
as pathogenic variants, in the genes encoding the proteins of
the highly conserved DNA mismatch repair (MMR) system:
mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS
homolog 6 (MSH6) and PMS1 homolog 2 (PMS2).6
Any cancer (81%)
Brain (5%)
Breast (13%)*
Stomach (8%)
Duodenum (7%)
Pancreas (6%)
Endometrium (57%)
Ovary (17%)
Colon (45%)
Bladder (8%) Sigmoid/rectum (13%)
Ureter/kidney (7%)
Figure 1. Percentage maximum risk of cancer in females at 75 years
of age across different pathogenic gene variants. *In path_PMS2, the
risk of breast cancer could be as high as 55%, but the data are of poor
quality because of low incidence.
10 ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
Deletions involving epithelial cell adhesion molecule
(EpCAM) can lead to downstream epigenetic silencing of
MSH2.7 Less commonly, inherited inactivation of the MMR
system can arise from germline hypermethylation of the
promoter region of MLH1.8
The role of the MMR system in maintaining genomic
stability is shown in Figure 2. Without a functioning MMR
system, the uncorrected mutation rate accompanying DNA
synthesis increases by 1000-fold.9 An individual with Lynch
syndrome inherits one pathogenic allele of an MMR gene. In
keeping with the Knudson hypothesis, once the second allele
acquires a somatic inactivating mutation, the MMR system is
nonfunctional, leading to widespread genomic instability as
errors made during replication go uncorrected.
Hypermutation may eventually lead to carcinogenesis –
although it is important to note that in the lifetime of a
Lynch syndrome carrier, thousands of cells become MMR-
deficient, but very few cause cancer. This is in part associated
with the immune response they elicit. This phenomenon has
been observed in the endometrium, where normal glands
demonstrate MMR deficiency.10
The epidemiology of Lynch syndrome
The exact prevalence of Lynch syndrome in the general
population is unclear. The American Gastroenterological
Association estimates the prevalence to be 1 in 440.11 A
recent study from Denmark estimated the prevalence to be as
high as 1 in 278 in the general population.2 This would make
Lynch syndrome the most common inherited cancer
predisposition syndrome. Most (up to 95%) individuals
who carry a Lynch syndrome-causative pathogenic variant
are unaware of it.2
In cancer populations, a recent systematic review and
meta-analysis concluded that around 3% of endometrial
cancers are caused by Lynch syndrome, although the quality
of the evidence is poor.12 This is equivalent to the rate of
Lynch syndrome seen in colorectal cancer,13 and current UK
guidance from the National Institute for Health and Care
Excellence (NICE) supports the universal screening of
individuals with colorectal cancer,14 and more recently,
those with endometrial cancer,15 for Lynch syndrome. The
number of Lynch syndrome diagnoses associated with
ovarian cancer is less clear.16 A single centre study found
21% of non-serous epithelial ovarian cancer to be MMR
deficient;17 however, there is currently insufficient high
quality evidence to give reliable estimates.
Lynch syndrome is not a uniform disorder. The degree of
penetrance, disease spectrum and age of cancer onset vary
according to the mutated gene.4 For example, the incidence
of endometrial cancer in MSH6 pathogenic variant carriers is
as high as that in MLH1 and MSH2 pathogenic variant
carriers,4 and the risk is much higher than in PMS2
Figure 2. A functional DNA mismatch repair system recognising and removing an insertion/deletion loop that has arisen during cellular
replication.
pathogenic variant carriers. However, the risk of colorectal
cancer associated with MSH6 is much lower4 (Table 1). This
has implications for gynaecological surveillance and risk-
reducing strategies.
Colorectal cancer and Lynch syndrome
Colorectal cancer is the most common and lethal cancer seen
in Lynch syndrome carriers. The risk of developing colorectal
cancer depends on the affected gene and the sex of the
individual. For those with MLH1 pathogenic variants, the
cumulative lifetime risk of colorectal cancer is 47% (95%
confidence interval [CI] 39–54%). For those with PMS2
pathogenic variants, the risk is 14% (95% CI 3–25%).4 Lynch
syndrome-associated colorectal cancer has an earlier age of
onset, with a crude median age at diagnosis of 52 years versus
69 years in sporadic disease.11 Women have a lower
penetrance than men, which means their risk of colorectal
ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
cancer is less, yet still considerably higher than the
general population.4
Biennial colonoscopic colorectal surveillance forms the
bedrock of management.11 High quality surveillance is
associated with a significant reduction in deaths from
colorectal cancer in Lynch syndrome carriers.4 The
pathophysiology of Lynch syndrome-associated colorectal
cancers makes colonoscopic detection difficult because
tumours arise from flat adenomas that are hard to detect.
These cancers have a propensity for the right side of the
colon, rather than the rectum or sigmoid colon.4
Furthermore, synchronous and metachronous cancers are
common, so more extensive surgery with ileo-sigmoidal or
ileo-rectal anastomosis is often required or preferred.6
For the gynaecologist, this information should help
counsel women undergoing Lynch syndrome testing
because the main effect of a Lynch syndrome diagnosis is
the need for regular colonoscopies. Gynaecologists should
11
 Lynch syndrome for the gynaecologist

of such surgery is gene-specific, as shown in Table 2. The

Table 1. The cumulative risk of endometrial and ovarian cancer in
women with Lynch syndrome at 40 and 70 years of age, stratified by survival benefit achieved by risk-reducing surgery is minimal
mutated gene because Lynch syndrome-associated endometrial and ovarian
cancers have a good prognosis. However, for many women
Endometrial cancer
Gene with Lynch syndrome, avoiding a cancer diagnosis and the
harms associated with its treatment is sufficient to choose
Cumulative incidence Cumulative incidence risk-reducing surgery. Preoperative counselling by both a
at 40 years % (95% CI) at 70 years % (95% CI)
clinical geneticist and gynaecologist is seen as best practice.
The laparoscopic approach is preferred because it leads to a
MLH1 3.1 (0.4–5.8) 42.7 (33.1–52.3) shorter recovery time and improved short-term quality of
life;20 however, it can be challenging for women who have
MSH2 1.5 (0.0–4.4) 56.7 (41.8–71.6) previously received surgery and/or radiotherapy for
MSH6 0 46.2 (27.3–65.0)
colorectal cancer. To reduce a woman’s exposure to
multiple surgeries/anaesthetics, where possible,
PMS2 0 26.4 (0.8–51.9) hysterectomy should be coordinated with other risk-
reducing interventions, such as colonoscopy or colorectal
Ovarian cancer
surgery. Hysterectomy and bilateral salpingo-oophorectomy
at 40 years of age has been shown to be a cost-
effective strategy.21
Cumulative incidence Cumulative incidence
In premenopausal women, bilateral oophorectomy at the
at 40 years % (95% CI) at 70 years % (95% CI)
time of risk-reducing hysterectomy results in surgical
menopause, causing vasomotor symptoms, urogenital
MLH1 2.6 (0.1–5.2) 10.1 (4.8–15.4) dryness and atrophy and, often, reduced sexual function,
emotional lability and cognitive decline. It also increases the
MSH2 3.8 (0.0–8.0) 16.9 (5.7–28.0)
risks of osteoporosis, cardiovascular disease and colorectal
MSH6 4.2 (0.0–12.3) 13. 1 (0.0–31.2) cancer.22 To mitigate these risks, women should be
counselled about the benefits of estrogen replacement
PMS2 0 0 therapy (ideally a transdermal application) for quality of
life and future health. Estrogen has a protective effect against
Abbreviations: CI = confidence interval colorectal cancer and does not appreciably increase breast
cancer risk.
Women with Lynch syndrome should be encouraged to
aim to coordinate surveillance and surgery with their explore other ways of addressing their cancer risk (Table 2).
colorectal colleagues, wherever possible.18 For example, The risk factors for endometrial cancer in the general
risk-reducing gynaecological surgery could be combined population include age, obesity, type 2 diabetes mellitus,
with colorectal surveillance or surgery. It is also important to nulliparity, early menarche/late menopause and tamoxifen
include colorectal colleagues in any relevant clinical exposure.23 There is limited evidence about how lifestyle
communications; Lynch syndrome increases the risk of affects gynaecological cancer risk in women with Lynch
cancer at multiple sites and care of affected individuals is syndrome. The oral contraceptive pill is known to reduce the
necessarily multidisciplinary. risk of sporadic endometrial and ovarian cancer,24,25 as well
as BRCA1/2-associated ovarian cancer,26 and the
levonorgestrel-releasing intrauterine system reduces the risk
Risk-reducing strategies in women with
of endometrial cancer in the general population.27 While
Lynch syndrome
there are no conclusive data to support the use of these
Ideally, women with Lynch syndrome should be seen at interventions in women with Lynch syndrome, the prevailing
around the age of 25 years by an expert gynaecologist to learn wisdom is that they probably have a beneficial effect on
about the red flag symptoms of cancer, discuss family gynaecological cancer risk.
planning and explore risk-reducing strategies.18 Raising Taking aspirin has been shown to reduce the risk of all
awareness about red flag symptoms empowers women to cancer types in Lynch syndrome carriers.5 Aspirin appears to
seek help appropriately. The lifetime risk of gynaecological reduce endometrial cancer risk in obese women with Lynch
cancer is sufficiently high to offer total hysterectomy and syndrome compared with nonobese women.28 Lifestyle
bilateral salpingo-oophorectomy for women with Lynch factors may also affect cancer risk in Lynch syndrome
syndrome who have completed childbearing.19 The timing carriers. Smoking, alcohol and increased body mass index

12 ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
 Table 2. An overview of cancer risk-reducing strategies for women with Lynch syndrome
Hysterectomy ( bilateral
Considerations salpingo-oophorectomy)
Target population Female LS carriers, family
completed
Timing For path_MLH1 and
path_MSH2 at 35 years
For path_MSH6 at 40 years
For path_PMS2 at 50 years
Mechanism of Removes organs prone to
action cancer
Evidence Retrospective cohorts
Contraindications Surgical and anaesthetic
contraindications, wish for
future fertility
Harms Surgical harms such as
infection, pain, visceral injury,
death, etc. Also risks of early
menopause (if BSO) such as
vasomotor symptoms,
increased risk of
cardiovascular disease,
osteoporosis
Unknowns Whether two-stage surgical
procedure to remove uterus
after childbearing and ovaries
after menopause improves
outcomes
Abbreviations: BMI = body mass index; BSO = bilateral salpingo-oophrectomy; EC = endometrial cancer; LS = Lynch syndrome; OC = ovarian cancer;
path_ = pathogenic variant
increase the risk of colorectal cancer in individuals with
Lynch syndrome; however, few studies have specifically
explored the effect of lifestyle choices on gynaecological
cancer risk.29 Despite a lack of robust evidence, it would seem
sensible for women with Lynch syndrome to eat a healthy
diet, maintain a healthy weight, take regular exercise, avoid
smoking cigarettes and either abstain from or reduce alcohol
intake to a moderate level.
ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
Lifestyle (smoking
cessation, reduce weight,
increase exercise, healthy
Aspirin diet) Hormone-based therapy
All LS carriers, especially those All LS carriers Females of reproductive age
with a raised BMI
From 18 years Any age From the age of menarche
until natural age of
menopause
Not fully understood General cancer risk factor Reduced endometrial
reduction proliferation, anti-
inflammatory effect
Large international Limited evidence in LS Retrospective cohort data
randomised controlled populations mostly drawn
studies from non-LS population and
small retrospective cohort
data
Peptic ulcer disease, bleeding Those with pre-existing health History of estrogen-
disorders/haemophilia, severe conditions that would dependent or breast
cardiac failure, active alcohol prohibit excessive physical cancer, active arterial
abuse exercise thromboembolic disease,
undiagnosed vaginal
bleeding, thrombophilia
disorder, history of venous
thromboembolism
Dyspepsia, haemorrhage None Dysuria, skin reactions,
(usually minor as young mood alterations
population – trial data would
support prescription unless
any contraindications)
Optimal dosage The effectiveness of such Benefit of intrauterine
strategies in LS-specific systems in reducing
cancer risk endometrial cancer risk in
LS carriers
Gynaecological surveillance in women with
Lynch syndrome
Not all women with Lynch syndrome wish to undergo risk-
reducing gynaecological surgery; indeed, fertility-sparing
options are required for those who wish to pursue
motherhood.30 Gynaecological surveillance aims to reassure
women or detect cancer at a precancerous or early stage to
13
 Lynch syndrome for the gynaecologist

Table 3. Gynaecological surveillance methodologies currently used in women with Lynch syndrome

Estimated Estimated
Type of Surveillance sensitivity specificity
cancer method Benefit Disadvantage (%) (%)

Endometrial Pelvic ultrasound Cheap, widely accessible, acceptable In premenopausal women, 15–100 55–100
cancer to women, minimal complications, difficult to interpret; no tissue
can assess ovaries diagnosis; risk of incidental
findings

Endometrial biopsy Outpatient procedure, tissue Painful, risk of infection/ 80–100 60–100
diagnosis, widely accessible perforation, sampling error, need
for repeat procedure

Outpatient hysteroscopy  Outpatient procedure, tissue Small evidence base in LS, risk of 90–100 90–100
directed biopsy diagnosis, widely accessible, target infection/perforation, visceral
biopsy injury, relatively expensive, can be
prohibitively painful

Ovarian Pelvic ultrasound Cheap, widely accessible, acceptable Small evidence base in LS, high 10–60 40–100
cancer to women, minimal complications, rate of incidental findings leading
can assess endometrium to unnecessary interventions

Serum CA125 Cheap, widely accessible, acceptable Small evidence base in LS, 20–58 80–98
to women, minimal complications, nonspecific and therefore can
can be done in primary care lead to unnecessary anxiety and
intervention

Combined (CA125 + Cheap, widely accessible, acceptable As above 70–89 80–99

pelvic ultrasound) to women, minimal complications,
can assess endometrium, improved
sensitivity compared with ultrasound
alone

NB: Sensitivity and specificity data for ovarian cancer is taken from wild type and other high-risk populations; the figures in women with Lynch
syndrome are not known. CA125 = cancer antigen 125; LS = Lynch syndrome

improve morbidity and survival outcomes. Trials have
investigated many modalities (Table 3). Transvaginal
ultrasound has limited utility for detecting endometrial
abnormalities in premenopausal women, as endometrial
thickness fluctuates naturally during the menstrual cycle.
On the other hand, hysteroscopy and endometrial biopsy are
invasive procedures, with 30–40% of women suffering pain
during their completion. Overall, data relating to
gynaecological surveillance are of low quality, with a
predominance of single-centre, retrospective studies. The
results are contradictory, with some studies showing benefit
and others not.18 Many women diagnosed with
gynaecological cancers through surveillance were
symptomatic at the time. Furthermore, endometrial cancer
survival rates in women with Lynch syndrome are extremely
good anyway, with a 10-year survival of 90% or more.31
Thus, the benefit for endometrial cancer-specific survival is
uncertain. The literature does not support gynaecological
surveillance for improving outcomes from ovarian cancer in
Lynch syndrome. The United Kingdom Familial Ovarian
Cancer Screening Study (UKFOCS) found that a
combination of serum CA125 and transvaginal ultrasound
scanning was sensitive and led to a stage shift in disease in
women with a lifetime risk of ovarian cancer >10%.
However, few Lynch syndrome-associated ovarian cancers
informed this analysis.32
Fertility and Lynch syndrome
There is no evidence that Lynch syndrome has any effect on
fertility. However, as an autosomal dominant condition,
carriers of Lynch syndrome have a 50% chance of passing on
the defective MMR gene to their children. Lynch syndrome is
on the list of conditions curated by the Human Fertilisation
and Embryology Authority (HFEA), for which those affected
can access pre-implantation genetic testing (PGT). PGT
allows embryos lacking the MMR pathogenic variant to be
selected for transfer following in vitro fertilisation (IVF). This
reduces the risk of transmission, but IVF is a demanding
process and many couples affected by Lynch syndrome prefer

14 ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
to conceive naturally, whatever the risk. The uptake of PGT
by women or their partners affected by Lynch syndrome is
variable, but patient survey data indicate a significant
minority would consider it.33 In the UK, it is convention
for genetic counsellors to lead on referral for PGT; however,
gynaecologists may be asked for advice, so they should know
what is possible and what is involved. Those wishing to
conceive naturally should be advised that the risk of
endometrial cancer rises sharply for women older than
40 years and may frustrate pregnancy plans that are left
too late.
Screening gynaecological cancers for Lynch
syndrome
The prevalence of Lynch syndrome in women with
endometrial and ovarian cancer is around 3% and 1–2%,
respectively.12,34 There is an emerging consensus that all
women with endometrial cancer should be screened for
Lynch syndrome, where resources permit.18 Indeed, this is
what NICE recommends.15 Where resources are limited,
testing can be restricted to those who develop endometrial
cancer under the age of 70 years, or where other clinical
features are suggestive of Lynch syndrome; for example, a
strong family history of Lynch syndrome-
associated cancers.18
Diagnosing Lynch syndrome in women
with endometrial cancer
Clinical criteria
Warthin and Lynch discovered Lynch syndrome through
careful documentation of their patients’ pedigrees. The
importance of taking a detailed family history in an
oncology clinic cannot be overestimated. The Amsterdam II
criteria33 and revised Bethesda guidelines36 are age and family
history-based prediction tools that were designed to target
Lynch syndrome testing in colorectal cancer. Use of these
tools in endometrial cancer has been explored in several
studies, and the reported specificity is 61% and 49% for
Amsterdam II criteria and revised Bethesda guidelines,
respectively.37 Unfortunately, such family history scores
have very low sensitivity to identify MSH6 or PMS2
pathogenic variant carriers.38 The newer prediction tools
MMRpredict,39 MMRpro40 and PREMM541 have increased
diagnostic accuracy. MMRpredict has a reported sensitivity
of 94% and a specificity of 91% for MLH1 and MSH2
pathogenic variant carriers, while discrimination of MSH6
was more difficult and PMS2 was not assessed.42 A head-to-
head comparison of these new family history-based tools
concluded that MMRpro and PREM1,2,6 could be
implemented in both clinical and population settings using
a risk cut-off of 5%.43 However, the precision of these tools
ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
relies on the patient describing, and the clinician recording,
an accurate family history. This is not always practical in busy
outpatient departments. If your patient has a particularly
strong family history of cancer, it is best to seek advice from
your local clinical genetics service.
Women with Lynch syndrome develop endometrial cancer
at an earlier age than those with sporadic tumours.18 While
younger women may be more likely to have Lynch
syndrome-associated endometrial cancer, restricting Lynch
syndrome testing to women under the age of 50 years would
miss cases of Lynch syndrome. The same is true for
histological subtype; endometrioid endometrial and ovarian
tumours34 are most commonly associated with Lynch
syndrome, but other histological subtypes have been
reported.44 It is widely held that restricting Lynch
syndrome testing according to clinical parameters is
imperfect and that tumour-based testing is the most
effective way of triaging women for germline analysis.45
Tumour-based testing
A defective MMR system leads to phenotypical features
within the tumour. When a pathogenic variant is acquired
within a gene, it affects the expression of that gene’s
corresponding protein, either through the amount of
protein produced or changes in its structure and function.
Tumour-based testing does not identify people with Lynch
syndrome; it stratifies their risk for the condition. This is
important because it is widely accepted that tumour-based
tests can be done without explicit consent.18 They are used to
identify individuals who should undergo definitive, but
expensive, germline testing to ensure testing strategies remain
cost effective46 (Figure 3).
Immunohistochemistry
Loss of tumour expression of one or more MMR proteins,
known as MMR deficiency, is a feature of Lynch syndrome
(Figure 4). MMR protein immunohistochemistry has a
sensitivity of 80–100% and a specificity of 60–80% for
detecting Lynch syndrome-associated endometrial cancer.18
The relative lack of specificity is associated with somatic loss
of MMR expression – usually as a consequence of
hypermethylation of the promoter region of the MLH1
gene.47,48 MLH1 methylation testing correctly identifies
tumours caused by somatic methylation events, thereby
reducing the proportion of patients who need to undergo
definitive germline Lynch syndrome testing.
Microsatellite instability testing
Microsatellites are small DNA motifs that are repeated
throughout the genome.49 They comprise 2–5 nucleotides
repeated 5–50 times. These sequences are highly conserved in
the offspring of an individual; however, there is marked
variation across a population.50 Microsatellite instability
15
 Lynch syndrome for the gynaecologist

Tumour tissue

Immunohistochemistry testing for Microsatellite instability

MLH1, MSH2, MSH6 and PMS2 proteins analysis

MLH1 or PMS2 No protein loss MSI-L/MSS MSI-H

protein absent

Unlikely to be LS Unlikely to be LS MLH1 promoter

MLH1 promoter methylation testing
methylation testing
MSH2 or MSH6
protein absent

Hypermethylated Normal Normal Hypermethylated

Unlikely to be LS Germline testing for LS-associated pathogenic variants Unlikely to be LS

Figure 3. Outline of a potential diagnostic schema used to risk stratify tumours for Lynch syndrome. Abbreviations: IHC = immunohistochemistry;
LS = Lynch syndrome; MMR = mismatch repair; MSI-H = microsatellite instability high; MSI-L = microsatellite instability low; MSS = microsatellite
stable. *Indicates that IHC and MSI-based tumour triage can be used in combination or individually.

(a) (b)

(c) (d)

Figure 4. Mismatch repair immunohistochemistry showing loss of A: MLH1, B: MSH2, C: MSH6 and D: PMS2 protein in endometrial cancer
glands, with conserved expression in stromal tissue.

16 ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
Figure 5. Comparison of CD8+ cytotoxic T-cell infiltration in a sporadic mismatch repair proficient endometrial cancer (top panels) with a Lynch
syndrome-associated endometrial cancer (bottom panels). The abundance of neoantigens expressed by Lynch syndrome-associated tumours leads
to enhanced immunogenicity and a robust anti-cancer T-cell response.

(MSI) is a marker of hypermutation as seen in Lynch
syndrome-associated tumours.51 As Lynch syndrome
tumours have multiple insertion/deletion mutations, there
is inevitably variation within the tumour microsatellites.
Detecting these variations gives a means of diagnosis through
polymerase chain reaction (PCR) testing. Tumours are
categorised as MSI-stable (MSS), or MSI-low (MSI-L) if
<30% of markers are unstable, and MSI-high (MSI-H) if
>30% of markers are unstable; this is the category to which
most Lynch syndrome tumours belong. Sporadic tumours
can also be MSI-H;40 usually as a result of hypermethylation
of the promoter region of MLH1. The diagnostic accuracy of
MSI testing has been reported as high, with a sensitivity of
92% and a specificity of 59% in colorectal cancer, where most
research has concentrated.52 Similar accuracy is reported for
endometrial cancer, although the number of tested tumours
and the quality of available studies is much lower.18 There is
good reported concordance between MSI and
immunohistochemistry testing for Lynch syndrome tumour
identification,18 but more recent data suggest that MSI
testing is less accurate in endometrial cancer – particularly at
identifying MSH6 carriers.53
Genomic diagnosis
Genomic testing of the tumour or the patient is referred to
as somatic and germline testing, respectively. Both are
done using next-generation sequencing (NGS). While
germline testing is the only means by which a diagnosis
of Lynch syndrome can be made, it is not always
straightforward. First, the PMS2 gene is very hard to
sequence, so it can only be done in specialist centres.
Second – and more importantly – when a gene is

ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists. 17
 Lynch syndrome for the gynaecologist
sequenced, a list of bound nucleotides (A, C, T, G) is
generated; an error in this list does not always have a
pathological consequence. Sequencing is analogous to
detecting spelling errors in a book: the meaning of those
spelling errors is sometimes very hard to deduce. If you
spell the word ‘cosy’ or ‘cozy’, it has the same meaning. If,
however, you change ‘now’ to ‘not,’ the meaning is very
different. When the meaning of a mutation/pathogenic
variation cannot be determined it is classified as a variant
of unknown significance (VUS). The determination and
management of individuals with VUS is best left to
geneticists. Germline sequencing is the definitive test for
Lynch syndrome and must always be preceded by informed
consent taken by a trained individual.
Targeted treatments in Lynch syndrome-
associated gynaecological cancers
MMR-deficient cancers have certain characteristics that are
important when planning treatment and follow-up. These
tumours are very immunogenic, eliciting a marked and unique
immune response (Figure 5).54 The main mechanism of
immune evasion seen in MMR-deficient cancers is exploitation
of the PD-1/PD-L1 pathway.55 This is a druggable pathway,
which has been explored in recent clinical trials with excellent
results.56 The PD-1 checkpoint inhibitor pembrolizumab is an
IgG4 isotype antibody that targets the PD-1 receptor expressed
by peripheral lymphocytes. It binds and blocks the PD-1
receptor, preventing its activation by the cancer.57 It is one of
few drugs to be licenced by the United States Food and Drug
Administration for all tumours of a specific phenotype; in this
case, those that are MSI-H or MMR-deficient, as opposed to
those originating at a particular site.58 Lynch syndrome-
associated gynaecological cancers have improved survival
outcomes compared with sporadic cancers.31,59 This is
important when counselling patients regarding prognosis. It
may also enable shorter or less intensive follow-up; however,
more data are needed before definitive recommendations can
be made.
The future
Many unknowns remain regarding Lynch syndrome and its
associated gynaecological cancers. The benefits and harms of
gynaecological surveillance and the effectiveness of risk-
reducing interventions, particularly oral and intrauterine
progestins, have yet to be established. Novel strategies are
being tested to harness the Lynch syndrome patient’s own
immune system to prevent cancers through vaccination.60
Novel diagnostic methods, with the potential for complete
automation, are in development. Such technologies would
simplify and reduce the costs of Lynch syndrome screening
and diagnostic pathways.
18 ª 2021 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
Key resources
One published guideline, written by the Manchester
International Consensus Group, looks specifically at the
gynaecological manifestations of Lynch syndrome and offers
clear and comprehensive guidance for clinicians and patients.18
The European Hereditary Tumour Group61 produces broad
guidelines on the clinical management of Lynch syndrome,
with guidance reviewed and updated regularly. The
prospective Lynch syndrome database62 has produced a risk
prediction tool that clinicians can use to identify an individual
patient’s risk of developing cancer as they age, enabling more
personalised management. For patient support and
information, Lynch Syndrome UK (LSUK)63 is a patient
support group with excellent resources. Finally, the PREMM5
model64 is useful for directing family history-taking during
initial consultations with patients. High scores (>5%) should
prompt referral to the local clinical genetics team. All those
with a score >2.5% should have tumour testing (if applicable)
for Lynch syndrome, according to the algorithm.
Disclosure of interests
There are no conflicts of interest.
Contribution to authorship
EJC is this article’s guarantor. NAJR and EJC designed and
wrote the article. NCR aided in design of the figures and
tables. RFTM, MWS and DGE provided expert material and
review. All authors provided critical comment, edited the
manuscript, and approved its final version.
Funding
NAJR is a Doctoral Medical Research Council (MRC)
Research Fellow (MR/M018431/1). DGE is a National
Institute for Health Research (NIHR) Senior Investigator
(NF-SI-0513-10076). DGE and EJC are supported through
the NIHR Manchester Biomedical Research Centre (IS-BRC-
1215-20007).
Supporting Information
Additional supporting information may be found in the
online version of this article at http://wileyonlinelibrary.
com/journal/tog
Infographic S1. Lynch syndrome for the gynaecologist
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 DOI: 10.1111/tog.12704 2021;23:21–7
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Raised CA125 – what we actually know. . .

Tamara Howe MBBS MRCOG PGDipMedEd,a* Nava Sokolovsky BA MSc BM BCh,b Ahmad Sayasneh MBChB MD(Res)
c d d
MRCOG, Kazal Omar MBChB MD FRCOG, Farshad Tahmasebi MD MRCOG MSc
a
ST7 Trainee in Obstetrics and Gynaecology, Department of Obstetrics and Gynaecology, Princess Royal University Hospital, Kings’s College
Hospital NHS Foundation Trust, Farnborough Common, Orpington BR6 8ND, UK
b
ST2 Trainee in Obstetrics and Gynaecology, Department of Gynaecological Oncology, St Thomas’ Hospital, London SE1 7EH, UK
c
Consultant Gynaecologist and Gynaecological Oncology Surgeon, Department of Gynaecological Oncology, St Thomas’ Hospital,
London SE1 7EH, UK
d
Consultant Obstetrician and Gynaecologist, Department of Obstetrics and Gynaecology, Princess Royal University Hospital, Kings’s College
Hospital NHS Foundation Trust, Farnborough Common, Orpington BR6 8ND, UK
*Correspondence: Tamara Howe. Email: tamara.howe@nhs.net

Accepted on 16 April 2020. Published online 2 December 2020.

Key content  To understand how CA125 is used as a diagnostic tool and to

 Carbohydrate antigen 125 (CA125) is an antigen used
in the diagnosis of epithelial nonmucinous ovarian
cancers.
 CA125 may be elevated in many benign and malignant
conditions, so elevated levels can cause confusion over
patient management.
 The multidisciplinary team is important when planning care for
patients with suspected ovarian cancer.
Learning objectives
 To know the factors leading to CA125 production and its
mechanism of action.
assess the treatment response of ovarian cancer.
 To appreciate patient care options in cases of falsely
elevated CA125.
Ethical issues
 Is the CA125 blood test being used in patients appropriately
and safely?
 In patients with elevated CA125 levels, does this lead to
unnecessary investigations and invasive treatments?
Keywords: CA125 / gynaecological causes of raised CA125 /
nongynaecological causes of raised CA125 / ovarian cancer / ovarian
cancer follow-up

Please cite this paper as: Howe T, Sokolovsky N, Sayasneh A, Omar K, Tahmasebi F. Raised CA125 – what we actually know. . . The Obstetrician & Gynaecologist
2021;23:21–7. https://doi.org/10.1111/tog.12704

assays, a normal level of CA125 is considered to be

Introduction
Ovarian cancer is the leading cause of death from any
gynaecological malignancy.1 Its insidious nature means that
over 70% of women diagnosed will present with late stage
disease (stage III or IV). For this reason, screening for ovarian
cancer has the potential to considerably affect mortality by
detecting it at an earlier stage. For many years, analysis of
carbohydrate antigen 125 (CA125) levels has been the ‘go-to’
investigation for ovarian cancer screening, despite no true
evidence of its efficacy.2
CA125 was first identified by Bast et al. in 1981.3 Bast and
his team isolated the murine monoclonal antibody OC125,
which recognises an epitope on a molecule called CA125 –
so-named because it is the 125th antibody produced against
the ovarian cancer cell line. To date, many other monoclonal
antibodies have been found to target CA125, though OC125
remains the best known.3 CA125 is also known as mucin 16
(MUC16) because it is encoded by the MUC16 gene, located
on chromosome 19 (see Figure 1).4 In most commonly used
<35 IU/ml.5
CA125 levels can increase in both physiological and
pathological conditions. Most research has focused on the
antigen’s molecular structure, with its function remaining a
source of much speculation. CA125 is expressed in tissues
derived from embryonic coelomic epithelia. These include
the endometrium, m€ ullerian epithelium, peritoneum, pleura
and pericardium.2 Within these epithelia, CA125 is
synthesised by mesothelial cells in response to assorted
stimuli, most notably mechanical stress and inflammation.6 It
has been postulated that CA125 plays a role in cell-mediated
immunity by suppressing the response to natural killer cells
and promoting attachment to mesothelial cells by binding
to mesothelin.7
Production of CA125 in response to stress
It is the clinician’s role to discern whether or not elevated
serum CA125 is associated with a benign condition or a

ª 2020 Royal College of Obstetricians and Gynaecologists 21

 Raised CA125 – what we know. . ..
Tandem repeats
≥ 60
(heavily glycosylated)
N-terminal
domain
(heavily
glycosylated)
SEA modules
Putative
cleavage site
TM
Cytoplasmic tail
COOH
Figure 1. CA125, also known as mucin 16 (MUC16), is a protein
encoded by the MUC16 gene on chromosome 19.8 TM =
transmembrane domain.
malignant process. To establish this, it is initially important to
ascertain the biological mechanisms and pathophysiological
processes that stimulate CA125 production. In turn, this
permits us to understand why the CA125 antigen is raised in
such a diverse range of conditions. Current theories suggest
that CA125 is synthesised in the mesothelial cells as a stress
response. This may either occur because of mechanical stress
caused by fluid congestion, or inflammatory stress instigated
by the release of cell mediators, such as tumour necrosis
factors and interleukins.9
CA125 and mechanical stress
Many studies have demonstrated a link between elevated
CA125 and the presence of fluid overload in serosal spaces,
regardless of fluid aetiology. Hung et al.10 looked at patients
with pulmonary oedema, with or without evidence of
associated chronic heart failure (CHF). The study showed
that CA125 levels were higher in patients with pleural
effusions, regardless of CHF status. They also found a
moderate relationship between raised CA125 and decreasing
22
albumin, which can be linked to fluid overload. Comparable
results have been shown in patients with ascites: CA125 levels
are elevated both in association with benign conditions, such
as liver cirrhosis,11 and in association with malignancies, such
as tumours of the digestive tract.12
Topalak et al.13 investigated the link between fluid and
serum CA125 levels for many different gynaecological and
nongynaecological diseases, such as hepatic disease, lung
cancer and nongynaecological peritoneal carcinomatosis.
Patients were divided into those with and without features
of peritoneal or pleural effusions. Raised CA125 levels were
identified in many different conditions, in particular in the
presence of effusions. Despite this, the highest levels are seen
in patients with ascites associated with ovarian cancer, with a
positive correlation between ascites volume and CA125 level.
This suggests that the CA125 antigen is not produced directly
by the tumour and is therefore not a tumour marker per se.
Instead, it is released by the mesothelial cells in response to
the mechanical stretch produced by the fluid. Levels of
CA125 in the ascitic fluid do correlate with the serum levels,
but are much higher than those seen in the blood. This
indicates that the antigen originates in the ascitic fluid, rather
than in the tumour itself.12 In vitro studies have
demonstrated that mechanical stretch of mesothelial cells
causes upregulation of MUC16, lending further support to
this theory.10
CA125 and inflammatory stress
Alternative evidence suggests that CA125 may also be
released in response to inflammatory stress. This may
explain why elevated levels are seen when there is no sign
of serosal effusion;13 for example, in cases of subhepatic
abscess or well-controlled CHF, when there is no evidence of
oedema. Indeed, in vitro studies have demonstrated secretion
of CA125 in response to stimulation with tumour necrosis
factors and interleukins.7
Ovarian cancer and CA125
CA125 testing and the diagnosis of ovarian cancer
Serum CA125 levels are often elevated in ovarian epithelial
cancers but less commonly seen to be in non-epithelial
cancers of the ovary.14 For this reason, in the diagnosis of
ovarian cancer, a CA125 test is often used in conjunction
with transvaginal ultrasound scanning (TVUSS). However,
there is little evidence that this approach can reduce mortality
from ovarian cancer, partly because 50% of women with
stage I disease, and those with occult cancers identified at
prophylactic surgery, have normal levels of this
tumour marker.14
For patients with symptoms of ovarian cancer, current
national guidance recommends CA125 testing as an initial
investigation.1 CA125 level is also required to calculate a risk
ª 2020 Royal College of Obstetricians and Gynaecologists

of malignancy index (RMI) for patients presenting with
ovarian cysts. A level of over 250 IU/ml should trigger
referral to a cancer centre for subsequent management.15
Although CA125 screening is used in the diagnosis of
symptomatic patients, there is currently no evidence to
suggest that screening postmenopausal women with a one-off
CA125 serum blood test will reduce patient mortality.16
CA125 testing in patient follow-up of ovarian cancer
CA125 level may also be used to assess patient response to
chemotherapy and surgical treatment.15 Serum levels are
expected to fall by half within 10 days of surgical resection.17
Postoperative levels correlate with residual tumour mass18
and have a considerable value, which is predictive for
survival.19 For patients who enter complete remission with
chemotherapy treatment, the median time for CA125
normalisation is 1.5 months, while for patients achieving
partial remission it is 4 months.20 Despite this, for 40% of
patients achieving normal CA125 concentrations,
microscopic or macroscopic disease will be found at
second-look surgery.21
The British Gynaecological Cancer Society (BGCS)
advises that CA125 measurement during follow-up is not
mandatory and has not been proven to be of survival
benefit.15 One study demonstrated a shorter interval to
deterioration in global health score or death when treatment
was initiated by an abnormal CA125, compared with those
who received no treatment until they were symptomatic.22
However, the decision for CA125 follow-up must be
individualised: since a rising CA125 level may indicate
recurrence of surgically resectable disease, some patients
may wish to know what might lie ahead, while for others, it
may trigger an image that will determine timing and value
of further treatment.23
Raised CA125 without ovarian cancer
The sensitivity and specificity of CA125 assay is known to be
poor. CA125 levels are elevated in only 75–90% of patients
with advanced disease,24 so it is not an effective screening
tool or stand-alone measurement.25 False-positive results
have been identified in both malignant and benign
conditions.26 Subsequently, it may now be used as a
surrogate biomarker for screening and diagnosis in diseases
other than ovarian cancer.27
Alternative causes of raised CA125 levels may be
physiological or pathological. Johnson et al.28 used data
from a cohort of postmenopausal women in a large cancer
screening trial in the USA to assess lifestyle factors that can
increase CA125 levels. Results demonstrated higher levels in
smokers, women with breast cancer and women using
hormone replacement therapy (HRT), although in most
women these levels were still within the normal range.28
ª 2020 Royal College of Obstetricians and Gynaecologists
Howe et al.
CA125 in pregnancy and the menstrual cycle
CA125 levels fluctuate across the menstrual cycle, with a
peak during menstruation followed by a steady decline until
the end of the cycle.29 Since this fluctuation is not seen in
women who have undergone hysterectomy with ovarian
conservation,30 it suggests that CA125 is linked to the
endometrium. In vitro studies have demonstrated that a
higher concentration of CA125 is produced in endometrial
stromal cells during the proliferative and early secretory
phases; this indicates that production of CA125 is associated
with estrogen-dominated cell growth and activity.31 It has
been postulated that the cause of this may be linked to the
tissue–blood barrier being temporarily weakened at
menstruation. Therefore, endometrial cells release CA125
into the blood, exhibiting higher serum levels. Despite this,
changes in CA125 levels remain mostly within the normal
range in most women.29,30
Serum CA125 levels are altered in pregnancy, with a rise in
the first trimester being attributed to increased production by
the decidua.32 From the start of the second trimester, a
reduction in values can be observed;32 however, some studies
have suggested levels may be further increased by pregnancy
complications, such as pre-eclampsia.33 For these reasons, a
higher cut-off value for serum CA125 levels in pregnancy
may be applicable,34 but no consensus has been reached.
When appropriate, analysing CA125 in pregnancy can help to
support or refute a diagnosis, but the test should only be
undertaken when clinically indicated and always interpreted
with care.
CA125 and endometriosis
A clear link has been identified between raised CA125 levels
and endometriosis. For patients with stage II and above
endometriosis, CA125 levels may reach into the hundreds of
units per millilitre, compared with healthy controls. Levels
have also been shown to be predictive of considerable pelvic
adhesions in such patients.35
CA125 and benign conditions
CA125 levels have been shown to be elevated in various benign
conditions, including gynaecological pathologies such as benign
ovarian cysts, tubo-ovarian abscess, endometriosis, pelvic
inflammatory disease, fibroids and ovarian hyperstimulation
syndrome.26 Many nongynaecological conditions are also
associated with markedly elevated CA125 levels, including
liver cirrhosis;13 lung diseases like interstitial lung disease and
tuberculosis;36 and heart diseases such as heart failure, atrial
fibrillation and pericardial disease.8,9 Observations also suggest
that, in patients with heart disease, CA125 may be used as a risk
stratification tool because particularly high levels have been
linked to rehospitalisation and death.8
Figure 2 summarises the physiological and pathological
causes of raised CA125 levels.
23
 Raised CA125 – what we know. . ..

Raised serum CA125

Pathological causes Physiological causes

Benign causes Malignant causes - Pregnancy

(levels fluctuate with (levels progressively - Menstruation
disease severity) rise over time) - Age

Gynaecological causes - Ovarian cancer

- Endometriosis - Endometrial cancer
- Benign ovarian tumours - Pancreatic cancer
- Acute/chronic salpingitis - Primary peritoneal cancer
- Uterine fibroids - Lung cancer
- Pelvic inflammatory disease - Breast cancer
Nongynaecological causes - Bowel cancer
- Cirrhosis ± ascites - Lymphoma
- Chronic/active hepatitis
- Acute/chronic pancreatitis
- Renal failure
- Interstitial lung disease
- Tuberculosis
- Heart failure
- Atrial fibrillation
- Pericardial disease

Figure 2. Flow chart summarising the physiological and pathological causes of raised CA125.

pelvic or abdominal pain, increased urinary urgency/

CA125 testing in everyday clinical practice
CA125 testing in primary care
In 2011, the National Institute for Health and Care
Excellence (NICE) produced guidance for primary care
professionals on the use of CA125 testing (see Box 1 for a
summary). It recommended testing all women presenting
with symptoms of ovarian cancer. These symptoms included
persistent abdominal distension, early satiety/loss of appetite,
Box 1. Summary of NICE guidance for CA125 testing in primary
care.1
CA125 testing is advised for all women with red flag symptoms raising
suspicion of ovarian cancer (especially if 50 years or older)
Symptoms include:
Bloating
Early satiety  reduction in appetite
Pelvic  abdominal pain
Increased urinary urgency or frequency
Other symptoms to consider:
Unexplained weight loss
Unexplained fatigue
Unexplained change in bowel habit
New onset symptoms of irritable bowel syndrome in women >50 years
frequency, unexplained weight loss, fatigue or changes in
bowel habit. If the patient’s CA125 level is greater than
35 IU/ml, then an abdominal and pelvic ultrasound
is indicated.1
A recent study investigated the outcome of CA125 testing
in primary care in accordance with the NICE guidance. The
authors reviewed a cohort of 4379 women whose CA125
levels had been tested, identifying 152 patients with a newly
raised serum CA125 level (>35 IU/ml). Follow-up data
demonstrated the diagnosis of 16 ovarian cancers. They
concluded that CA125 testing in primary care has a high
specificity for identifying ovarian and primary peritoneal
cancer. It was further suggested that lowering the cut-off
value for CA125 may increase its sensitivity, but would likely
reduce the specificity.37
CA125 testing in patients with ovarian cysts
The Royal College of Obstetricians and Gynaecologists
(RCOG) advises that determining a CA125 level is not
routinely needed for the diagnosis of a simple cyst in
premenopausal women. It also advocates use of the
International Ovarian Tumor Analysis (IOTA) Group M
(malignant) and B (benign) rules for ovarian cyst

24 ª 2020 Royal College of Obstetricians and Gynaecologists


classification. Within this risk stratification process, a serum
CA125 level is not required. Any patient with a single
malignant feature (‘M-rule’) identified on ultrasound
requires referral to the gynaecological oncology team. In
large studies, this classification method reportedly has a
sensitivity of 95% and specificity of 91%.38 Current guidance
for CA125 testing in postmenopausal women with ovarian
cysts is more straightforward. At present, the
recommendation for this cohort of women is that a serum
CA125 level is crucial if any cystic lesion of more than 1 cm
in diameter is identified on the ovary. This is to support risk
stratification and calculation of the RMI.39
CA125 testing outside of clinical guidelines
It is not unusual for serum CA125 testing to be performed
outside of the current guidance, or for the levels to be
elevated in the absence of ovarian cancer. This can pose a
challenge to clinicians. For such patients, a thorough history
and clinical examination must be completed to exclude all
possible physiological and pathological causes of a raised
CA125 level. Involvement of the multidisciplinary team
(MDT) will make it possible to individualise patient
management plans. Traditionally, assays for carbohydrate
antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA)
have been used in the screening criteria for gynaecological
pelvic malignancies40 and may be beneficial for patients in
whom no obvious cause of a raised CA125 level is found.
Serial monitoring of CA125 levels is advantageous in such
patients41 because it has been observed that levels appear to
rise progressively over time in patients with malignancy. On
the contrary, with benign conditions, levels exhibit a more
stable pattern and have the potential to fluctuate with disease
severity.22 Hence, observing a trend of CA125 levels over time
will likely support or discredit any further management plan.
A decision for further imaging or invasive investigations
should be made by the gynaecological oncology MDT. The
risks and benefits should be weighed up against the
possibility of a delayed cancer diagnosis. In such a scenario,
delaying treatment may mean that the patient’s disease
reaches a more advanced stage at final diagnosis.
Investigations considered by the MDT should include
computed tomography (CT) of the patient’s chest,
abdomen and pelvis, and a diagnostic laparoscopy. Such
surgery will allow the surgeon to fully visualise the abdomen
and pelvis, including the peritoneal surfaces. If necessary,
biopsies can be taken and sent for histology to aid
a diagnosis.
CA125 testing – the unintended consequences
As clinicians, our intention is to do no harm; at the
forefront of our management, we are appropriately focused
on excluding a cancer diagnosis. However, patient-centred
care is always important, and communications about and
ª 2020 Royal College of Obstetricians and Gynaecologists
Howe et al.
explanations of tumour marker testing should begin in
primary care. Inappropriate use of CA125 testing may result
in unnecessary investigations and invasive treatments, which
– in turn – can lead to considerable anxiety for
the patient.42
Studies have demonstrated that investigations for
suspected cancer may have negative effects, even for
patients who are ultimately diagnosed with a benign
condition.43,44 Anxiety, psychological distress43 and
immune-endocrine changes44 may remain for weeks or
months after a benign diagnosis. This effect of screening on
mental health and quality of life can be difficult to quantify.5
We must understand the psychological impact of cancer
screening, even in the context of a non-cancer diagnosis.
There are two overriding themes in the literature to consider.
The first is ‘over-reassurance’ for patients, which may
subsequently delay seeking help in the future. This is
understood to be influenced by patients attributing
subsequent symptoms to the benign diagnosis, fear of the
distress caused by the previous ‘false alarm’, and concerns
about wasting doctors’ time. The second theme relates to
‘under-support’ following a non-cancer diagnosis. Patients
are concerned their symptoms will not be taken seriously or
will be dismissed as unimportant.45
The future of CA125 as a tumour marker
Despite CA125 being the most widely used biomarker, it is
neither sufficiently sensitive nor specific to determine a
diagnosis on its own. There has been a suggestion that using
age-specific CA125 cut-off points may be more accurate and
reduce false-positive results, but this requires further
research.5 Many efforts have been made to improve the
diagnostic performance of markers or marker combinations
in the hope that this would improve sensitivity for early
detection. Markers that have been investigated include
human epididymis protein 4 (HE4), mesothelia, CA72-4,
inhibin, kallikreins, and osteopontin.46
Human epididymis protein 4
Of all of these markers, HE4 is one of the most promising.5
HE4 is also known as WAP-type four disulphide core 2
(WFDC2) and is expressed in ovarian cancer cells, especially
in histological subtypes of serous and endometrioid
carcinoma.47 Studies have demonstrated that, as a single
marker or combined with CA125, HE4 has the highest
sensitivity compared with other combinations examined,
especially in early stage ovarian cancer. It is also not falsely
elevated as frequently as CA125. In one particular trial, HE4
was found to have a sensitivity of 73% (versus 86% with
CA125) when used to detect ovarian cancer.48 Moreover,
recent preliminary data have demonstrated elevated HE4
levels in newly diagnosed ovarian cancer patients with
25
 Raised CA125 – what we know. . ..
normal CA125 levels. Despite these data, HE4 has not yet
been approved for use in screening.5
Risk of ovarian malignancy algorithm
The risk of ovarian malignancy algorithm (ROMA) is a test
that has been devised as a first-line marker for referring high-
risk patients to tertiary centres.49 ROMA comprises assays of
HE4 and CA125 and considers the woman’s menopausal
status. One multicentre prospective study evaluated the use
of CA125, HE4 and ROMA in epithelial cancer diagnosis.
The authors concluded that ROMA helped to differentiate
epithelial ovarian cancer from benign disease and that HE4
was more effective in detecting patients with ovarian
cancer.50 ROMA has also been found to perform equally as
well as RMI in detection of ovarian cancer.49
Risk of ovarian cancer algorithm
To further improve the sensitivity and specificity of CA125,
the risk of ovarian cancer algorithm (ROCA) was created.
This looks at a patient’s age and serial CA125 levels over time,
without respect to the absolute value. Although it has been
shown to detect early stage cancers, these levels are not robust
in reducing mortality from ovarian cancers and are costly
to implement.5
Conclusion
CA125 has long been described as the ‘gold standard’ tumour
marker in ovarian cancer diagnosis. However, it is possible to
argue that this is not the case because CA125 testing offers no
reduction in patient mortality. It also unable to detect pre-
invasive disease, so cannot be utilised within a national
screening programme.5 Nevertheless, CA125 testing has a
role in everyday clinical practice because it supports
clinicians in risk stratification for both gynaecological and
nongynaecological conditions. It is the doctor’s responsibility
to use the test appropriately, while explaining its limitations
to the patient. It is becoming clear that we, as doctors,
underestimate both the physical and psychological
consequences of performing this ‘harmless’ blood test.
What the future holds for CA125 within the diagnosis of
ovarian cancer remains to be determined; meanwhile, in
today’s healthcare arena, we should be mindful of the
implications of such a test and interpret its results
with caution.
Disclosure of interests
There are no conflicts of interest.
Contribution to authorship
FT instigated, researched, wrote and edited the article. TH
researched, wrote and edited the article. AS instigated and
edited the article. NS researched and wrote the article. KO
26
wrote and edited the article. All authors read and approved
the final version of the manuscript.
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40 Chen F, Shen J, Wang J, Cai P, Huang Y. Clinical analysis of four serum tumor
markers in 458 patients with ovarian tumours: diagnostic value of the
combined use of HE4, CA125, CA19-9, and CEA in ovarian tumours. Cancer
Manag Res 2018;10:1313–8.
41 American College of Obstetricians and Gynecologists (ACOG). Management
of adnexal masses. ACOG Practice Bulletin No.83. Washington DC: ACOG;
2007.
42 Henderson JT, Webber EM, Sawaya GF. Screening for ovarian cancer:
updated evidence report and systematic review for the US Preventive
Services Task Force. JAMA 2018;319:595–606.
43 Pelletier M, Knauper B, Loiselle CG, Perreault R, Mizrahi C, Dube L.
Moderators of psychological recovery from benign cancer screening results.
Curr Oncol 2012;19:e191–200.
44 Witek-Janusek L, Gabram S, Mathews HL. Psychologic stress, reduced NK
cell activity, and cytokine dysregulation in women experiencing diagnostic
breast biopsy. Psychoneuroendocrinology 2007;32:22–35.
45 Heisey R, Clemons M, Granek L, Fergus K, Hum S, Lord B, et al. Health care
strategies to promote earlier presentation of symptomatic breast cancer:
perspectives of women and family physicians. Curr Oncol 2011;18:
e227–37.
46 Rosen DG, Wang L, Atkinson JN, Yu Y, Lu K, Diamonds EP, et al. Potential
markers that complement expression of CA125 in epithelial ovarian cancer.
Gynecol Oncol. 2005;99:267–77.
47 Drapkin R, von Horsten HH, Lin Y, Mom SC, Crum CP, Welch WR, et al. HE4
is a secreted glycoprotiein that is over expressed by serous and endometrioid
ovarian carcinomas. Cancer Res 2005;65:2162–9.
48 Cramer DW, Bast RC, Berg CD, Diamonds EP, Godwin AK, Hartge P, et al.
Ovarian cancer biomarker performance in Prostate, Lung, Colorectal, and
Ovarian Cancer Screening Trial specimens. Cancer Prev Res 2011;4:
365–74.
49 Karlsen MA, Sandhu N, Høgdall C, Christensen IJ, Nedergaard L, Lundvall L,
et al. Evaluation of HE4, CA 125, risk of ovarian malignancy algorithm
(ROMA) and risk of malignancy index (RMI) as diagnostic tools of epithelial
ovarian cancer in patients with pelvic mass. Gynaecol Oncol
2012;127:379–83.
50 Romagnolo C, Leon AE, Fabricio ASC, Taborelli M, Poles J, Del Pup L, et al.
HE4, CA125 and risk of ovarian malignancy algorithm (ROMA) as diagnostic
tools for ovarian cancer in patients with a pelvic mass: an Italian multicenter
study. Gynecol Oncol 2016;141:303–11.
27
 DOI: 10.1111/tog.12705 2021;23:28–37
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Does ovarian cystectomy pose a risk to ovarian reserve

and fertility?
Neerujah Balachandren iBSc MBBS MRCOG,a* Ephia Yasmin MBBS MD MRCOG,b
Dimitrios Mavrelos BA MBBS MD MRCOG,b Ertan Saridogan PhD FRCOGc
a
Specialty Registrar/Research Fellow in Reproductive Medicine, Reproductive Medicine Unit, University College London Hospital,
London NW1 2BU, UK
b
Consultant Obstetrician and Gynaecologist and Sub-Specialist in Reproductive Medicine and Surgery, Reproductive Medicine Unit,
University College London Hospital, London NW1 2BU, UK
c
Consultant in Reproductive Medicine and Minimal Access Surgery, Reproductive Medicine Unit, University College London Hospital,
London NW1 2BU, UK
*Correspondence: Neerujah Balachandren. Email: n.balachandren@nhs.net

Accepted on 6 April 2020. Published online 3 December 2020.

Key content Learning objectives

 The impact of benign ovarian cysts on a woman’s fertility is
dependent on the nature, size, number, bilaterality and risk of
recurrence of the cyst(s).
 Children and adolescents presenting with pathological ovarian
cysts require a multidisciplinary team approach and, where
possible, fertility sparing treatment should be offered.
 Laparoscopic detorsion has the potential to preserve ovarian
reserve and should remain the optimal treatment for ovarian
torsion in girls and premenopausal women.
 Surgery for bilateral endometriomas has been shown to increase
the risk of developing premature ovarian insufficiency.
 It is important to consider performing ovarian reserve assessments
before any ovarian surgery in women who have not completed
their family.
 To understand what factors need to be considered before making a
decision to perform an ovarian cystectomy.
 To be aware of different surgical techniques and their impact on
fertility outcomes.
 To take anatomical considerations into account to minimise
damage to healthy ovarian tissue.
Ethical issues
 The UK’s National Health Service does not routinely fund oocyte
freezing for benign conditions.
Keywords: endometriomas / fertility / ovarian cystectomy / ovarian
cysts / ovarian reserve assessments

Please cite this paper as: Balachandren N, Yasmin E, Mavrelos D, Saridogan E. Does ovarian cystectomy pose a risk to ovarian reserve and fertility?
The Obstetrician & Gynaecologist 2021;23:28–37. https://doi.org/10.1111/tog.12705

Introduction Functional ovarian cysts and their effects

Ovarian cystectomy is a common procedure for the
management of benign ovarian cysts in premenopausal
women.1,2 The procedure is usually performed to prevent
cyst complications such as pain, rupture or torsion, or when
there is concern of malignancy, while preserving fertility in
those of reproductive age.3 It is not, however, easy to
determine the effect of the cyst or a cystectomy on a
woman’s future fertility. This will depend on specific
characteristics of the cyst(s); for example, the nature, size,
number, bilaterality and risk of recurrence.3 The scope of
this Review article is to understand how these factors
can affect the decision to perform a cystectomy, as well as
determine when and how a cystectomy can be performed
to reduce the risk of damage to a woman’s reproduc-
tive potential.
on fertility
The ovary has two main functions: folliculogenesis and
steroidogenesis. The process of folliculogenesis – that is, the
progression of primordial follicles into large pre-ovulatory
follicles – makes the ovary intrinsically prone to developing
functional cysts. Functional ovarian cysts have been described
as nonpathological follicular cysts that failed to ovulate, a
persistent corpus luteum cyst, or other unspecified ovarian
cysts measuring more than 20 mm in diameter.4 They are the
most common ovarian cysts in adults and children and
account for 46–53% of all adnexal pathologies.5 They almost
always regress spontaneously within one to three menstrual
cycles, so should not require any surgical or hormonal
interventions.6 With the exception of luteal cysts and
persistent functional cysts, functional ovarian cysts are

28 ª 2020 Royal College of Obstetricians and Gynaecologists


simply by-products of ovulation, so – in theory – they should
not have any effect on fertility. Luteal cysts are thought to
result from failure of the ovulatory follicle to rupture.7 The
unruptured follicle undergoes luteinisation under the action
of luteinising hormone (LH); it still produces normal levels
of progesterone and has the same duration of luteal phase.8
Luteal cysts are observed in 10% of natural menstrual cycles
in fertile women, but are thought to occur more frequently in
the infertile population.8 Qublan and colleagues8 found that
luteal cysts occurred in 25% of intrauterine insemination
(IUI) cycles in women with unexplained infertility.
Persistent functional cysts are sometimes seen in women
undergoing controlled ovarian stimulation (COS), or in
those with extensive peri-ovarian adhesions. Women with
low ovarian reserve and those on a gonadotrophin-releasing
hormone agonist (GnRHa) cycle are at increased risk of
developing functional cysts.9 The incidence of persistent
functional cysts in those undergoing COS ranges between 8%
and 53%.10 The effect of functional cysts on in vitro
fertilisation (IVF) success remains contentious. Although
some studies suggest very poor outcome of cycles where
functional cysts were detected, including high cancellation,
decreased follicular recruitment and low pregnancy rates,11,12
others have failed to report a difference in any outcome.13
The first line of treatment is usually prolonged
downregulation with either a progesterone-only pill or the
combined contraceptive pill and, as a last resort, ultrasound
guided or laparoscopic drainage.
Dermoid cysts and their effects on fertility
A dermoid cyst is a benign type of germ cell tumour arising
from totipotent ovarian cells. They are the most common
pathological cysts in premenopausal women.14 They are
bilateral in 10–20% of cases and grow at a rate of 1.7–1.8 mm
per year.3 The recurrence rate following cystectomy is
3–4%.14 Few studies have looked at the effects of dermoid
cysts on ovarian function and fertility, and none have shown
a negative effect. Kim and colleagues15 compared the anti-
m€ullerian hormone (AMH) levels in women with unilateral
and bilateral dermoid cysts with those of controls and found
no significant difference. The mean size of the dermoid cysts
in their study was 6.3  0.3 cm.15 Schubert and colleagues16
histologically assessed the ovarian cortex surrounding
dermoid cysts, serous cysts and endometriomas taken at
cystectomy. The follicular density was higher in dermoid
cysts than in endometriotic and serous cysts. There was also a
clear limit between the dermoid cyst and the ovarian cortex,
thus the ovarian cortex seemed to be stretched but not
damaged by the dermoid cyst.16 Maneschi and colleagues17
also studied the ovarian cortical tissue surrounding benign
cysts removed at cystectomy. The cortical tissue surrounding
dermoid cysts showed normal morphological patterns and a
ª 2020 Royal College of Obstetricians and Gynaecologists
Balachandren et al.
regular vascular network similar to that of the normal
ovarian cortex.17 One small study also looked at IVF
outcomes in six patients with dermoid cysts with a mean
size of 2.4 cm and showed no difference in the number of
eggs collected.18 Overall, the presence of a dermoid cyst
appears to have very little or no effect on fertility. However,
dermoid cysts frequently occur bilaterally and have a
relatively high recurrence rate.1 These factors, along with
their ability to grow to relatively large sizes, can lead to
repeated surgery, bilateral procedures and relatively large
cystectomies; all of which can have an adverse effect on
fertility. One study showed a statistically significant reduction
in AMH following surgery for cysts over 5 cm in diameter.19
Therefore, operating early, while the cyst is still small, may
prevent the need for a large cystectomy and thus lower the
effect on the ovarian reserve.
Endometriomas and their effects on
fertility
Endometriomas, or ovarian endometriotic cysts, are reported
in 17–44% of women with endometriosis and are a marker of
more severe, deeper disease.20 Furthermore, 28% of
endometriomas are bilateral.21 The risk of recurrence of
endometriomas in the same ovary or contralateral ovary
following surgery is high, with cumulative rates of 12–30%
after 2–5 years of follow-up.22 Exacoustos and colleagues23
reported that 81% had recurrence in the treated ovary, 11%
on the contralateral untreated ovary and 8% in both the
treated and untreated ovaries. Overall, most recurrence
occurs in the treated ovary, suggesting that the recurring
cysts seem to grow from residual loci.23 The mean monthly
rate of growth of endometriomas following postoperative
recurrence was about 0.48 cm in those not using any
hormonal therapies.22
The effects of endometriosis and endometriomas on
fertility have been extensively studied. Overall, their
presence has a detrimental effect. Several causes have been
implicated, including chronic inflammation affecting quality
of oocytes and impaired ovarian function resulting in
defective folliculogenesis and fertilisation; poor embryo
quality secondary to an altered follicular environment,
resulting in embryos with reduced implantation capacity;
poor ovarian reserve with a significant reduction in the
primordial follicle cohort secondary to fibrosis from
increased tissue oxidative stress;24 and anatomical
distortion and tubal damage or occlusion secondary to
pelvic adhesions.
The evidence for poorer oocyte and embryo quality in
patients with endometriosis and endometriomas remains
patchy and inconclusive; most studies have only evaluated
this indirectly. Two such studies found higher rates of
miscarriage in patients with endometriosis/endometriomas
29
 Ovarian cystectomy and fertility
than in healthy controls following spontaneous
conception.25,26 Sanchez and colleagues27 performed a
systematic review of the literature to evaluate the effect of
endometriosis on oocyte quality from a clinical and
biological perspective. They found that oocytes retrieved
from women affected by endometriosis are more likely to fail
in vitro maturation and showed altered morphology and a
lower cytoplasmic mitochondrial content than in women
with other causes of infertility.27 A meta-analysis of 36
published studies involving women with all stages of
endometriosis found that clinical pregnancy rate was
significantly lower for endometriosis patients (odds ratio
[OR] 0.78; 95% confidence interval [CI] 0.65–0.94).28
Another meta-analysis showed live birth rates were not
statistically different, although women with endometriosis
had lower clinical pregnancy rates.29 Similarly, a third meta-
analysis looking specifically at the effects of endometriomas
on IVF outcomes included 30 retrospective and three
randomised controlled trials (RCTs). This analysis found
similar live birth rates and clinical pregnancy rates, but a
lower mean number of eggs retrieved and higher cancellation
rates in women with endometriomas compared with
no endometriomas.30
With regard to effects on ovarian reserve, two prospective
studies demonstrated lower AMH levels and antral follicle
counts (AFC) in women with endometriomas compared with
age-matched controls.31,32 In a systematic review and meta-
analysis looking at the effect of surgery for endometriomas,
pooled analysis of preoperative AFC showed that the mean
AFC for the ovary with the endometrioma was lower than
that for the contralateral one (mean difference 2.79, 95% CI
7.10 to 1.51), but statistical significance was not reached
(p = 0.20).33 On histological studies, Schubert et al.16
showed that endometriotic cysts had lower follicular
density than dermoid and serous cysts. Endometriotic cysts
also showed invasion of the surrounding cortex resulting in
fibrosis and the surrounding cortical tissue had abnormal
morphological patterns and irregular vascular networks.16,17
Endometriomas were also thought to negatively affect
ovulation, with one study showing lower ovulation rates in
ovaries containing endometriomas greater than 10 mm in
diameter compared with the healthy contralateral ovary.34
However, more recently, Maggiore and colleagues35
conducted a larger prospective study involving 244 women,
all of whom had a unilateral endometrioma greater than
20mm in diameter, and performed ultrasound monitoring
for ovulation over six cycles. No difference was found in the
ovulation rates between the affected ovary and healthy ovary
(50.3% versus 49.7%, p = 0.919).34
A haemorrhagic cyst is the result of bleeding into a
follicular or corpus luteum cyst. Like other functional cysts,
most will resolve spontaneously, but occasionally they can
become trapped by pelvic adhesions. On ultrasound imaging
30
and at laparoscopy, persistent haemorrhagic cysts can be
mistaken for endometriomas, and diagnosis can only be
confirmed by histology. Like other functional cysts,
haemorrhagic cysts are unlikely to have any effect on
fertility, thus cystectomy for a haemorrhagic cyst is more
likely to have an adverse effect.
Other benign ovarian cysts and their
effects on fertility
Ovarian cystadenomas are common benign epithelial
neoplasms, of which serous and mucinous are two of the
most common types seen.36,37 Serous cystadenomas are more
prevalent in menopausal women, while the mucinous type
mainly occurs during the third to sixth decade.38 Mucinous
cystadenomas are usually unilateral, but they can grow large
in size – on average between 15 and 30 cm.39,40 To the best of
our knowledge, nothing has been reported in the literature
about the effect of a mucinous cystadenoma on fertility.
However, owing to the relatively large sizes of these cysts,
there is a greater chance of oophorectomy. In addition,
surgical spill of mucinous material can lead to pelvic
adhesions and subsequent infertility.
Benign ovarian cysts in children and
adolescents
Malignant ovarian cysts are uncommon in children and
adolescents. Despite this, oophorectomy is frequently
performed in this age group. One study found that 75% of
oophorectomies in children and adolescents had been carried
out for benign ovarian cysts.41 Functional ovarian cysts
account for about 45% of all paediatric adnexal
abnormalities5 and usually resolve spontaneously.
Teratomas constitute about half of all ovarian neoplasms in
children42 and 1% of these are malignant immature
teratomas.43 Since laparoscopic cystectomy has become the
accepted practice for the management of mature cystic
teratomas in adults, the same approach should apply to
children and adolescents.43 With greater use of preoperative
investigations, including pelvic imaging and tumour markers,
along with a multidisciplinary team approach and
conservative surgery, we should be able to better protect
the future fertility of these young girls.
Ovarian torsion and its effect on fertility
Ovarian torsion is a rare gynaecological emergency.
Approximately 3% of all emergency gynaecological
surgeries are for ovarian torsion.44,45 One study conducted
over a 24-month period found the cumulative incidence of
ovarian torsion in women with ovarian tumours was 0.3%.46
Torsion usually involves the ovary and fallopian tube and is
ª 2020 Royal College of Obstetricians and Gynaecologists

more commonly seen with benign cysts greater than 5 cm
in diameter.45
Conservative management, which involves laparoscopic
unwinding of the twisted ovary, is the treatment of choice in
prepubescent girls and women of reproductive age,
regardless of the colour of the ovary at the time of
surgery.47,48 When an ovary undergoes torsion and
detorsion, it results in haemorrhage, congestion and
apoptosis secondary to ischaemia, which can affect the
ovarian reserve.49 One retrospective study found that
detorsion of the ischaemic ovary preserved ovarian
function in 91.3% of patients; this was demonstrated by
follicular development on ultrasound, normal ovary at
subsequent laparotomy for other indications and successful
fertilisation of oocytes retrieved from the ischaemic ovary
following controlled ovarian stimulation.50 To our
knowledge, only one study has assessed ovarian reserve
post-detorsion and found no difference in the AFC between
the affected and contralateral ovary 3 months after surgery.49
Similarly, they found no difference in the AMH level
taken preoperatively on the day of detorsion and at 1 and
3 months postoperatively.49 Thus, compared with
oophorectomy, laparoscopic detorsion has the potential to
preserve the ovarian reserve and should remain the optimal
treatment in girls and premenopausal women. In cases where
torsion has occurred in the presence of an ovarian cyst, an
elective cystectomy 2–3 weeks later is advised to allow time
for the congestion and oedema to resolve.51
Ovarian cystectomy and its effect on
ovarian reserve
There are several ways to perform ovarian cystectomy, but, in
principle, it involves incising the ovarian cortex to identify
the cyst capsule, removing the cyst wall, with or without
draining the cyst, and finally applying haemostatic
measures.20 The size and nature of the cyst being removed,
bilaterality and/or repeated surgery, method of cystectomy,
method of haemostasis and – of course – the skill and
experience of the surgeon are all important factors that will
determine how much of an effect, if any, the cystectomy will
have on the ovarian reserve.
Stripping and removing the cyst wall and the thermal
damage provoked by coagulation can lead to loss of healthy
ovarian tissue and subsequent reduction in the follicle
density. Muzii et al.52 histologically analysed excised
specimens following laparoscopic excision of ovarian cysts
using the stripping technique. The primary outcome in this
study was to evaluate the presence and nature of ovarian
tissue adjacent to the cyst wall. Fifty-four percent of ovarian
tissue was inadvertently excised along with the cyst wall in
those with endometriotic cysts, compared with 6% in those
with non-endometriotic cysts.35 The excised ovarian tissue
ª 2020 Royal College of Obstetricians and Gynaecologists
Balachandren et al.
did not show morphological characteristics seen in normal
ovarian tissue.35
Several other studies have also demonstrated a reduction
in the ovarian reserve following cystectomy for
endometriomas. The literature includes a meta-analysis of
seven published studies, which showed a 30% decrease in
postoperative AMH levels, and a systematic review also
demonstrating a decline in ovarian reserve following
surgery.3,53,54 Two prospective longitudinal studies showed
partial recovery of AMH levels 3 months after surgery to
about 65% of the preoperative level in both endometriotic
and non-endometriotic cysts.55,56 Similar findings of reduced
ovarian reserve were seen in studies assessing ovarian reserve
following cystectomy for non-endometriotic cysts, primarily
dermoid cysts.55,57,58
In contrast, Muzii et al.33 analysed data from 13
publications reporting AFC levels before and after
endometrioma surgery. They showed that ovarian reserve,
as assessed by AFC, did not change significantly. The
differences between the changes of these two surrogate
markers (AMH and AFC) can probably be explained by the
fact that AFC assessment is likely to be less reliable in the
presence of endometriomas and that the preoperative AFC
underestimates the value; this may then obscure the
postoperative reduction in AFC.59
The size of the cyst being removed is another important
factor when determining the effect on ovarian reserve and
future fertility. Using histological measurements of
endometrioma cystectomy specimens, Roman et al.60 found
an average loss of 200 µm of ovarian tissue per centimetre
increase in endometrioma diameter. Several other studies
also demonstrated a more significant decline in ovarian
reserve following removal of endometriomas greater than 5–
7 cm in diameter.32,61,62 There is also a higher risk of
oophorectomy when performing large cystectomies.
Clinicians frequently advise patients to delay surgery until a
cyst reaches a particular size, when there is a significant risk
of ovarian torsion. It may be wiser to proceed with surgery
when the cyst is small; especially in those with mucinous
cystadenomas, which have a propensity to grow into
large cysts.63
Bilateral cystectomy can also lead to a greater decline in the
ovarian reserve than with unilateral surgery.3,64 In particular,
women having surgery for bilateral endometriomas have
been shown to have an increased risk of developing
premature ovarian insufficiency.21,65
Ovarian cystectomy and spontaneous
conception
Higher rates of spontaneous conception have been shown in
infertile women who had surgical treatment for
endometriomas.66 Maggiore and colleagues35 looked at
31
 Ovarian cystectomy and fertility

spontaneous pregnancy rates of women who tried to conceive

Table 1. Clinical variables to be considered when deciding whether or
spontaneously for 1 year, with known rectovaginal not to perform surgery in women with endometriomas selected for IVF
endometriosis with or without endometriomas and treated
with expectant or surgical management. The crude and Favours Favours expectant
Characteristics surgery management
cumulative spontaneous pregnancy rate was higher in those
treated surgically (30.4% and 34.5% versus 11.7% and 18.0%,
respectively).35 It must be emphasised that these data apply Previous interventions for None ≥1
to women with a history of infertility; it would be difficult to endometriosis
recommend routine surgical treatment of endometriomas to
Ovarian reservea Intact Damaged
improve chances of spontaneous conception in those without
proven infertility. Even in the infertile woman with an Pain symptoms Present Absent
endometrioma, the potential benefit of improving her
Bilaterality Monolateral Bilateral disease
chances of spontaneous conception through surgical
disease
management must be balanced with the risk of reducing
her ovarian reserve and worsening the pelvic anatomy. The Sonographic feature of Present Absent
European Society of Human Reproduction and Embryology malignancyb
(ESHRE) Guideline Group for the management of women
Growth Rapid growth Stable
with endometriosis recommends clinicians to counsel
women about the risk of a reduction in the ovarian reserve, a
Ovarian reserve is estimated based on serum markers or previous
along with the possible loss of the entire ovary – in particular hyperstimulation cycles. bSonographic feature of malignancy refers
for those who have had previous ovarian surgery.66 to solid components, locularity, echogeniety, regularity of shape,
wall, septa, location and presence of peritoneal fluid. Republished
with permission.70
Ovarian cystectomy and IVF outcomes
Cystectomy for endometriomas prior to IVF treatment is not
routinely recommended because it has not been shown to better preservation of ovarian reserve when using laser
improve IVF outcomes.67 A Cochrane review assessed the ablation or plasma energy rather than cystectomy,72–74
effectiveness of surgery versus no treatment for women with although recurrence rates at 1 year post-laser ablation
an endometrioma prior to undergoing assisted reproductive were higher.75
technology (ART).67 They included two trials comparing Following cystectomy, haemostasis can be achieved using
surgery (aspiration and cystectomy) with expectant diathermy, suturing or haemostatic sealants. A systematic
management and found no evidence of benefit for clinical review and meta-analysis of 12 published controlled trials
pregnancy rates.68,69 In fact, one study showed a decreased showed that laparoscopic suturing was superior to bipolar
ovarian response to gonadotrophins following cystectomy coagulation when comparing AMH and AFC – even
for endometriomas.68 12 months after surgery.76 When comparing bipolar with
Surgery should be considered under some clinical haemostatic sealants, the results favoured the use of
circumstances. Garcia-Velasco and Somigliana70 created the haemostatic agents.76
following table (Table 1) to help guide clinicians on the
clinical variables to be considered when deciding whether or
Recommendations for ovarian cystectomy
not to perform surgery in women with endometriomas
selected for IVF. 1. Perform ovarian reserve assessments
For women who have not completed their family, ovarian
reserve assessments should be carried out before any
Effect of surgical technique on fertility
cystectomy in the following situations:
outcomes
 those requiring repeat surgery on the same or
Apart from cyst excision, several other surgical techniques contralateral ovary
exist, including drainage and bipolar coagulation or ablation  women diagnosed with severe endometriosis and
using plasma or laser energy. A systematic review of two bilateral endometriomas
RCTs revealed cystectomy to be superior to drainage and  those with coexistent aetiologies for subfertility, including
bipolar coagulation in terms of spontaneous pregnancy rates, low sperm parameters in the male partner
lower risk of recurrence and pain symptoms among subfertile  women of advanced reproductive age
patients with endometriomas greater than 3 cm in  women with coexistent risk factors for premature
diameter.71 Several comparative studies have also showed ovarian insufficiency.

32 ª 2020 Royal College of Obstetricians and Gynaecologists


These patients are more likely to need ART to help them
conceive in the future and/or are at increased risk of
premature ovarian failure. Ovarian cystectomy can reduce a
woman’s ovarian reserve, which can hinder the chance of
success with IVF treatment.77
Ovarian reserve assessments provide an indirect measure
of oocyte quantity but are poor predictors of oocyte quality78
and should not be used to predict spontaneous conception in
ovulatory couples.79 The accuracy of ovarian reserve
assessments in the presence of ovarian cysts has not been
well studied. AFC and serum AMH have been shown to be
lower in the presence of endometriomas, but they did not
appear to be affected by the presence of other types of
cysts.31,32,80 The reduced AFC associated with
endometriomas could be associated with an inability to
visualise the antral follicles on ultrasound scan in the
presence of an endometrioma.81 This theory is further
supported by Lima et al.,82 who analysed the number of
oocytes retrieved during IVF or intracytoplasmic sperm
injection (ICSI) cycles in women with a unilateral
endometrioma. Although the AFC was reduced in the
ovaries with an endometrioma, the median number of
oocytes retrieved was similar (p = 0.60) between ovaries with
an endometrioma (2.0; interquartile range [IQR] 0.5–5.0)
and the contralateral ovaries (2.0; IQR 0.0–4.0).73
2. Discuss fertility preservation options
If the ovarian reserve is already compromised or there is a
considerable risk of premature ovarian insufficiency, fertility
preservation should be discussed prior to cystectomy. For
postpubertal females, egg or embryo storage following
ovarian stimulation is an established technique that allows
subsequent IVF and embryo transfer.83 However, ovarian
stimulation may be unsuccessful if the ovarian reserve is
already compromised. The disadvantages of fertility
preservation before cystectomy include delay in surgery,
visceral injury during egg collection, pelvic infection
from accidental puncture of the cyst84 and a theoretical
increase in the risk of torsion of the hyperstimulated
ovary.
In the UK, NHS funding is not routinely available for
oocyte or embryo cryopreservation for benign conditions.
However, if there is a considerable risk of permanent
infertility, such as previous oophorectomy or repeat surgery
for severe endometriosis, individual funding requests can be
made to the relevant clinical commissioning group.
3. Perform pelvic ultrasound scan and a bimanual
examination
Assess the type, size, number and location (unilateral or
bilateral) of the ovarian cysts before surgery using pelvic
ultrasound and bimanual examination. Bimanual
examination can help identify deep endometriotic nodules
ª 2020 Royal College of Obstetricians and Gynaecologists
Balachandren et al.
in the Pouch of Douglas, which can be difficult to visualise
on ultrasound.
4. Obtain appropriate consent
The patient should be fully informed of all possible risks
associated with the surgical procedure, including reduction
in ovarian reserve and risk of oophorectomy.
5. Refer the woman to a centre of expertise
If the surgery cannot be performed or completed safely, the
patient should be referred to a centre of expertise.
Anatomical consideration during
cystectomy
The ovary receives its blood supply from two sources: the
ovarian artery and an anastomosis between the ovarian artery
and the ascending branch of the uterine artery/tubal artery.
The ovarian artery approaches the ovary through the
infundibulopelvic ligament, while the uterine/tubal artery is
found within the ovarian ligament. These intra-ovarian
vessels are found in the anterolateral aspect of the ovary, at
the insertion of the mesovarium.
Surgical recommendations
Non-endometriotic cysts
1. Make an incision on the anti-mesenteric surface of ovarian
cortex (Figure 1a).
2. Identify the plane between the cyst wall and the ovarian
cortex; develop this plane further (Figure 1b).
3. Enucleate the cyst or cyst wall (if the contents are spilled
or aspirated) by a combination of blunt and sharp
dissection, traction and countertraction.
4. Achieve haemostasis by targeted coagulation of blood
vessels (Figure 1c) or suturing (Figure 1d). Avoid
indiscriminate use of diathermy and consider using
haemostatic sealants instead of excessive diathermy.
Endometriotic cysts
The European Society of Gastrointestinal Endoscopy (ESGE)/
ESHRE/World Endometriosis Society (WES) Working Party
on the surgical techniques for ovarian endometriomas
recommends the following approaches:18
1. Mobilise the ovary and drain the cyst (Figure 2a and 2b).
2. Make an incision to reveal the cleavage plane (Figure 2c),
either on the edge of the cyst opening or a central incision,
which divides the cyst into two halves. Incision should be
away from the blood vessels in the hilum/mesovarium.
Use of cold cut at the edge of the cyst opening may assist
in identifying the cleavage plane.
3. To aid dissection and identification of the cyst wall, saline
or diluted synthetic vasopressin (0.1–1 unit/ml) may be
33
 Ovarian cystectomy and fertility

(a) (b)

(c) (d)

Figure 1. Ovarian cystectomy. (a) Reveal cleavage plane. (b) Dissect the cyst wall from the ovarian parenchyma. (c,d) Achieve haemostasis by
targeted coagulation and/or suturing and then reconstruct the ovary.

(a) (b)

(c) (d)

(e) (f)

(g)

Figure 2. Ovarian cystectomy of an endometrioma. (a) Right ovarian endometrioma and adherent right ovary. (b) Drainage of endometrioma
after mobilising the ovary. (c) Exposure of the plan between the cyst wall and ovarian cortex. (d) Vasopressin injection under the cyst capsule. (e)
Dissect cyst capsule from the ovarian parenchyma. (f) Cyst capsule after complete removal. (g) Precise spot bipolar diathermy to achieve
haemostasis.

34 ª 2020 Royal College of Obstetricians and Gynaecologists


injected under the cyst capsule (Figure 2d). This has the
additional advantage of reducing bleeding during
cyst removal.
4. Once the cleavage plane is identified, use gentle traction
and countertraction to dissect the cyst capsule from the
ovarian parenchyma (Figure 2e and 2f). Avoid excessive
force to separate a highly adherent cyst from the ovary.
This is likely to tear the ovarian tissue, causing excessive
bleeding and the need for coagulation or diathermy, which
will further damage normal ovarian tissue.
5. Precise spot bipolar coagulation will prevent unnecessary
damage to healthy tissue and avoids blind or excessive
diathermy (Figure 2g).
6. Ensure final haemostasis after complete removal of the
cyst capsule. Bipolar coagulation, suturing or intra-
ovarian haemostatic sealant agents may also be used for
this purpose. It is important to avoid damaging the major
blood supply at the hilum coming in from the ovarian and
infundibulopelvic ligaments at this stage.
7. After removal of large cysts, reconstruct the ovary and
achieve haemostasis with monofilament sutures. For small
cysts, suturing is often not required because the ovarian
opening usually approximates spontaneously. If a suture is
used, it should ideally be placed inside the ovary, as the
exposed suture may be prone to adhesion formation.
Two-step approach for large
endometriomas
After opening and draining the endometrioma as described
previously, the cyst wall is inspected and a biopsy taken.
GnRHa therapy is then given for 3 months to reduce the
thickness of the cyst wall through atrophy and reduction in
stromal vascularisation.85 The surgery is completed with a
second laparoscopy in the form of cystectomy, CO2
vaporisation, bipolar diathermy or plasma ablation of the
cyst wall lining.20 Although women have to undergo two
invasive procedures, the potential benefit is that this may
facilitate the management of larger ovarian endometriomas,
reduce recurrence rates and limit the damage to the
ovarian reserve.20
Conclusion
The management of benign ovarian cysts in women of
reproductive age, children and adolescents is complex. Those
experiencing considerable pain related to the cyst and who
are unsuitable for hormonal therapy will often require
surgery. Before an ovarian cystectomy, the surgeon should
carefully consider the age of the patient, the nature of the
cyst, rate of growth, risk of recurrence, surgical history and
future fertility plans. They should also assess other causes of
subfertility that would increase the likelihood of needing
ª 2020 Royal College of Obstetricians and Gynaecologists
Balachandren et al.
ART in the future, including the male partner’s sperm
parameters.3
Performing ovarian reserve assessments would be
recommended in all women having repeated surgery on the
ovaries, as well as in those with severe endometriosis, or if
there is a high chance of needing ART to conceive. Regardless
of whether or not a cystectomy is performed, it is imperative
that the risk to fertility and ovarian function is discussed with
all patients. The lack of routine NHS funding for oocyte
cryopreservation for benign conditions should not deter
clinicians from discussing fertility preservation options when
there is a significant risk of injury to a woman’s
reproductive potential.
Disclosure of interests
EY is an Associate Editor of The Obstetrician & Gynaecologist;
she was excluded from editorial discussions regarding the
paper and had no involvement in the decision to publish.
Contribution to authorship
NB and ES conceived the topic. NB planned the scope of the
article, researched and wrote the initial draft. EY, DM and ES
reviewed and revised the manuscript. All authors approved
the final version.
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37
 DOI: 10.1111/tog.12710
The Obstetrician & Gynaecologist
http://onlinetog.org
Very advanced maternal age
a b
Alice Howell MBBS MA MSc MRCOG,* Margaret Blott
a
Specialist Registrar (ST4), Royal Free London NHS Foundation Trust, London NW3 2QG, UK
b
Consultant Obstetrician, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
*Correspondence: Alice Howell. Email: alice.howell6@nhs.net
Accepted on 14 July 2020. Published online 21 December 2020.
Key content
 Increasing fertility options have led to increased birth rates among
women over the age of 45 years.
 Most women aged 45 years or older conceive via assisted
reproductive technologies, which are associated with increased
risks to both mother and fetus.
 Multiple pregnancies are disproportionately common in this group
of women as a result of multiple embryo transfer. The maternal
and fetal risks are increased significantly in multiple pregnancies.
 A maternal age of 45 years or more is associated with
complications in early pregnancy and the antenatal period and
with significant obstetric complications.
 Fetal complications are increased in this group; in particular there
is an increased risk of multiple births, increased rates of preterm
birth and higher perinatal mortality rates.
Please cite this paper as: Howell A, Blott M. Very advanced maternal age. The Obstetrician & Gynaecologist 2021;23:38–47. https://doi.org/10.1111/tog.12710
Introduction
Since the mid-1970s, the average age of childbearing has
steadily increased in England and Wales.1 Assisted
reproductive technology (ART) is an available choice in
many countries and has given older women the possibility of
having a baby.
In 2018, there were 2366 live births to women aged
45 years or older in England and Wales, compared with
1619 births in 2008.2 Of women having a baby who are
aged 48 years or more, 53% are primiparous compared
with 44% of younger women.3 Medical literature uses the
term ’very advanced maternal age’ (vAMA) to refer to
women who are aged 45 years or more at the time
of delivery.
Although the relationship between advancing maternal age
and increased risks of adverse maternal and infant outcomes
is well established, most studies have only reported outcomes
in women older than 35 years or older than 40 years. This
review aims to establish an evidence-based approach to the
care of women aged 45 years or more using studies that
specifically assess the risks in this group of pregnant women
and their babies.
38
2021;23:38–47
Review
MBBS FRCOG
Learning objectives
 To understand the maternal implications, complications and risks
of pregnancy in women of very advanced maternal age, to aid
counselling this group of women prior to and during pregnancy.
 To understand the fetal complications associated with pregnancy
in women of very advanced maternal age, including stillbirth and
preterm labour.
 To establish an evidence-based approach to the antenatal
management and care of women of very advanced maternal age.
Keywords: antenatal care / assisted conception / medical disorders
in pregnancy / multiple pregnancy / pre-eclampsia
Assisted reproductive technologies
Spontaneous conception in women of vAMA is rare, but
more common in parous women.4,5 Conception using
autologous embryos is also rare; the live birth rate is 2.9%
in a cycle for women aged 45 years. For women aged 46 years
and older, the live birth rate was so low, it was reported as
being 0%.6
In 2016, Fitzpatrick et al.3 conducted a UK cohort study to
describe the characteristics, management and outcomes of
women of vAMA, focusing on women aged 48 years and
over. It showed that 78% of the women delivering had
conceived using ART.3 Of these, 51% had assisted conception
performed outside the UK, 91% reported using egg donation
and 21% had used donor sperm. Of these women, 40% had
one embryo transferred, 45% had two embryos transferred
and 15% had three or more embryos transferred. Just under
half of those who had multiple embryos transferred went on
to have a multiple pregnancy.
ART is associated with an increased risk of ovarian
hyperstimulation syndrome, miscarriage, ectopic pregnancy,
pregnancy-induced hypertension, pre-eclampsia, venous
thromboembolism (VTE), genetic and chromosomal
ª 2020 Royal College of Obstetricians and Gynaecologists

disorders, structural abnormalities, fetal growth restriction
(FGR), stillbirth and preterm labour.7–10 These risks also
increase with maternal age and multiple pregnancies.
Pre-eclampsia complicates just 1.1% of natural conception
pregnancies and 12.6% of oocyte donation conceptions in
women of vAMA.10 Among oocyte donation pregnancies, the
risk of pre-eclampsia is the same among primiparous and
multiparous women, but as maternal age increases, the risks
increase. Guesdon et al.11 demonstrated that in women of
vAMA undergoing oocyte donation with singleton
pregnancies, the risk of gestational hypertension was 5.5%
in women aged 45–49 years, rising to 19.2% above the age of
50 years. In the same study, babies born to women aged
45–49 years had a 14.3% risk of FGR compared with 30.7%
in women aged above 50 years.
Studies demonstrate women of vAMA who conceive by
ART have a 23.3% risk of delivering a baby before 36 weeks
of gestation compared with a 9.3% risk in vAMA women
who conceive spontaneously,9 independent of parity. Babies
conceived by ART had a 22.1% risk of being born with a low
birth weight (<2500 g), while babies conceived
spontaneously have a 7.4% risk. Studies in this area are
often limited in information as to whether the embryo was
autologous or donated.
Women of vAMA who become pregnant as a consequence
of ART should, like all women, have a risk assessment at
booking; they should be offered low-dose aspirin (150 mg)
from 12 weeks of gestation until delivery.12 They should also
be assessed for VTE, since women who have conceived with
ART are at increased risk, particularly in the first trimester.
The most recent review of maternal deaths in the UK
recommends clear pathways for women to access early
prescriptions and support for thromboprophylaxis to
ensure compliance.13
Table 1. Summary of the risks from the current evidence for women
of very advanced maternal age, comparing conception with assisted
reproductive technologies (ART) and spontaneous conception
Pregnancy Pregnancy
conceived by ART conceived
and oocyte spontaneously
Condition donation (%) (%)
Maternal pre-eclampsia 12.6 1.1
Delivery before 23.3 9.3
36 weeks of gestation
Risk of baby being born 22.1 7.4
with low birth weight
(<2500 g)
ª 2020 Royal College of Obstetricians and Gynaecologists
Howell and Blott
Table 1 shows a summary of the risks for women of vAMA,
from the current evidence, comparing conception with ART
and spontaneous conception.
Early pregnancy complications
Miscarriage rates increase with increasing maternal age. In
women of vAMA, the overall risk of miscarriage is 53%.14
Rates of miscarriage beyond the first trimester are also
increased.15 There is currently no intervention for the
prevention of miscarriage in this group. The management
of women of vAMA with both sporadic and recurrent
miscarriage is no different to younger women and has been
covered elsewhere.16
The risk of an ectopic pregnancy in women with vAMA is
three times the overall risk of ectopic pregnancy in all
women, with studies17 demonstrating a 6.9% risk of ectopic
pregnancy in women aged 44 years or older. Conception by
ART is not protective against ectopic pregnancy. It is likely
that age-related changes associated with exposure of risk
factors are directly related to maternal age.18
Management of ectopic pregnancies should follow local
protocols based on national guidelines.16,19 Clinicians should
be aware there is some evidence that women aged 40 years
and older with ectopic pregnancies are twice as likely to need
a blood transfusion than younger women.20 A VTE
reassessment after miscarriage or ectopic pregnancy should
be performed, following findings from the most recent
confidential enquiry into maternal deaths in the UK.13
Multiple pregnancy
Women of vAMA are more likely to have a multiple
pregnancy than younger women.2,3,21 Figure 1 shows the
rates of multiple births in women of vAMA and all women in
the UK from 1938–2018. In 2018, women of vAMA in the UK
had a multiple pregnancy rate of 79.3/1000 compared with
15.4/1000 in all women.2
Since 1993, women of vAMA have consistently recorded
the highest multiple pregnancy rate, secondary to increasing
availability of ART and the number of embryos transferred.
In January 2009, the Human Fertilisation and Embryology
Authority (HFEA) recommended elective single embryo
transfer in an effort to reduce the overall national multiple
birth rate through ART to 10%. Clinics are not to exceed a
maximum multiple birth rate;2 however, women of vAMA
are often the group that receives more than one embryo. Half
of women aged 48 years and older who had a double embryo
transfer went on to have a multiple pregnancy. This is higher
than reported rates in double embryo transfers in a younger
population, likely associated with the use of donated ova.3
Clinicians should be aware that patients travelling abroad
for ART are more likely to undergo multiple embryo transfer.
39
 Very advanced maternal age
Figure 1. Rates of multiple births in women of very advanced maternal age (vAMA) and all women, 1938–2018.2HFEA = Human Fertilisation and
Embryology Authority; IVF = in vitro fertilisation.
Women of vAMA with multiple pregnancy have increased
rates of fetal and maternal complications compared with
women of vAMA with singleton pregnancies11,22–24 and
younger women with multiple pregnancies.25
In women of vAMA, the risks associated with a multiple
pregnancy as a result of ART are different to a singleton
pregnancy conceived spontaneously or by ART. Twin
neonates born to women of vAMA will sustain more
adverse outcomes than singletons.22–26 After ART they are
56–65% more likely to be born before 37 weeks of
gestation.23,25,26 Birth before 32 weeks of gestation is also
significantly increased.25 Twin infants are four times more
likely to need intubation and are 1.5–3 times more likely to
be admitted to neonatal intensive care.23,26
Maternal complications associated with ART and multiple
pregnancy are worse in women of vAMA.23–25 They are
significantly more likely to suffer life-threatening
complications, such as bleeding requiring a blood
transfusion and maternal admission to the intensive care
unit (ICU);25 10–42% of women develop gestational
hypertension,23,25 26–32% develop pre-eclampsia,23,25
10–35% develop gestational diabetes mellitus (GDM),22,25
and 79.0–91.8% had a caesarean section delivery.22,25
Antenatal care should be in line with guidance published
by the National Institute for Health and Care Excellence
(NICE) on multiple pregnancy,27 but individualised
according to obstetric factors. Fetal surveillance should be
offered and recommended in line with the NICE twins and
triplets guideline.27 We recommend early discussions
between clinician and patient about the mode of delivery,
in light of the increased risk of preterm delivery. There is
currently no effective intervention proven to decrease the risk
of preterm delivery.
40
Table 2 shows a summary of the evidence, risks and
recommendations for fetal, neonatal and maternal morbidity
and mortality in women of VAMA with twin and
singleton pregnancies.
Maternal complications, risks and
recommendations
Pregnancies in women of vAMA have increased risks of pre-
existing medical conditions, GDM, gestational hypertension,
pre-eclampsia, abnormal placentation, ICU admission,
caesarean delivery, postpartum haemorrhage (PPH), blood
transfusion and prolonged admission to hospital.3,5,21,24,28–31
They are less likely to smoke cigarettes.3
Fitzpatrick et al.3 found that 44% of women aged 48 years
or older had a reported pre-existing medical condition
compared with 28% of younger women. There is little
evidence to suggest which pre-existing medical conditions
have the best and worst outcomes, but women over the age of
40 years are three times more likely to die than women in
their early 20s.13 We recommend early referral to a high-risk
antenatal clinic or maternal medicine clinic.
Care must be individualised. Many of the studies looking
at outcomes in women of vAMA have not separated
primiparous from multiparous women, multiple from
singleton pregnancies, pregnancies conceived spontaneously
from those conceived with ART, or pregnancies in women
with or without pre-existing co-morbidities.
Obesity
Women aged 48 years or more are more likely to be
overweight or obese than younger women.3 Pregnant
women who are obese are at greater risk of pre-eclampsia,
ª 2020 Royal College of Obstetricians and Gynaecologists
 Howell and Blott

Table 2. Summary of the evidence, risks and recommendations for

Diabetes
fetal, neonatal and maternal morbidity and mortality in women of very Maternal age is known to be a risk factor for the development
advanced maternal age with twin and singleton pregnancies of GDM. Studies have demonstrated rates of 12.6–21.0% in
women of vAMA,3,21,28–31 rising to 28% in women aged
Risk in Risk in
twins singletons 50 years and above and 35.1% in twin pregnancies conceived
Condition (%) (%) Recommendation by ART.24 Women of vAMA are nine times more likely to
require insulin to treat GDM than younger women.3 We
recommend offering screening at 16–18 weeks of gestation,
Delivery 56–65 8–14 Ensure that women are
in addition to screening at 26–28 weeks of gestation. Should a
before being cared for in a
37 weeks of specialist multiples clinic woman screen positive, her care should follow national
gestation with a neonatal intensive guidance.33 Care may need to be shared between a diabetes
care unit that can provide specialist multidisciplinary care, a multiples clinic and a
Delivery 22.67 2 appropriate levels of care
lead consultant.
before for babies born
34 weeks of prematurely
gestation Have early discussions about Hypertensive disease
steroids and the location of Pre-eclampsia, severe or early onset pre-eclampsia and
Delivery 8.2 1.3 birth
before
eclampsia are more common in women of vAMA than in
32 weeks of younger women.3,24,28–31 Fitzpatrick et al.3 found that 6% of
gestation women aged 48 years and older developed pre-eclampsia or
eclampsia compared with 2% of younger women. Meyer24
Admission to 36 8
neonatal
found that 32% of vAMA with multiple pregnancy conceived
intensive care by ART developed pre-eclampsia or eclampsia compared
with 6.2% of younger women who conceived a twin
Fetal growth 18.6 7.6 Scans as recommended by pregnancy by ART.
restriction the NICE twins and triplets
guideline27 Despite these figures, most maternal outcomes are good
and there is some evidence that women of vAMA are not at
Maternal 10–42 14 Regular blood pressure greater risk of complications from hypertension solely based
hypertensive monitoring in the third
on their age.34 Older women without pre-existing
disease trimester
hypertension have been shown to have favourable
Maternal pre- 26–32 4–12 Advise low-dose aspirin outcomes, with rates of severe pre-eclampsia being
eclampsia 150 mg from 12 weeks of significantly higher in women above 50 years of age in
gestation until delivery
whom there are higher rates of pre-existing hypertension.34,35
GDM 10–35 8.0–23.8 Advise glucose tolerance When pre-existing maternal health is documented, it seems
test at 16–18 weeks of that the main predictor of outcomes is maternal health and
gestation, as well as at 26– not maternal age.
28 weeks of gestation to
screen for GDM
Pre-pregnancy counselling should be offered to all women
with pre-existing hypertension, including a review of anti-
Caesarean 79.0– 50 Early discussions about the hypertensive medications, an up-to-date echocardiogram,
section 91.8 mode of delivery renal function tests and renal imaging.
delivery

GDM = Gestational diabetes mellitus; NICE = National Institute for
Health and Care Excellence.
GDM and caesarean birth than women with a normal body
mass index (BMI). There is also a higher risk of fetal neural
tube defects associated with obesity.32 The management of
women with vAMA who are overweight or obese is no
different to that of younger overweight or obese women and
has been covered elsewhere.32 In our experience, the early
initiation of high dose folic acid (5 mg) is often missed in
this group.
Hypothyroidism
Hypothyroidism is more common in women of vAMA.30 The
relationship between pre-existing hypothyroidism and
adverse pregnancy outcomes is well established.
Surveillance of thyroid function and treatment with
levothyroxine is an effective management strategy.
Venous thromboembolism
Evidence that maternal age affects rates of VTE is conflicting:
Fitzpatrick et al.3 found that rates of thrombotic events were
the same in women across all age groups; however, previous
large studies have shown that women over the age of 35 years

ª 2020 Royal College of Obstetricians and Gynaecologists 41

 Very advanced maternal age
have a 70% increase in VTE in the postpartum period.36
Current guidance in the UK simplifies risk and states that age
greater than 35 years is a risk factor for VTE antenatally
and postnatally.37
Thrombophrophylaxis is recommended for women of
vAMA with additional risk factors. The duration of
prophylaxis should be based on individual risk factors, in
keeping with national guidance.37 Admission alone increases
VTE risk 12-fold.37 Following the confidential enquiry into
the death of a woman in the UK, it was advised that VTE
reassessment occurs at every opportunity; the woman was
over the age of 40 years with a pregnancy as a result of ART.
She collapsed immediately after a caesarean section following
a 10-day admission for pre-eclampsia.13
Previous uterine surgery
Women aged 48 years or older have a 26% risk of having had
previous uterine surgery, not including a caesarean section,
compared with 7% of younger women.3 The type of uterine
surgery was not specified in the study. In our experience,
women of vAMA are more likely to have undergone uterine
surgery related to fibroids. We advise early referral to a high-
risk antenatal clinic to discuss options and risks regarding
mode of delivery. Women may have access to previous
medical records or operation notes and should be
encouraged to share these with her consultant team. The
management of delivery following myomectomy may be
influenced by the operation performed and if the cavity has
been breached, many women are advised at the time of the
myomectomy to request caesarean sections for any
future deliveries.
Placental complications
Women of vAMA are three times more likely to have
placenta praevia.3 In primiparous women, this may be as a
result of ART, multiple pregnancy or damage to the
endometrium during previous uterine surgery.38 In
multiparous women, a previous caesarean section may be
a contributing factor.3 All women should be advised to
have a fetal anomaly ultrasound scan between 18 and
21 weeks of gestation and those involved in scanning
should be aware of the increased risk of placenta praevia in
women of vAMA. The investigation and management of
placenta praevia and placenta accreta is covered by
national guidelines.39
Women of vAMA are three times more likely to have a
placental abruption than younger women.3 It is difficult to
predict and no effective prevention treatments are currently
available. Women of all ages are advised to report all vaginal
bleeding to their antenatal care provider. Placental abruption
is a clinical diagnosis and there are no sensitive or reliable
diagnostic tests available. Ultrasound has limited sensitivity
in the identification of retroplacental haemorrhage.38
42
Postpartum haemorrhage
PPH has been shown to be the most statistically significant
complication affecting women of vAMA, whether they are
primiparous or multiparous, having a singleton or multiple
pregnancy, conceived spontaneously or by ART. PPH affects
one in four women of vAMA.3 Women with multiple
pregnancies, pre-eclampsia and those receiving
thromboprophylaxis are at particular risk. Women of
vAMA are almost four times more likely to need blood
products following a PPH than younger women.3 Plans and
precautions to minimise the risk of PPH should be discussed
with the mother in the antenatal period, including the
investigation and treatment of anaemia and the role of
prophylactic uterotonics in the management of the third
stage of labour.40
Caesarean section
Caesarean section rates are high in women of vAMA, but
only in primiparous women.3 Primiparous women of vAMA
are eight times more likely to deliver by caesarean section
than women aged 30–34. Women of vAMA who conceived
by ART are six times more likely to deliver by caesarean
section.5 Of women of vAMA with multiple pregnancy who
conceive by ART, 91.8% deliver by caesarean section.24 These
studies do not separate emergency from elective caesarean
sections, but in Fitzpatrick’s large UK study, in which 78% of
women aged 48 years or older had a caesarean section, the
indications were as follows: maternal age (21%), fetal
compromise (19%), maternal compromise (14%), failure to
progress (14%), abnormal presentation (10%), previous
caesarean section (9%) and maternal request (5%). These
figures indicate that most, but not all caesarean sections are
performed electively.
Women should be offered and supported in their decision-
making. Discussions should be initiated early on in antenatal
care. Women should be made aware of the national guidance
when requesting a caesarean section.41 It is recommended
that intrapartum care takes place in a maternity unit with
facilities for emergency caesarean delivery and access to
appropriately skilled clinicians.
Admission to hospital and intensive care
Women of vAMA have a 30% risk of antenatal hospital
admission21 and are 33.5 times more likely to be admitted to
ICU than younger women.3 A study of singleton pregnancies
demonstrated that women aged 40 years or older had
significantly elevated rates of renal failure, shock, cardiac
morbidity and serious complications following obstetric
interventions contributing to increased admission to ICU.42
We recommend that care is offered in a place with
appropriate intensive care support for both mother and
neonate(s), that high-risk women of vAMA are seen in a
high-risk anaesthetic clinic at 30–32 weeks of gestation and
ª 2020 Royal College of Obstetricians and Gynaecologists
 Howell and Blott

Table 3. A summary of maternal complications, risks and recommendations in women of very advanced maternal age (vAMA)

Maternal complication Risk Recommendation

Pre-existing medical 44% (of women aged 48 years or older) Early referral to a high-risk antenatal clinic or maternal medicine
complication clinic

Gestational diabetes mellitus 12.6–21.0% Offer screening at 16–18 weeks of gestation in addition to screening
35.1% (in twin pregnancies conceived by at 26–28 weeks of gestation
assisted reproductive technology) Women of vAMA are nine times more likely to require insulin

Hypertensive disease
6–32% Pre-pregnancy counselling should be offered to all women with pre-
existing hypertension, including a review of antihypertensive
medications, an up-to-date echocardiogram, renal function tests
and renal imaging
Advise low-dose aspirin 150 mg from 12 weeks of gestation until
delivery
Regular blood pressure monitoring in the third trimester

Previous uterine surgery 26% (of women aged 48 years or older) Early referral to a high-risk antenatal clinic

Placenta praevia Three times more likely to have placenta Fetal anomaly ultrasound scan between 18 and 21 weeks of
praevia than younger women gestation
Those involved in scanning should be aware of the increased risk of
placenta praevia in women of vAMA

PPH 25% Plans and precautions to minimise the risk of PPH should be
Women of vAMA are almost four times discussed. Investigate and treat anaemia
more likely to need blood products than Discuss the role of prophylactic uterotonics in the management of
younger women the third stage of labour

Antenatal hospital admission 30% Thrombophrophylaxis is recommended for women of vAMA with
additional risk factors
Admission alone increases venous thromboembolism risk 12-fold

Admission to intensive care unit
33.5 times more likely to be admitted than
younger women
Consider offering care in a place with appropriate intensive care
support for both mother and neonate(s)
High-risk women of vAMA to be seen in a high-risk anaesthetic clinic
at 30–32 weeks of gestation
On-call consultant anaesthetist should be made aware when a
woman of vAMA is admitted to the unit

PPH = postpartum haemorrhage.

that the on-call consultant anaesthetist be made aware when

a woman of vAMA is admitted to the unit.
In the UK, if the mother is not married then a father only
has parental responsibility if he is named on the child’s birth
certificate. Women of vAMA are as likely to be single as
women of other ages,3 but they are more likely to be using
donated sperm or embryos. Owing to the increased risks
discussed, it is advised that the mother has a will in place
prior to delivery, to clarify the legal status of the donor or any
co-parent and to confirm who will be legally and financially
responsible for the child in the case of maternal illness
or death.
Table 3 shows a summary of maternal complications, risks
and recommendations in women of vAMA.
Effect on fetal and neonatal morbidity
and mortality
Little is known about the long-term effect of being born when
your mother is of vAMA. Some studies have suggested that
women are more likely to have stable careers and finances,
with one large study showing that increasing maternal age is
associated with children having fewer hospital admissions,
fewer unintentional injuries, better language and fewer social
and emotional difficulties.43
Perinatal morbidity
Many studies demonstrate that children born to women of
vAMA have increased perinatal morbidity; they are more

ª 2020 Royal College of Obstetricians and Gynaecologists 43

 Very advanced maternal age
often born before 37 weeks of gestation,3,921,22,28,30,44
admitted to the neonatal intensive care unit (NICU),29,30
more often born small for gestational age (SGA),28,34,45–47 or
born with a birthweight of less than 2500 g.3,29,48
Fitzpatrick et al.3 found that women aged 48 years and
above are twice as likely to deliver spontaneously before
37 weeks of gestation and 4.5 times more likely to deliver
prematurely because of iatrogenic intervention. Women of
vAMA are twice as likely to have a SGA baby28 and have a
32% chance of having a baby with a birthweight of less than
2500 g.3 The high rate of babies born with a weight below
2500 g was shown to be associated with prematurity rather
than FGR.3 One in six babies born to women of vAMA need
admission to NICU.30 Appropriate plans for care need to be
made; such plans may involve a transfer of care, in liaison
with the neonatology team. The increased risk of neonatal
admission means that having premature and SGA babies can
have significant long-term and short-term economic and
psychosocial effects on the mother and family.21,29,30
Studies have shown that singleton pregnancies are likely to
have less perinatal morbidity than multiples;35 however, there
is currently a paucity of studies looking at how maternal
complications and risk factors lead to iatrogenic preterm
delivery, neonatal admissions, lower birthweight and
perinatal morbidity and mortality.
Perinatal mortality
Although many studies report adverse perinatal outcomes in
women of vAMA, the absolute rate of stillbirth and perinatal
death is between 1.00 and 1.87%3,5,49 compared with 0.55%
in younger women.49,50
Perinatal mortality rates are 2.0–3.8 times higher in babies
born to women of vAMA3,9,49–52 and, as with women of all
ages, prematurity and SGA babies account for a significant
number of stillbirths and early neonatal deaths in the UK.
Clinicians must be aware that primiparous women and
black women are the highest risk group for stillbirth and that
obesity and additional medical comorbidities are additional
risk factors for stillbirth.50,53 While women should be
encouraged to address factors such as obesity, the only way
to prevent antepartum stillbirth is to offer timed delivery in
the form of an induction of labour or an elective caesarean
section.53–55 There is some evidence that women aged
44 years and older benefited from delivery by 38 weeks of
gestation to reduce stillbirth.56
We recommend that all women of vAMA are advised to
take low-dose aspirin from 12 weeks of gestation, have
their pregnancy associated plasma protein-A (PAPP-A)
measured, have serial assessment of fetal size and umbilical
artery Doppler from 26–28 weeks of gestation and regular
blood pressure monitoring in the third trimester.46 High-
risk cases must be identified and the potential
consequences of early delivery and prematurity
44
discussed.52 There is currently no consensus on the
management of later pregnancy for these women. In
addition to serial growth scans for women of vAMA, we
recommend asking women to monitor fetal movements
until delivery and informing them to sleep in the right or
left lateral position. An induction of labour can be offered,
particularly beyond 37 weeks of gestation. Clinicians and
women of vAMA must be able to discuss balancing the
benefits and risks of remaining pregnant and waiting for
spontaneous labour against the benefits and risks of
induction of labour and elective caesarean section.
Trisomy and congenital anomalies
The risk of Down syndrome (trisomy 21) is directly related to
maternal age if a pregnancy is conceived spontaneously. In
donor embryos, it is related to the age of the donor. The
incidence of trisomy 21 at term is 1:1350 for a 25-year-old
woman (or donor). This increases to 1:35 at the age of
45 years and 1:25 at the age of 49 years.57 The live birth rate
of cases of trisomy 21 to women of vAMA is significantly
lower than 1:35, probably owing to the use of younger donor
embryos and, possibly, the availability of legal termination of
pregnancy services.
In the UK, the combined test is part of a national screening
programme. An older woman is more likely to have a screen-
positive result than a younger woman because she starts with
a higher age-specific risk of Down syndrome. The test is more
likely to detect a Down syndrome pregnancy in an older
woman than in a younger woman. In women of vAMA who
have conceived with their own embryos, there is a 95%
detection rate for Down syndrome (higher than in any other
age group).58
Using a cut-off of 1 in 150 at term as a screen-positive
result, one in four women of vAMA will screen positive.58
A screen-positive result requires careful counselling.
Invasive diagnostic testing (amniocentesis or chorionic
villous sampling) can be offered; it gives accurate results
but has a small risk of miscarriage. Non-invasive prenatal
testing (NIPT) may be an alternative to invasive testing; it
detects 99% of Down syndrome cases and has no risk of
miscarriage; some women may prefer this option. A small
risk of false-positive results means it is recommended that
any positive NIPT result is confirmed with invasive
diagnostic testing if the woman is considering termination
of pregnancy on the basis of trisomy. There is currently no
national guidance on the role of NIPT in antenatal care
and screening.
There is a significant association between congenital
anomalies and trisomy; however, Fitzpatrick et al.3 found
similar rates of congenital anomalies between women
aged 48 years and older and younger women (1.9%
versus 1.5%). This should be reassuring to women
of vAMA.
ª 2020 Royal College of Obstetricians and Gynaecologists
 Howell and Blott

Preconception advice regarding:

- Individualised risks to mother and fetus
- Folic acid 400 μg or 5 mg depending on risk factors
- Medication review
- Optimising body mass index
- Benefits of single embryo transfer
Women with pre-existing hypertension:
- Anti-hypertensive medication review
- Up-to-date echocardiogram
- Renal function tests
- Renal imaging

Immediate venous thromboemolism risk assessment once pregnant:

Clear pathway for women to access prescriptions and support for
thromboprophylaxis to ensure compliance

Low threshold for referral to early pregnancy unit in light of increased

rates of miscarriage and ectopic pregnancy
Venous thromboembolism reassessment after miscarriage or ectopic pregnancy

Booking appointment to establish:

- Method of conception
- Previous uterine surgery. If so, for early referral to a high-risk antenatal clinic to
discuss options and risks regarding mode of delivery
- Risk assessment for venous thromboembolism
- Advise low-dose aspirin (150 mg) from 12 weeks of gestation until delivery

Multiple pregnancy diagnosed in first trimester Singleton pregnancy

- Early referral to multiples clinic (or high-risk antenatal clinic) with a dedicated - Early referral to a high-risk antental clinic or
consultant lead in a hospital with a neonatal intensive care unit that can provide maternal medicine clinic if required
appropriate levels of care for babies born prematurely - PAPP-A measured and noted
- Venous thromboembolism risk assessment at every appointment or admission (significant if less than 0.4 multiples of the median)
- Advise low-dose aspirin (150 mg) from 12 weeks of gestation until delivery - Request serial growth scans at 28, 32 and 36 weeks’ gestation
- PAPP-A measured and noted (significant if less than 0.4 multiples of the median) Venous thromboembolism risk assessment at every
appointment or admission

Screening for gestational diabetes mellitus with a glucose

tolerance test at 16–18 weeks Screening for gestational diabetes mellitus with a glucose
tolerance test at 16–18 weeks

Early discussion regarding risk of preterm delivery,

mode of delivery, place of delivery and the role of steroids and Screening for gestational diabetes mellitus with a glucose
magnesium sulphate tolerance test at 26–28 weeks if screen negative at 16–18 weeks

Screening for gestational diabetes mellitus with a glucose Regular blood pressure monitoring and urine analysis, increasing
tolerance test at 26–28 weeks if screen negative at 16–18 weeks in frequency in the third trimester of pregnancy
Venous thromboembolism risk re-assessment if
hypertensive disease develops or admission required

Regular blood pressure monitoring and urine analysis, increasing

in frequency in the third trimester of pregnancy
Early discussion regarding risk of preterm delivery, mode of
Venous thromboembolism risk re-assessment if
delivery and place of delivery
hypertensive disease develops or admission required

Women with additional risk factors (e.g. high body mass index,
Women with additional risk factors (e.g. high body mass index, multiple pregnancy, hypertensive disease, placenta praevia)
multiple pregnancy, hypertensive disease, placenta praevia) should be referred to high-risk obstetric
should be referred to high-risk obstetric anaesthetic clinic at 30–32
30 32 weeks ‘gestation
anaesthetic clinic at 30–32
30 32 weeks ‘gestation

Timing of delivery with multiple pregnancy to be guided by fetal Aim to deliver by 38 weeks’ gestation to
surveillance and maternal risk factors. No current evidence on reduce risk of stillbirth
optimum timing of delivery.

Figure 2. Suggested additional considerations in the antenatal care of women of very advanced maternal age (vAMA).

ª 2020 Royal College of Obstetricians and Gynaecologists 45

 Very advanced maternal age
Conclusion
The number of women of vAMA becoming pregnant is
increasing, but the rate of multiple births in this group
appears to be beginning to decrease, in part because of HFEA
multiple birth policy. However, many women are seeking
ART abroad, where multiple embryo transplant is
more common.
Multiple birth, primiparity and pre-existing maternal
hypertension appear to be the most significant risk factors
in women of vAMA and pre-pregnancy counselling has an
important role to play in the care of these women.
Most women with vAMA have successful pregnancy
outcomes; however, clinicians must be aware of the women
of vAMA with higher risks, as well as the preventative and
surveillance strategies available for women during
their pregnancies.
Caring for a woman with multiple risk factors can be
complex and maintaining continuity of care can be
challenging. Figure 2 shows a flow chart summary of the
suggested additional recommendations in the antenatal care
of women of vAMA. We advise women to have a named
consultant obstetrician who oversees her care and develops a
personalised care plan with her59– this may be an expert in
multiple pregnancy, maternal medicine or high-risk
obstetrics. As risk factors develop, reviewing the
personalised care plan at each antenatal visit can ensure
good communication. This will ensure a high standard of
care, the reduction of risk and will help her manage her own
health and that of her baby into the long term.
Disclosure of interests
There are no conflicts of interest.
Contribution to authorship
AH instigated, researched and wrote the manuscript. MB
edited the manuscript. Both authors read and approved the
final version of the manuscript.
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birth and with multiple births, and stillbirths by age of parents and calendar
quarter. London: Office for National Statistics; 2019.
3 Fitzpatrick K, Tuffnell D, Kurinczuk J, Knight M. Pregnancy at very advanced
maternal age: a UK population-based cohort study. BJOG
2017;124:1097–106.
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27 National Institute for Health and Care Excellence (NICE). Multiple
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28 Haslinger C, Stoiber B, Capanna F, Schaffer M. Postponed pregnancies and
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47
 DOI: 10.1111/tog.12708 2021;23:48–59
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Care in pregnancies subsequent to stillbirth

or perinatal death
MRCOG, *
a b c
Nicole Graham Louise Stephens RM, Alexander EP Heazell PhD MRCOG
a
Consultant Obstetrician, Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, Faculty of Biology,
Medicine and Health, University of Manchester, and Department of Obstetrics, St Mary’s Hospital, Manchester M13 9WL, UK
b
Research Midwife, Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and
Health, University of Manchester, and St Mary’s Hospital, Manchester M13 9WL, UK
c
Professor of Obstetrics and Honorary Consultant Obstetrician, Maternal and Fetal Health Research Centre, Division of Developmental Biology and
Medicine, Faculty of Biology, Medicine and Health, University of Manchester, and Department of Obstetrics, St Mary’s Hospital,
Manchester M13 9WL, UK
*Correspondence: Nicole Graham. Email: nicole.graham@mft.nhs.uk

Accepted on 15 May 2020. Published online 10 December 2020.

Key content information to be covered in such an appointment in a

 Pregnancies following stillbirth have an increased risk of adverse
outcome, including a 4.8-fold increased risk of stillbirth.
 Risk factors for stillbirth include obesity, smoking, advanced
maternal age, fetal growth restriction, hypertension and diabetes.
 Increased risk of medical problems may result from recurrent
placental pathologies or genetic conditions or persistent maternal
disease; thus, care for a subsequent pregnancy should commence
with investigation of the index stillbirth.
 Parents also require additional psychological support to navigate
mixed emotions, particularly anxiety, about the development of
pregnancy complications.
 Antenatal care in a subsequent pregnancy after stillbirth should
ideally be delivered by a multidisciplinary team to provide
continuity of physical and psychological care.
Learning objectives
 To improve understanding of the importance of a
pre-conception/early pregnancy appointment and the key
pregnancy after stillbirth.
 To know what information can be gained from postnatal
investigations and the placental histology report and the
relationship between this information and a subsequent pregnancy
after stillbirth.
 To be able to describe an example of a model of care used to
address medical and psychological needs of parents in
subsequent pregnancy.
Ethical issues
 Failing to appreciate the medical and psychological significance of
a history of stillbirth may lead to suboptimal antenatal care that
does not meet women’s needs.
 Lack of robust evidence may lead to prescription of medication
without clear evidence of benefit.
Keywords: adverse pregnancy outcome / placental histopathology /
small for gestational age / stillbirth / subsequent pregnancy

Please cite this paper as: Graham N, Stephens L, Heazell AEP. Care in pregnancies subsequent to stillbirth or perinatal death. The Obstetrician & Gynaecologist
2021;23:48–59. https://doi.org/10.1111/tog.12708

rates, which have fallen at a faster pace.4 Definitions of

Stillbirth
Stillbirth, the death of a baby before birth or during labour,
has been described as a worldwide epidemic.1 With
2.6 million stillbirths estimated in 2015,2 its burden is
greatly underappreciated. Ninety-eight percent of stillbirths
occur in low- and middle-income countries (LMICs).
Importantly, the aetiology of stillbirth differs between high-
income countries (HICs) and LMICs. For example, the
estimated proportion of intrapartum stillbirths varies from
approximately 10% in HICs to 60% in South Asia;3 this is
closely related to access to high-quality antenatal and
intrapartum care. Globally, the rate of stillbirth reduction
has remained beneath that of infant and maternal mortality
stillbirth vary internationally, with the lower gestational age
limit used to define stillbirth ranging between 16 and 28
weeks of gestation.5 In the UK, stillbirth is defined as ‘a baby
delivered with no signs of life known to have died after 24
completed weeks of pregnancy.’6
There is greater than six-fold variation in stillbirth rates
between HICs (from 1.3 per 1000 total births in Iceland to
8.8 per 1000 births in Ukraine). There is also wide variation
in the rate of reduction in stillbirth rates in HICs. Between
2000 and 2015 the annual rate of reduction in the UK was
1.4% per year, placing it in the lowest third of HICs, i.e. those
with the slowest rates of reduction.7 In the UK in 2017, there
were approximately 2800 stillbirths, which equates to roughly

48 ª 2020 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-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

1 in 270 pregnancies after 24 weeks of gestation. Six of the 49
HICs (Andorra, Croatia, Denmark, Finland, the Netherlands
and Iceland) showed third trimester stillbirth rates of 1 per
500 births or lower.7 Despite reductions in stillbirths in
recent years, this strongly suggests that more can be done in
the UK to reduce stillbirth rates.
The Lancet’s ‘Ending Preventable Stillbirth’ series1-4, set a
target of 12 stillbirths per 1000 total births or fewer by 2030
for all countries. It encourages HICs who have already met
this target to continue to reduce their stillbirth rate and, since
impoverished or socially excluded women are among those at
highest risk, to close inequality gaps. One approach to
reducing stillbirth is to identify pregnancies with risk factors
for stillbirth and implement increased surveillance and/or
directed intervention to mitigate the additional risks.
Risk factors for stillbirth in high-income
countries
Numerous risk factors for stillbirth in HICs have been
identified through observational studies and subsequent
meta-analyses (Table 1). Risk factors such as low socio-
economic status, advanced maternal age, essential
hypertension, pre-eclampsia, antepartum haemorrhage
(APH) and fetal growth restriction (FGR) were examined
in these studies; their hazard ratios (HRs), odds ratios (ORs)
and population attributable risks (PARs) are shown in
Table 1. Except for APH and FGR, the ORs for these risk
factors have a range of 1.2–3.5-fold increased risk of stillbirth.
Critically, the Stillbirth Collaborative Research Network
study in the USA8 found that only 18% of stillbirths
occurred in women with risk factors identified at booking.
The authors concluded that pregnancy history was the
strongest risk factor for stillbirth.
A history of previous stillbirth is a recognised risk factor
for stillbirth in a subsequent pregnancy.9–11 As these studies
analysed population-level data, recurrence risks for
individual causes of stillbirth could not be examined.
Nevertheless, comparison with other risk factors
demonstrates that prior stillbirth has a comparable or
greater risk for stillbirth than many other risk factors that
already have robust recommendations for additional
antenatal surveillance (e.g. diabetes12).
Addressing many of these risk factors is challenging; some
risk factors such as obesity, advanced maternal age and
cigarette smoking require broad public health initiatives,
reaching beyond the remit of UK National Health Service
(NHS) maternity services. For example, women must be
aware of risk factors for stillbirth, such as advanced maternal
age, illicit drug use and treatment of pre-existing medical
conditions, to enable informed decision-making with regards
to childbearing. The focus of strategies from a maternity care
perspective is on women at highest risk of stillbirth and to
ª 2020 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
Graham et al.
institute appropriate interventions. For example, both Hirst
et al.13 and Gardosi et al.14 demonstrate the importance of
antenatal detection of small-for-gestational-age (SGA)
infants (as a proxy for FGR) because when this is identified
during pregnancy, the risk of stillbirth is considerably lower
than when SGA is undetected. To date, efforts to reduce
stillbirth have been directed towards additional monitoring
in high-risk populations to detect FGR.15 Thus, an effective
strategy to reduce stillbirth in HICs might be to identify
women at high risk and provide them with optimal care.
Risk of stillbirth and other complications
in a subsequent pregnancy
Stillbirth in a previous pregnancy is a risk factor for stillbirth
in a subsequent pregnancy (Table 1). A large systematic
review and meta-analysis of 16 studies,16 including
3 412 079 pregnancies in HICs, demonstrated a stillbirth
rate in 2.5% of women with a previous history of stillbirth
compared with a rate of 0.4% when previous pregnancy
resulted in a livebirth. This gave a pooled OR of 4.8 (95%
confidence interval [CI] 3.77–6.18). In addition, a case
control study in the Grampian region of Scotland17 found
that previous stillbirth also increases the risk of other adverse
pregnancy outcomes, such as pre-eclampsia (OR 3.1, 95% CI
1.7–5.7), placental abruption (OR 9.4, 95% CI 4.5–19.7), low
birthweight (OR 2.8, 95% CI 1.7–4.5), prematurity (OR 2.8,
95% CI 1.9–4.2) and intervention at delivery with induction
of labour (OR 3.2, 95% CI 2.4–4.2), instrumental delivery
(OR 2.0, 95% CI 1.4–3.0), elective caesarean section (OR 3.1,
95% CI 2.0–4.8) and emergency caesarean section (OR 2.1,
95% CI 1.5–3.0). These studies were not able to identify
whether the risks of complications in subsequent pregnancy
were affected by the cause of the stillbirth, although –
interestingly – many of the associated pathologies are
associated with abnormal placentation.
Although the risk of stillbirth is increased in subsequent
pregnancy after stillbirth, few studies have investigated the
cause of recurrent stillbirth. Interpretation of published data
is hampered by small study size, the use of different
classification systems, a lack of consensus in terminology
and limited information on the cause of index stillbirth. A
recent US cohort study,18 which included 3003 women,
found that stillbirth recurrence was more likely when a
maternal or placental condition occurred in the second
trimester of the index pregnancy (13–24 weeks of gestation).
This study found recurrent fetal causes were less common.
There was a trend towards increased risk of recurrence in
women with diabetes mellitus (4% versus 3.5%) or
hypertension (5% versus 3%). Nijkamp et al.19
demonstrated an association between cause of death in the
index pregnancy and cause of death in the subsequent
pregnancy in half of the cases examined. The relationship was
49
 Care in pregnancies after stillbirth

Table 1. Risk factors for stillbirth

Hirst et al., 201813 Flenady et al., 201183 Gardosi et al., 201314

Study

Brazil, China, India, Italy, Meta-analysis of

Kenya, Oman, UK, USA. international studies UK

Setting HR (95% CI) PAR (%) OR (95% CI) PAR (%) RR (95% CI) PAR (%)

Maternal medical factors

Diabetes mellitus - - 2.9 4.0 3.9 (1.7–8.9) 2.0

Essential hypertension 4.0 (2.7–5.9) 5.5 2.6 13.6 1.4 (0.8–2.5) -

HIV/AIDS 4.3 (2.0–9.1) 0.3 - - - -

Pre-eclampsia 1.6 (1.1–3.8) 1.4 1.6 (1.1–2.2) 3.1 2.8 (1.5–5.1) -

Severe pre-eclampsia with antepartum haemorrhage 4.2 (1.3–13.6) 2.2 - - - -

Severe pre-eclampsia with no antepartum 2.8 (1.5–5.1) 1.6 - - - -

haemorrhage

Previous stillbirth - - 2.6 (1.5–4.6) 0.8 3.3 (1.8–6.0) 8.0

Fetal/pregnancy factors

Multiple pregnancy 3.3 (2.0–5.6) 7.4 - - - -

Birthweight < 3rd centile/<10th centile 4.6 (3.4–6.2) 11.1 3.9 (3.0–5.1) 23.3 7.8 (5.6–10.9) 22.2

SGA at birth – FGR not detected antenatally 5.0 (3.6–7.0) 9.4 - - 6.5 (4.9–8.4) 32.0

SGA at birth – FGR detected antenatally 3.5 (1.9–6.4) 2.2 - - 3.4 (2.2–5.2) 6.2

Post term pregnancy >42 weeks of gestation - - 1.3 (1.1–1.7) 0.3 - -

Maternal–sociodemographic factors

Age > 40 years/>45 years 2.2 (1.4–3.7) 3.0 2.9 (1.9–4.4) - 1.2 (0.9–1.6) -

Primiparity - - 1.4 (1.3–1.42) 14.7 1.8 (1.3–2.5) 21.3

Body mass index >30/>35 - - 1.6 (1.3–1.9) 1.6 (1.1–2.4) 4.2

Smoking - - 1.4 (1.2–1.46) 14.7 2.5 (1.7–3.6) 9.4

No antenatal care accessed - - 3.3 (3.1–3.6) 0.7 - -

Low socio-economic status 1.6 (1.2–2.1) 9.7 1.2 (1.0–1.4) 9.0 1.6 (1.3–2.0) -

Single marital status 2.0 (1.4–2.8) 4.8 - - - -

Illicit drug use - - 1.9 (1.2–3.0) 2.1 - -

FGR = fetal growth restriction; HR = hazard ratio; OR = odds ratio; PAR = population attributable risk; RR = relative risk, SGA = small for gestational
age

50 ª 2020 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.

more evident in stillbirths at early gestations. Owing to the
small population size, they were unable to establish the risk of
recurrence of specific causes, but cited placental bed
pathology, placental pathology and preterm prelabour
rupture of membranes as relevant causes. Monari et al.20
conducted a larger prospective study and concluded that the
risk of adverse pregnancy outcome (defined as perinatal
death, FGR, preterm birth at less than 34 weeks of gestation,
hypoxic ischaemic encephalopathy or respiratory distress) is
more frequent when stillbirth was related to placental
vascular disorder (39.6%) than when stillbirth was related
to a different cause (OR 2.1, 95% CI 1.2–3.8). Taken
together, these studies suggest that placental dysfunction,
particularly that originating from maternal vascular
malperfusion, may underlie recurrent adverse pregnancy
outcome. Other causes, such as umbilical cord occlusion or
fetal–maternal haemorrhage may be less likely to recur;
therefore, accurate investigation and classification of the
cause of stillbirth is important to inform care in subsequent
pregnancy. This would allow individualised antenatal care
and increased surveillance for those who need it and would
potentially reduce anxiety and unnecessary intervention in
women with a low risk of recurrence.
Establishing cause of stillbirth and
classification of stillbirth
Stillbirth classification is important to direct care in a
subsequent pregnancy. Classification of stillbirth has recently
been reviewed by Allanson et al.21–23 to coincide with the
launch of the World Health Organization (WHO)’s ICD-PM
(application of the International Classification of Diseases
during the perinatal period) classification system. Currently,
many different classification systems are used worldwide – 81
between 2009 and 2014, which makes data analysis and
comparison extremely difficult. There is also huge variation
in the utility of classification systems; for example, only a
small number distinguish between intrapartum and
antepartum stillbirth and a high proportion, approximately
80%, excluded FGR/SGA in their list of causes of stillbirth
despite the known strong association.24,25 Current, common
systems include Aberdeen,26 Wigglesworth,27 ReCoDe
(Classification of stillbirth by Relevant Condition at
Death),28 PSANZ-PDC (Perinatal Society of Australia and
New Zealand Perinatal Death Classification),29 CoDAC
(Causes of Death and Associated Conditions)30 and
Tulip,31 the characteristics of which are summarised
in Table 2.
The proportion of stillbirths classified as ‘unexplained’
varies greatly depending on the classification system used.
Aberdeen and Wigglesworth have the highest proportion of
unexplained stillbirths (44.3% and 50.2%, respectively), while
ReCoDe has the lowest proportion at approximately 15%.32
ª 2020 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
Graham et al.
Importantly, the inclusion of placental histology in the
classification of stillbirth reduces the number of stillbirths
classified as ‘unexplained’.33 This may be because, in 11–65%
of stillbirth cases, placental lesions cause or are associated
with fetal death.34 The most recent Perinatal Mortality
Surveillance Report, released in June 2019 and covering all
births during 2017, reported on 2840 stillbirths. The cause of
death by CoDAC was recorded as ‘unknown’ in 34.6% of
cases. Other causes of stillbirth included placental problems
(31.8%) and congenital anomalies (9.2%). Intrapartum
complications accounted for 1.8% of stillbirths.35
Importantly, classification of stillbirth relies upon
information obtained at the time of stillbirth from the
maternal history and investigations.
Post mortem examination, placental examination and
cytogenetic analysis are the most valuable investigations
available after a stillbirth. A study of 1025 stillbirths in the
Netherlands36 found placental examination helped to
determine the cause of death in 95%, post mortem
examination provided cause of death information in 72%
of cases and cytogenetics in 29% of cases. A post mortem
following stillbirth provides new information that changes
the diagnosis in between 9% and 34% of stillbirths, provides
some additional information in 22% of stillbirths and
confirms the clinical diagnosis in between 49% and 58% of
stillbirths.37–40 Histopathological examination of the placenta
by a pathologist provides useful information in at least 50%
of stillbirths and reduces the reporting of ‘unexplained’
stillbirth from 30% to 10%.34 Haematological and
immunological investigations, especially in patients who
have experienced other forms of pregnancy loss, can
sometimes identify treatable conditions such as
antiphospholipid antibody syndrome or inflammatory
conditions associated with underlying pathology (Table 3).
Observed changes can be related to placental structure and
placental function. Placental lesions can be broadly categorised
into four groups: inflammatory, obstructive, disruptive and
adaptive. Obstructive (e.g. maternal and fetal vascular
malperfusion) and adaptive lesions (villous dysmaturity) are
most commonly seen in SGA stillbirths and FGR live births.41
Importantly, the type of placental lesion varies with gestational
age: ascending infection is most common in the mid-trimester,
peaking at 22 weeks of gestation, and maternal vascular
malperfusion is most common in the early third trimester.42
Inflammatory lesions, such as chronic histiocytic intervillositis
(CHI) and villitis of unknown aetiology (VUE), are associated
with stillbirth. Although these are comparatively infrequent
(incidence of CHI is 0.06% of pregnancies;43 VUE incidence is
5.1%44), they are important findings because they are thought
to be recurrent – particularly CHI, which has a recurrence rate
of 80% in subsequent pregnancy and needs specific drug
therapy.45 Interpretation of histopathological findings should
be carefully related to clinical history since lesions can also be
51
 Care in pregnancies after stillbirth

Table 2. Characteristics of some commonly used classification systems for stillbirth

Timing of SB
Classification Associated (antepartum/ FGR Country
system Year Format Factors included conditions intrapartum) included Population origin

Aberdeen 1954 Hierarchical Maternal, fetal No No No SB and NND UK

No placental

Wigglesworth 1980 Hierarchical Maternal, fetal No Yes No SB and NND UK

No placental

ReCoDe 2005 Hierarchical Maternal, fetal Yes Yes Yes SB UK

Placental

PSANZ-PDC 2004 Mostly hierarchical Maternal, fetal Yes Yes Yes SB (20 weeks) Australia
Limited placental and NND

Tulip 2006 Mostly hierarchical Maternal, fetal No No No SB (16 weeks) Netherlands

Placental and NND

CoDAC 2009 Partly hierarchical Maternal, fetal Yes Yes Yes SB and NND Norway
Placental

CoDAC = Causes of Death and Associated Conditions; FGR = fetal growth restriction; NND = neonatal death; PSANZ-PDC = Perinatal Society of
Australia and New Zealand Perinatal Death Classification; ReCoDe = Relevant Condition at Death; SB = stillbirth

seen in apparently healthy pregnancies. Others are associated
with multiple unrelated conditions, such as fetal thrombotic
vasculopathy (which has been related to cord abnormalities),
cytomegalovirus and gestational diabetes.46 Table 4
summarises placental lesions associated with stillbirth.
Care in pregnancies after stillbirth
There is little high-level evidence to direct the management of
pregnancies following stillbirth.47 This absence of evidence
results in considerable variation in care for parents. An online
survey of UK maternity units48 demonstrated that a small
minority had specific written guidance to support care
delivery in a subsequent pregnancy following stillbirth or
neonatal death and that most parents did not receive
adequate emotional and psychological support. This, in
turn, increases the risk of poor health outcomes during
future pregnancies. An international multi-language web-
based survey of 2716 parents49 showed similar findings, with
wide variation in care received across geographic regions.
Sixty-seven percent of parents received additional antenatal
visits and 70% received additional ultrasound scans;
however, only 10% had access to a bereavement counsellor.
A meta-synthesis 50,51 demonstrated that a relationship
with healthcare professionals, dedicated antenatal clinics,
psychological support and continuity of care are important
when caring for women and their families in a subsequent
pregnancy. Thus, care in the subsequent pregnancy not only
needs to focus on the increased risk of adverse pregnancy
outcome, but also on the emotional and psychosocial effects
on parents that persist into the subsequent pregnancy. In
particular, parents are at increased risk of intense anxiety,
depression, fear, complex emotional responses and refrain
from forming bonds with the unborn baby as a coping
mechanism.52 Providing this level of emotional care requires
specially trained staff, bereavement counsellors and time,
which can rarely be adequately provided in a busy ‘routine’
antenatal clinic.
Care in a subsequent pregnancy following stillbirth should
ideally start following the index stillbirth, with access to
appropriate investigations, perinatal review and a
consultation with an obstetrician who will offer continuity
of care. This postnatal consultation following the stillbirth
gives the opportunity for investigation results to be discussed,
modifiable risk factors to be reviewed and for plans for a
subsequent pregnancy to be made, including dietary and
supplementation advice, smoking cessation and weight loss
prior to conception.53 There is no ‘ideal’ inter-pregnancy
interval to reduce adverse outcome in a subsequent
pregnancy; in particular, the risk of stillbirth/SGA/pre-
eclampsia in HICs is not altered by short or long inter-
pregnancy intervals.54,55 Many families embark on a
pregnancy within 12 months of the stillbirth; indeed, 66%
of parents who participated in a large international survey
reported conceiving their subsequent pregnancy within
1 year of the stillbirth.49

52 ª 2020 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.

Table 3. Haematological and immunological investigations after stillbirth in specific clinical contexts
Test Association
Inherited thrombophilia screen (factor V Leiden Maternal or fetal vascular
mutation, prothrombin gene variant, protein S malperfusion of placenta
deficiency, protein C deficiency, antithrombin
deficiency)
Acquired thrombophilia screen (anticardiolipin Maternal vascular
antibodies, lupus anticoagulant) malperfusion, CHI, VUE
Autoimmune screen (antinuclear antibodies) CHI, VUE
CHI = chronic histiocytic intervillositis; VUE = villitis of unknown aetiology
Care in a pregnancy after stillbirth should be
individualised, taking into consideration the cause of
stillbirth and the wishes of the woman and her family.
Therefore, efforts should be made to obtain the results of
investigations into the cause of stillbirth, or to undertake a
verbal autopsy to deem the most likely cause in the absence of
other information.56 Women who have a history of stillbirth
should be referred for consultant-led care and a plan of care
made with the woman in early pregnancy. This plan of care
should include screening for established risk factors, such as
smoking and gestational diabetes, with carbon monoxide
detectors and oral glucose tolerance tests, respectively.57,58
Importantly, women who have had a stillbirth are more likely
to stop smoking than women whose prior pregnancy ended
in a livebirth.59 If a woman stops smoking before 16 weeks of
gestation, risk is the same as that for nonsmokers; therefore,
early intervention reduces the risk of adverse outcome.60
Where indicated, drug therapy to reduce recurrent placental
complications (e.g. aspirin) should be commenced in the
first trimester.
Models of care: the role of a specialist
antenatal service
As with other conditions associated with higher risk of
complications (e.g. previous preterm birth, diabetes), a
specialist clinical service improves clinical outcome and
parents’ experience. There are few dedicated clinical services
(‘Rainbow Clinics’) that care for women in a subsequent
pregnancy after stillbirth or neonatal death.48 Models of
multidisciplinary continuity of care combined with regular
antenatal surveillance are associated with improved clinical
outcomes, particularly a reduction in preterm birth and
improved patient experience.61 A recommended pathway for
care is shown in Figure 1. In this pathway, planning for a
subsequent pregnancy commences with the investigation of
ª 2020 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
Graham et al.
Notes
Antithrombin, protein C and S levels can be affected by pregnancy.
Best performed ≥6 weeks postnatal
Association with inherited thrombophilia and stillbirth is
contentious, particularly when women are heterozygous
If positive, tests should be repeated after 6–12 weeks to confirm
whether levels remain elevated
Autoimmunity is more common in women with VUE and CHI
Autoimmunity is more common in women with VUE and CHI
the index stillbirth and follow-up at a postnatal appointment,
commencing appropriate treatment early in the subsequent
pregnancy and implementation of screening for SGA/FGR
with involvement of other relevant specialist services (e.g.
maternal medicine clinics, fetal medicine unit). As pregnancy
progresses, a plan for birth should be developed, addressing
the wishes of the woman and her family.
Role of ultrasound surveillance in
pregnancies after stillbirth
Women who have had a stillbirth are at increased risk of
giving birth to an SGA infant (OR 6.4 95% CI 0.78–52.662).
The Royal College of Obstetricians and Gynaecologists’
(RCOG) guideline for the detection of SGA fetus63
recommends that women with a history of stillbirth should
have ultrasound measurement of fetal biometry. Assessment
of fetal growth is recommended to be undertaken on
multiple occasions because serial fetal biometry to generate
an estimated fetal weight with growth velocity plotted on a
growth chart has the best detection rate for SGA and FGR.63
Practitioners should be aware that while ultrasound scans
provide a degree of reassurance for parents, this reassurance
is short lived. Parents may also be anxious prior to scans
because the in utero fetal death in their previous pregnancy
would likely have been confirmed by ultrasound scan.52
Other methods of screening for SGA or FGR, or to identify
increased risk of stillbirth, include measurement of blood
flow through the umbilical or uterine arteries by Doppler
ultrasound. This stems from observations that abnormal
blood flow through the uterine artery in the second trimester
is associated with an increased risk of developing pre-
eclampsia and FGR, both of which are associated with
abnormal placentation and stillbirth.64,65 In addition,
ultrasound has also been used to assess placental structure;
this may be relevant because placental disorders are
53
 Care in pregnancies after stillbirth

Table 4. Placental lesions associated with stillbirth42–44

Category Placental lesions Associated with Subsequent pregnancy

Maternal vascular Placental hypoplasia Fetal growth restriction Assess maternal

malperfusion Placental weight <10th centile  thin cord <10th centile Pre-eclampsia cardiovascular status
Infarction Preterm and term stillbirth Glucose tolerance test
Crowding and congestion of villi, migration of Spontaneous preterm birth Thrombophilia screen
neutrophils into intervillous space, compressed or Renal function
obliterated intervillous space, increased fibrin Low dose aspirin
deposition, pyknosis and karyorrhexis of trophoblast, Preconception weight loss
ghost villi 10–25% recurrence risk
Acute, subacute or chronic
Retroplacental haemorrhage
Blood accumulation on maternal surface, compression of
overlying parenchyma
Distal villous hypoplasia
Paucity of villi in relation to surrounding stem villi, villi thin
and elongated, increased syncytial knots
Focal or diffuse
Accelerated villous maturation
Small or short hypermature villi for gestation, increased
syncytial knots, increased intervillous fibrin
Mild, moderate or severe

Fetal vascular Thrombosis Fetal growth restriction Thrombophilia screen

malperfusion Arterial or venous Preterm and term stillbirth Glucose tolerance test
Acute, subacute or chronic
Fibrin deposits, endothelial oedema, iron deposits in
basement membrane, thrombi attached to vessel wall,
fibrosis in proximal villi, calcification
Avascular villi
Loss villous capillaries, fibrosis of villous stroma, small,
intermediate or large foci
Villous stromal-vascular karyorrhexis
Rupture of fetal vessels in primary villi with haemorrhage
and inflammatory cells
Stem vessel obliteration
Oedema in fetal vessel wall, obliteration vessel lumen
Intramural fibrin deposition

Delayed villous Reduced vasculosyncytial membranes Term stillbirth Glucose tolerance test
maturation Continuous cytotrophoblast layer Preconception weight loss
Centrally placed capillaries Unknown recurrence risk
Focal or diffuse

Ascending uterine Maternal stage 1: acute subchorionitis or chorionitis Spontaneous preterm birth If spontaneous preterm birth with
infection Maternal stage 2: acute chorioamnionitis Adverse neonatal outcome chorioamnionitis, 10–25%
Maternal stage 3: necrotising chorioamnionitis recurrence risk
Fetal stage 1: chorionic vasculitis or umbilical phlebitis
Fetal stage 2: involvement of umbilical vessels
Fetal stage 3: necrotising funisitis

Immune inflammatory Villitis of unknown aetiology Fetal growth restriction Maternal autoimmune testing
lesions Low or high grade Miscarriage Preconception weight loss
Lymphohistiocytic  occasional plasma cells Preterm stillbirth Low dose aspirin
Chronic villitis  LMWH
Fibrous villi, obliterated fetal vessel, perivillous fibrin  Immunosuppressive therapy
Intervillositis Villitis of unknown aetiology,
Acute: neutrophils in villi/intervillous space, fibrin 25–50% recurrence risk

54 ª 2020 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.

Table 4. (Continued)
Category Placental lesions
Chronic: small placenta, diffuse intervillous invasion of
lymphocytes, macrophages and oesinophils, villous
necrosis, perivillous fibrin
Histiocytic: small placenta, diffuse intervillous invasion of
histiocytes
LMWH = low-molecular-weight heparin
implicated in recurrent pathologies.34 Abnormal uterine or
umbilical artery flow with a thickened placental disc are
associated with complications such as FGR and stillbirth.46
This approach may be effective in a high-risk population.
Toal et al.66 examined the predictive accuracy of a
combination of maternal serum screening (for serum
alphafetoprotein and human chorionic gonadotrophin at
16–18 weeks of gestation), second trimester uterine artery
Doppler and placental morphologic condition (shape and/or
texture). They found no cases of unexpected stillbirth in the
cohort and no cases of severe early-onset FGR after a normal
placental profile. Combining ≥2 abnormal components of the
test predicted 14 of 19 pregnancies that developed severe
early-onset FGR (sensitivity 74%) and 15 of 22 pregnancies
that ended in stillbirth (sensitivity 68%). In another
population, Viero et al.67 showed the combination of
abnormal uterine artery Doppler, abnormal placental shape
and echogenic cystic lesions was strongly predictive of
stillbirth with a sensitivity of 81% and a positive predictive
value of 52%. Therefore, assessment of uterine artery Doppler
and placental size, shape and echotexture may be of benefit in
identifying women at high risk of adverse outcome in a
subsequent pregnancy so that surveillance can be put in place
(e.g. earlier or more frequent ultrasound scans). Of these
different elements, the uterine artery Doppler appears to be
the most informative component of this screen.68
Specific pharmacological treatments
Pharmacological interventions may be directed at optimising
maternal health or reducing the risk of placental disorders.
Maternal medical conditions should be treated with
therapeutic agents that are effective and safe in pregnancy.
Vitamin D should be prescribed according to guidelines
from the National Institute of Health and Care
Excellence (NICE).69
The most commonly used intervention to reduce recurrent
stillbirth from placental causes is aspirin: 150 mg once at
night, ideally commenced before 16 weeks of gestation and
continued until at least 36 weeks (when some trials cease
ª 2020 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
Graham et al.
Associated with Subsequent pregnancy
Chronic histiocytic intervillositis,
75–90% recurrence risk
use). This is recommended because aspirin commenced
before 16 weeks of gestation reduces the risk of perinatal
death (relative risk [RR] 0.41, 95% CI 0.19–0.92).70 Evidence
from a subsequent meta-analysis71 also suggests that higher
doses of aspirin (e.g. 150 mg rather than 75 mg) are more
effective at preventing FGR and pre-eclampsia. Although
there are no data specifically on women whose previous
pregnancy ended in stillbirth, this is thought to be beneficial
for women whose stillbirth was associated with
placental disease.
There is currently no high-grade evidence to support the
use of low-molecular-weight heparin (LMWH) with the
primary aim to prevent fetal complications in women with a
history of stillbirth. However, it should be used in women at
high risk of maternal venous-thromboembolism. Some
smaller studies show a potential benefit; one Indian study72
showed that prophylactic LMWH commenced before
15 weeks of gestation substantially reduced admissions to
the neonatal intensive care unit (NICU) by 80%. However,
the EPPI73 and TIPPS74 studies, which were both large,
multicentre, randomised controlled trials, failed to
demonstrate benefit in fetal outcomes. Presently, it should
be reserved for women with antiphospholipid antibody
syndrome or CHI.
CHI is a rare placental lesion associated with poor obstetric
outcome and has a high risk of recurrence in subsequent
pregnancies (80%). One prospective multicentre study75
described the efficacy of different treatment regimes: the
number of live births increased in the treatment group from
32% to 67% with quadruple therapy of aspirin, LMWH,
prednisolone and hydroxychloroquine and resulted in better
pregnancy outcomes than aspirin alone.
Timing of birth
Increasing evidence suggests the optimal time for delivery for
the general obstetric population is at 39 weeks of gestation
because after this point the risk of neonatal death does not
fall, but the risk of stillbirth increases.76 A Cochrane
systematic review77 suggests routine induction of labour
55
 Care in pregnancies after stillbirth

Death of a baby

Investigations
e.g. postmortem/placental histopathology,
maternal blood tests

Postnatal/preconception appointment:
Offer services, make plan for pregnancy
Community midwife/
primary care
First point of contact
EPAU

Self-referral Commence appropriate interventions

Other specialist review

Booking appointment/dating scan (11–13 weeks)
if required

Anomaly scan at 20 weeks

Does the mother

accept referral to
Rainbow Clinic?

Yes

Placental scan at 23 weeks

unless specifiic early onset pathology

Phone contact
Glucose tolerance test (if indicated) at 26 weeks
and support

Ultrasound scan as required to monitor growth,

e.g. if abnormal, placental screen fortnightly from
26 weeks of gestation, or if normal, placental
screen 3-weekly from 28 weeks of gestation

Monitor and deliver as Yes Abnormality detected on

indicated by relevant
scanning or screening?
national guidance
No

Plan for birth – offer elective birth from 38 weeks

Figure 1. Pathway for care of women who have a history of stillbirth. Care is initatied from the time of death. Postnatal care is shown in purple
boxes, initial antenatal care is shown in green boxes and care in a dedicated antenatal service is shown in blue boxes. EPAU = early pregnancy
assessment unit.

56 ª 2020 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.

(IOL) ‘at term’ would reduce perinatal mortality by 70%. A
population study,78 a systematic review 79 and a recent
randomised trial80,81 demonstrated no increase in caesarean
section rates associated with planned IOL at 39 weeks of
gestation, suggesting that this approach does not increase
harm for women. However, additional emotional care is
required in many women who have previously suffered
stillbirth and induced delivery from 38 weeks of gestation
may be indicated. One observational study from South
Africa82 found that, of 306 women with a history of stillbirth,
203 (66%) had an indication for birth before 39 weeks of
gestation. Of the remaining women, 51% went into
spontaneous labour before the proposed date of induction.
Two-thirds of women in this study required early
intervention with a clear indication – this demonstrates the
importance of specialised antenatal care in a pregnancy
following stillbirth owing to the high-risk nature of the
subsequent pregnancy.
Conclusion
Stillbirth has a devastating effect on parents and their families
and bears increased costs, particularly in subsequent
pregnancies. Advances in understanding the causes of stillbirth
and the potential risk of recurrence will enable management
strategies and possible treatments to be developed for women in
subsequent pregnancies who are at increased risk of stillbirth.
More evidence is required, especially from larger, more robust
studies, to guide practice in these high-risk pregnancies; many
current studies are limited by small participant numbers or
methodological weaknesses. In particular, studies are needed to
determine the origins of the increased risk of placental problems
in subsequent pregnancies and whether this is restricted to
specific causes of stillbirth. Evidence is needed to determine
effective therapies for recurrent placental conditions. Further
research is also needed to discern the optimal method of
supporting families through these medically and emotionally
complex pregnancies. Importantly, stillbirth is an established
risk factor for subsequent adverse outcome. Specialist antenatal
care and increased surveillance throughout pregnancy should be
provided, especially to address the emotional and psychological
effects of previous stillbirth on a woman and her family.
Disclosure of interests
There are no conflicts of interest.
Contribution to authorship
NG and AEPH instigated, researched and wrote the article,
LS wrote the article and created the figure regarding pathway
of care. All authors approved the final version.
ª 2020 The Authors. The Obstetrician & Gynaecologist published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.
Graham et al.
Acknowledgements
The authors would like to thank Mrs Victoria Holmes,
Bereavement Midwife, St Mary’s Hospital, who assisted in the
development of the Rainbow Clinic service.
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59
 DOI: 10.1111/tog.12709
The Obstetrician & Gynaecologist
http://onlinetog.org
Developing situational awareness (‘helicopter view’)
Wai Yoong MD FRCOG,*a Sayantana Patra-Das
Wasim Lodhi FRCOGe
a
Consultant Obstetrician and Urogynaecologist, North Middlesex University Hospital, London N18 1QX, UK
b
ST7 Obstetrics and Gynaecology trainee, Homerton University Hospital, London E9 6SR, UK
c
Chief Pilot, London’s Air Ambulance, The Helipad, Royal London Hospital, London E1 1BB, UK
d
General Practitioner, Camden Health Improvement Practice, London NW1 2LS, UK
e
Consultant Obstetrician and Gynaecologist, North Middlesex University Hospital, London N18 1QX, UK
*Correspondence: Wai Yoong. Email: waiyoong@nhs.net
Accepted on 4 June 2020. Published online 28 December 2020.
Key contents
 Reports such as Each Baby Counts and the Confidential Enquiry
into Maternal Deaths and Morbidity increasingly recognise that
human factors contribute to significant events such as hypoxic
ischaemic encephalopathy and maternal deaths.
 Loss of situational awareness (SA) has been implicated in at least
50% of such cases.
 A clinician’s SA involves information gathering, comprehension of
data in real time and developing the crucial skills to project ahead
and anticipate potential errors and threats.
Please cite this paper as: Yoong W, Das S, Jeffers N, Nauta M, Lodhi W. Developing situational awareness (‘helicopter view’). The Obstetrician & Gynaecologist
2021;23:60–6. https://doi.org/10.1111/tog.12709
Introduction
An understanding of human factors is a requirement of the
General Medical Council’s Generic Professional Capabilities.1
The Non-Technical Skills for Surgeons (NOTSS) tool,2
originally developed by the University of Aberdeen and the
Royal College of Surgeons of Edinburgh, has now been
incorporated into the new Royal College of Obstetricians and
Gynaecologists’ (RCOG) training curriculum. Reports such
as Each Baby Counts3 and the Confidential Enquiry into
Maternal Deaths and Morbidity4 recognise the contribution
of human factors to important events such as hypoxic
ischaemic encephalopathy and maternal deaths. Loss of
situational awareness (SA), in particular, is implicated in at
least 50% of such cases. In a study of 252 laparoscopic bile
duct injuries, 97% of errors were attributed to surgeons
having incorrect SA, rather than lacking technical skills or
having poor judgement.5 Similarly, inadequate SA was
implicated in over 80% of serious incidences in the
German Anaesthetic Critical Reporting System.6
Here, we explain the concept of SA (‘helicopter view’),
discuss examples of how SA can be lost in clinical practice
and present some practical suggestions on how to improve
and maintain SA.
60
2021;23:60–6
Education
MRCOG,
b
Neil Jeffers,c Maud Nauta MRCGP,
d
 Good communication and shared mental models are important to
maximise team SA in theatre, clinic and the labour ward.
Learning objectives
 To understand the concept of SA.
 To appreciate how SA can be lost and to recognise the ‘red flag’
signs for this.
 To learn practical tips on how to maintain SA in day-to-day
clinical practice.
What is situational awareness?
Dr Mica Endsley, former Chief Scientist of the United States
Air Force, defined SA as, “. . .the perception of the elements
in the environment within a volume of time and space, the
comprehension of their meaning and the projection of their
status in the near future. . .”.7 SA is the cognitive state of
being vigilant and “knowing where you are, what is going
on around you and therefore, being able to anticipate
events”.8 SA is also described as having the ability to see the
‘bigger picture’, or having a ‘helicopter view’. A person is
deemed to have maximum SA when they are able to
anticipate how a situation is likely to develop in the
immediate future.
Factors that positively influence SA include experience,
adherence to standard operating procedures (SOPs),
communication (briefings, mini-briefings and ‘sharing
mental models’) and the ability to manage workload
and distractions.
For practical purposes, a simple acronym for SA could be
NUPA, where:
 N = Notice (level 1)
 U = Understand (level 2)
 PA = Project Ahead (level 3)
ª 2020 Royal College of Obstetricians and Gynaecologists
 Yoong et al.

Below is a clinical scenario illustrating the different levels  Minimise distractions

of SA when closing the uterine incision following a  Watch for signs or ‘red flags’ of reduced SA (see Box 1)
postpartum haemorrhage (PPH) of 2 litres.  Speak up when you see SA breaking down
 N = Notice: “the more sutures I put in, the more it bleeds”  Delegate team members to oversee the ‘helicopter view’
 U = Understand: “the patient is probably developing when you need to focus or fixate during critical phases of
impending disseminated intravascular coagulation (DIC)” a procedure
 PA = Project Ahead: “I should stop putting sutures in –
let’s correct coagulation, let’s think about packing,
let’s escalate. . .” Assessing situational awareness in
SA, therefore, appears to be a state of continually changing healthcare
cognition because it relies on information being properly
Contemporaneous frameworks for assessing SA in clinical
perceived, comprehended and interpreted. An element of
practice are based on observations of positive and negative
conscious attention is needed because high SA does not
behavioural markers for the three elements that comprise SA;
appear passively or occur spontaneously. Good SA is linked
i.e., gathering information, understanding information and
to timely decision-making, and its absence often leads to
the ability to project ahead and anticipate. Well-researched
poor decisions and omissions. It would be reasonable to say
frameworks include Anaesthetists’ Non-Technical Skills
that a healthcare organisation with a good safety culture will
(ANTS)11–13 which observes and rates anaesthetists’
also have good SA.
behaviour in theatre on a four-point Likert-type scale.
To maintain and continually update overall SA, the
Since its introduction in 2006, the NOTSS tool14 has been
clinician must use multiple sources of information
adopted and adapted by many healthcare organisations
whenever possible, so as to triangulate data and to avoid
around the world. NOTSS is based on a non-technical
single unreliable sources or errors in interpretation of the
skills taxonomy comprising the four categories considered to
data. Problems often occur when clinicians rely on only one
be relevant to surgeons’ skills in terms of human factors (SA,
source of data, making their SA vulnerable. Interestingly, SA
decision-making, communication, and teamwork and
can equally apply to individuals9 as well as to teams
leadership). This tool has been modified for use in the
of clinicians.10
most recent RCOG training curriculum in 2019.15 With
If you have good SA, you:
regards to the SA category in NOTSS, the three elements of
 Plan ahead and consider ‘what if’ contingencies. Pilots who
gathering information, understanding information and
do not actively engage in contingency planning are far
projection and anticipation can be evaluated for positive
more likely to be overloaded by events during high
and negative behavioural markers on a scale of 1–4:
workload periods
1. Poor: Performance endangered or potentially endangered
 Consistently evaluate current status relative to your plan
patient safety; serious remediation is required
 ‘Scan the big picture’
2. Marginal: Performance indicated cause for concern;
 Share ‘mental models’ with team members
considerable improvement is needed
3. Acceptable: Performance was of a satisfactory standard but
can be improved
Box 1. Warnings or ‘red flags’ for signs of situational awareness
4. Good: Performance was of a consistently high standard,
loss26
enhancing patient safety, and could be used as a positive
 Ambiguity: information from two or more resources that do not example for others.
agree An example of NOTSS is shown in Figure 1.
 Target fixation: focusing on any one thing to the exclusion of
everything else
 Confusion: uncertainty/lack of clarity about a situation (often
accompanied by anxiety or psychological discomfort) Target fixation versus situational
 Failure to pay attention: being focused on unimportant activities awareness
 Failure to meet expected targets
 Failure to adhere to SOPs Target fixation, or fixation error, occurs when individuals
 Failure to resolve discrepancies or teams focus on a single aspect of a situation while
 Inability to resolve discrepancies because of contradictory data or
personal conflicts
ignoring other potentially more relevant data.16,17 Target
 Failure to communicate fully and effectively: vague or incomplete fixation has been much maligned and implicated in many
statements root cause analyses, but can often be a normal phenomenon
Most human errors include at least four of these cues. However, such forming one end of the SA spectrum. For many surgeons,
statements should be treated with caution because they imply developing ‘tunnel vision’, or a fixation, is crucial during
causation and extrapolation without support. critical phases of a procedure. To this extent, we must

ª 2020 Royal College of Obstetricians and Gynaecologists 61

 Developing situational awareness

Figure 1. The Non-Surgical Skills for Surgeons (NOTSS) tool14, using behavioural markers to assess situational awareness

understand the concept of ‘working memory’: our

conscious awareness, which, like working storage space on
a computer, has a limited capacity. The working memory
store, i.e., ‘total SA’, can be compared with the capacity of a
bucket, with its content representing data input, assessment
and projection (Figure 2). Each person has a finite cognitive
capacity for assessing new data and maintaining conscious
mental awareness of those data. The more fixated one
becomes during a specific task, the less situationally aware
we become; the more we focus on one aspect, the less we Figure 2. Capacity for situational awareness (SA). Bucket represents
total SA capacity; the content of the bucket represents the sum of data
see of the ‘bigger picture’. When working memory reaches
input (level 1), comprehension (level 2) and projection ahead (level 3).
its capacity (the bucket content ‘overflows’ in Figure 2), When cognitive overload occurs (‘bucket overflowing’), SA is lost.
‘task shedding’ occurs, so that concentration is prioritised
and attention is narrowed onto the most important
information at the expense of losing overall SA.8 An concentrating hard, I don’t see what is around me and can’t
example of target fixation might be when a surgeon’s remember the instrument names. . .”).8
perception of sound becomes muted as they try to protect
their working memory capacity by minimising any
Loss of situational awareness
extraneous or distracting auditory input focus attention
onto the surgical site. Sometimes, because of this cognitive SA can degrade, especially when attention is narrowed
overload, the surgeon may also overlook objects outside the because of target fixation, as discussed previously. This can
surgical field or develop nominal aphasia (“. . .if I am really occur, for example, during the management of severe PPH,

62 ª 2020 Royal College of Obstetricians and Gynaecologists


when clinicians’ attention becomes so completely focused on
applying uterine compression sutures or selective
devascularisation that they lose appreciation for the severity
of bleeding or perception of time.
SA can be lost because of:
 Target fixation – focusing attention on a single aspect of a
situation at the expense of ignoring more
relevant data.16,17
 Excessive workload and task saturation – our conscious
cognitive capacity can probably revolve around three to
five items; being involved with many things at the same
time leads to rapid switching of attention to different tasks
and loss of SA.
 Distractions, which can divert the attention of a clinician
(or team members) from their set tasks and can interfere
with performance and safety.18,19 Types of distractions in
theatre include irrelevant communication, noises, theatre
traffic and equipment problems. These can be mitigated
using the ‘sterile cockpit’ concept, which mandates the
avoidance of unnecessary, concurrent, non-essential tasks
that may compromise safety during critical phases of
flight, such as take-off and landing; and a highly
professional work ethic. Mobile phones and social media
have become common sources of distraction diverting
clinicians’ attention from their primary tasks.20
 Lack of communication and having preconceived notions
– not sharing mental models with team members, or
having an incorrect mental model to begin with, is often a
key factor in loss of SA. In such situations, biases
(particularly confirmation and expectation biases) can be
rampant, leading to incoming misleading data being
conveniently interpreted as compatible; in other words,
“we bend the facts to fit preconceived notions”. Effective
teams share a mental model, which means establishing a
common understanding of the task and team members’
relevant roles in it, as well as an agreed approach;21 this
avoids professional silos and misconceptions. Interestingly,
44% of aircraft accidents happen on the first leg of the first
day on which a captain and first officer initially fly together
as a team, when good shared mental models may not have
yet been developed.22
 Lack of experience, which can lead to not recognising or
comprehending future changes or being aware of
potential errors.
 Fatigue – physical and mental exhaustion impair our
vigilance and judgement. Fatigue makes us more
susceptible to confirmation bias, and to accepting only
data that agree with a particular mental model and
ignoring information that disagrees with it.
 Complacency, which can be defined as overconfidence
from repeated experience with a specific activity.
Complacency has been implicated as a contributing
factor in numerous aviation accidents and incidents.
ª 2020 Royal College of Obstetricians and Gynaecologists
Yoong et al.
When a procedure becomes routine, surgeons have a
tendency to relax and become overconfident, neglecting to
collect or notice data at level 1 SA.
Retrospective accounts relating to erroneous or lost SA
often include comments such as:
 “I was so focused on removing the adherent cyst
laparoscopically that I didn’t see that the fallopian tube
was also removed. . .”
 “We were so sure that the bladder would be miles away. . .”
 “I was tired and distracted by the midwife trying to give
me a message from the ward. . .”
 “We were busy trying to stop the bleeding from the uterine
artery and didn’t realise that she had lost so
much blood. . .”
Teams, departments and hospital trusts can lose SA, as
evidenced by the Morecombe Bay and Mid Staffordshire
Inquiries. In the Morecombe Bay Inquiry in 2015, Dr
William Kirkup23 reported a distressing chain of events in a
dysfunctional maternity unit (resulting in three maternal and
16 perinatal deaths), which was mainly attributed to a
fixation on pursuing normal childbirth ‘at any cost’. Matters
were compounded by poor working relationships between
obstetricians, paediatricians and midwives. In the Mid
Staffordshire Inquiry, the Francis Report24 highlighted how
considerable, avoidable harm can arise from a loss of SA
when senior management collectively focus on financial
targets and performance indicators at the expense of critical
analysis, self-reflection and openness. In the report on the
Grenfell Tower fire,25 the term “situational awareness” was
mentioned 27 times (particularly in recommendations 5, 6
and 11). The Grenfell Tower Investigation and Review Team
(GTIRT) identified that the scale of the fire, together with a
lack of effective communication and briefing, overwhelmed
the mental processing capacity of the Incident Command
team, leading to lost SA. Table 1 summarises the stages of loss
of SA that can lead to critical errors.
Developing good situational awareness in
clinical practice
There is evidence that SA skills, as well as cognitive capacity
and speed, can be improved by appropriate training and
support. Training usually focuses on familiarity with the idea
of Notice, Understand and Project Ahead and managing
workload and minimising distractions to protect SA.8
Clinicians can also benefit from learning concepts such as
that of the Toyota Production System,27 which emphasises
common mental models and creating a shallow authority
gradient, in which individuals are given accountability to
identify and resolve problems collectively. Effective teams
with good SA acknowledge the value of involving individuals
with different Myers-Briggs Type Indicators (MBTI)28 that
complement and positively challenge each other.
63
 Developing situational awareness
Table 1. Situational awareness (SA) error taxonomy summarising
stages of loss of SA leading to critical errors7
Stage of loss
of SA
Failure to notice (N) Data not available/difficult to detect
Failure to observe data due to target fixation,
distractions and high workload
Memory failure
Failure to Lack of mental model
understand (U) Use of incorrect mental model
Over-reliance on default values in model
Lack of experience
Memory failure
Failure to project Poor mental model
ahead (PA) Lack of experience
Recommended good practice from other high-risk
disciplines for developing a high level of SA include:
 Informative briefing: Pre-task briefing allows team
introductions (so that skill mix and experience can be
acknowledged), communication sharing and identification
of potential challenges in labour wards, gynaecology
theatres and clinics.
 Planning and preparation: Mental rehearsals can be
beneficial for perception and anticipation, especially for
less experienced clinicians.29
 Minimising distractions and interruptions: This is
especially crucial during critical phases of procedures19
and borrows from aviation’s ‘sterile cockpit’ concept.
Adherence to the ‘sterile cockpit’ rule helps to manage
unnecessary concurrent tasks that may distract clinicians
and compromise safety.
 Creating a shallow authority gradient: This environment
empowers team members to speak up and thus contribute
to overall team SA.
 Workload and time management: Avoid cutting corners to
complete tasks under time pressure.
Boxes 2, 3 and 4 list examples of how the authors maintain
their SA during clinical practice.
Maintaining situational awareness in other
high-risk disciplines: the Helicopter
Emergency Medical Service pilot
There are parallels between the unpredictability of
emergencies on labour ward and those encountered by the
Helicopter Emergency Medical Service (HEMS) team.
London airspace is relatively complicated, and the two
HEMS pilots who man the helicopter must process rapidly
64
Box 2. How I maintain situational awareness (SA) in gynaecology
theatre
“I try to follow a simple sequence to maintain situational awareness in
theatre as so many things can happen simultaneously. This sequence
essentially involves:
 Briefing, which helps me identify experience level and skill mix
 Minimising changes in the list (but, if unavoidable, I always reprint
the new list rather than manually amend it)
 Team engagement during World Health Organization Safer Surgery
checklist
 Making sure you have the right patient, the right side and the right
site of surgery (paying attention to similar sounding names and non-
English speakers). The memory of one of my colleagues sterilising a
patient instead of doing a laparoscopy and dye test has always
stayed with me. . .
 Minimising distractions and task saturation
 Ensuring staggered breaks
 Encouraging team members to speak up
 Delegating a member of team to maintain the ‘helicopter view’ if I
need to focus on a critical part of a difficult operation
 Managing time and workload. I am often guilty of trying to do too
many cases on a list, thus putting myself under unrealistic time
pressures. Rushing through a procedure when behind schedule
exposes me to loss of SA and potential errors. Interestingly,
McElhatton and Drew31 noted that the ‘hurry up’ syndrome can be
a causal factor in over 50% of aviation accidents”.
(Wai Yoong)
changing information from Air Traffic Control and from the
London Ambulance Service. Helicopter pilots often use the
term ‘bandwidth’ to describe the amount of cognitive
capacity one can devote to tasks and problems. Bandwidth
has a functional limit whereby performance is dramatically
reduced when the limit is exceeded. For HEMS helicopter
pilots, the most critical phase of the flight is landing in an ad
hoc site; losing SA at this crucial time can have disastrous
consequences. When approaching the landing site, the pilots
consciously avoid having too much ‘eyes in’ (i.e. one or both
pilots focusing on checklists, gauges and instruments within
the cockpit); rather, one pilot will do the ‘eyes out’ (i.e.
scanning the external environment during the low level
approach). A strict ‘sterile cockpit’ discipline is enforced:
accompanying medical staff are asked to minimise
nonrelevant chatter and speak only in response to checklist
items, or to impart relevant safety-critical information. Our
HEMS co-author stated that during landing, he will
“verbalise the approach path and direction, identifying any
threats aloud so as to share information and to update team
SA”. In his world, the importance of continually talking
aloud and briefing team members cannot be overstated.
Models such as BASTE (blood, arterial blood gases, surgery,
temperature, equipment) and STACS (systolic, temperature,
acidosis, coagulation, surgery), called out every 10 minutes,
serve to maintain team SA in the emergency environment.
This practice of ‘flying by voice’ or articulating tasks being
ª 2020 Royal College of Obstetricians and Gynaecologists

Box 3. How I maintain situational awareness (SA) in a busy clinic
“I am a strong advocate of briefing. I always do a briefing at the start
to set the tone for my clinic and to ensure that we share the same
mental model. I keep the briefings short and cheerful, encouraging my
team to speak up if they see mistakes. The briefing allows us to identify
potential threats, errors and omissions that can endanger our patients.
I also become aware of inexperienced or new team members and will
keep an eye out for them.
I try to anticipate periods when distractions are likely – there are times
when patients or their children have distracted me and I ended up
reading an incorrect result or writing a wrong prescription.
Halfway through the clinic, I like to do a ‘fatigue check’ as well as a
mini-brief to update everyone’s SA.
I do a short debrief at the end of clinic using open-ended questions, so
that the team can comment on events that went well or not so well.
This reinforces learning and prepares us for things that we would do
differently the next time.”
(Maud Nauta)
Box 4. How I maintain situational awareness (SA) in a labour ward
“Labour ward is a dynamic and complex environment, where the
situation can change dramatically from nothing to crises within
seconds.
I always start my ward rounds with a multidisciplinary team handover,
which initiates communication and the sharing of mental models. This
is important because we have midwives and doctors who have
different cultures, understanding of English and communication
abilities. They also have different ‘bucket’ capacities. Labour ward can
be hectic and there is a need to prioritise cases and allocate the correct
tasks to the appropriate person. This helps avoid task overload,
especially for the registrar, who tends to be the ‘go-to’ person on
labour ward.
Team huddles every few hours serve as mini-briefs to update team SA. I
always remind the team that, during critical situations, one of them
needs to take a step back and keep the ‘helicopter view’. This is even
more important if they have had a long day and are tired.
On labour ward, I try to avoid confirmation bias and target fixation: a
good example would be when asked to review a cardiotocograph
(CTG) trace, I use an open-ended query, such as ‘What do you think of
this CTG?’ rather than stating ‘This CTG looks abnormal, doesn’t it?’”
(Wasim Lodhi)
performed to ensure clear sharing of mental models, can be
extrapolated to surgical procedures30 (for example, “I am
now mobilising the bladder and displacing the ureters from
the field of surgery. . . I will secure the uterine
vessels next. . .”).
Summary
A clinician’s SA involves information gathering,
comprehension of the data in real time and developing the
crucial skills to project ahead and anticipate potential errors
and threats. The authors elaborate on positive and negative
behavioural markers for assessing SA and highlight the
importance of good communication and shared mental
ª 2020 Royal College of Obstetricians and Gynaecologists
Yoong et al.
models to maximise team SA. At all times, trainees must be
aware of factors that can lead to loss of individual and team
SA, such as target fixation, workload pressures
and distractions.
Disclosure of interests
WY is an Associate Editor for The Obstetrician &
Gynaecologist; he was excluded from editorial discussions
regarding the article and had no involvement in the decision
to publish. WY, SD, MN and WL are certified Human
Factors facilitators (Global Air Training). WY and MN are
associate members of Chartered Institute of Ergonomics and
Human Factors. WY and MN are honorary faculty members
of Trainetics Ltd.
Contribution to authorship
WY initiated the article, performed the literature search,
provided the images and finalised the draft. SD co-wrote the
article. NJ and MN co-wrote the article. WL peer reviewed
the article.
Acknowledgements
The authors would like to dedicate this article to their late
anaesthetic colleague and friend, Dr Mohan Sivarajaratnam,
of North Middlesex University Hospital, who died
unexpectedly on 19 January 2020.
References
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nts/generic-professional-capabilities-framework–0817_pdf-70417127.pdf].
2 Mishra A, Catchpole K, McCulloch P. The Oxford NOTECHS system: reliability
and validity of a tool for measuring teamwork behaviour in the operating
theatre. Qual Saf Health Care 2009;18:104–8.
3 Royal College of Obstetricians and Gynaecologists (RCOG). Each Baby
Counts: 2015 Full Report. London: RCOG; 2017 [https://www.rcog.org.uk/
globalassets/documents/guidelines/research–audit/each-baby-counts-2015-
full-report.pdf].
4 Knight M, Bunch K, Tuffnell D, Jayakody H, Shakespeare J, Kotnis R, et al.
Saving Lives, Improving Mothers’ Care. Lessons learned to inform maternity
care from the UK and Ireland Confidential Enquiries into Maternal Deaths
and Morbidity 2014–16. Oxford: National Perinatal Epidemiology Unit,
University of Oxford; 2018 [https://www.npeu.ox.ac.uk/downloads/files/mb
rrace-uk/reports/MBRRACE-UK%20Maternal%20Report%202018%20-%
20Web%20Version.pdf].
5 Way L, Stewart L, Gantert W, Kingsway L, Lee C, Whang K, et al. Causes and
prevention of laparoscopic bile duct injuries. Ann Surg 2003;237:460–9.
6 Schulz CM, Krautheim V, Hackemann A, Kreuzer M, Kochs EF, Wagner KJ.
Situation awareness errors in anesthesia and critical care in 200 cases of a
critical incident reporting system. BMC Anesthesiol 2016;16:4.
7 Endsley MR. Toward a theory of situation awareness in dynamic systems.
Hum Factors 1995;37:32–64.
8 Flin R, Patterson-Brown S. Situational awareness. In: Flin R, Youngson GG,
Yule S, editors. Enhancing surgical performance. a primer in non-technical
skills. Boca Raton, FL: CRC Press; 2016. pp. 63–83.
9 Graafland M, Bemelman WA, Schijven MP. Appraisal of face and content
validity of a serious game improving situational awareness in surgical
training. J Laparoendosc Adv Surg Tech A 2015;25:43–9.
65
 Developing situational awareness
10 Hazlehurst B, Mullen C, Gorman P. Distributed cognition in the heart room:
How situational awareness arises from coordinated communications during
cardiac surgery. J Biomed Inform 2007;40:539–51.
11 Bolstad CA, Endsley MR, Howell C, Costello A. Situational awareness training
for general aviation pilots. In: Proceedings of the 14th Triennial Congress of
the International Ergonomics Association and the 44th Annual Meeting of
the Human Factors and Ergonomics Society. Marietta, GA: SASA Technology
Inc., 2000.
12 Fletcher G, McGeorge R, Flin R, Glavin R, Maran N. Anaesthetists Non-
Technical skills (ANTS) evaluation of a behavioural marker system. Br J
Anaesth 2003;90:580–8.
13 Flin R, Glavin R, Patey R, Maran N. Anaesthetists Non-Technical skills. Br J
Anaesth 2010;105:38–44.
14 Yule S, Flin R, Maran N, Rowley DR, Youngson GG, Paterson-Brown S.
Surgeons’ non technical skills in the operating room: Reliability testing of
the NOTSS behaviour rating system. World J Surg 2008;32:548–56.
15 Royal College of Obstetricians and Gynaecologists (RCOG) Core curriculum
for Obstetrics & Gynaecology. Definitive Document 2019. London: RCOG;
2019 [https://www.rcog.org.uk/globalassets/documents/careers-and-tra
ining/curriculum/curriculum2019/2020-07-23-core-curriculum-2019–-def
initive-document.pdf].
16 Fioratou E, Flin R, Glavin R. No simple fix for fixation errors: Cognitive
processes and their clinical applications. Anaesthesia 2010;65:61–9.
17 Chandran R, DeSousa KA. Human factors in anaesthetic crisis. World J
Anesthesiol 2014;3:203–12.
18 Healey AN, Primus CP, Koutanji M. Quantifying distraction and interruption
in urological surgery. Qual Saf Health Care 2007;16:135–9.
19 Yoong W, Khin A, Ramlal N, Loabile B, Forman S. Interruptions and
distractions in the gynaecological operating theatre: irritating or dangerous?
Ergonomics 2015;58:1314–9.
20 Avidan A, Yacobi G, Weissman C, Levin PD. Cell phone calls in the operating
theater and staff distractions: an observational study. J Patient Saf 2019;15:
e52–5.
21 Wu AW. Reaching common ground: the role of shared mental models in
patient safety. J Patient Saf Risk Manage 2018;23:183–4.
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22 Jones WM. Enhancing team situation awareness: aiding pilots in forming
initial mental models of team members. Proceedings of the Ninth
International Symposium on Aviation Psychology, 27 April–1 May 1997,
Columbus, OH.
23 Kirkup B. Executive summary. In: The Report of the Morecambe Bay
Investigation. London: The Stationery Office; 2015. p. 7–11 [https://assets.
publishing.service.gov.uk/government/uploads/system/uploads/attachme
nt_data/file/408480/47487_MBI_Accessible_v0.1.pdf].
24 Francis R. Report of the Mid Staffordshire NHS Foundation Trust Public
Inquiry. Executive summary. London: The Stationery Office; 2013 [https://
assets.publishing.service.gov.uk/government/uploads/system/uploads/attac
hment_data/file/279124/0947.pdf].
25 UK Government. Grenfell Tower Inquiry Phase 1 Report: Government
Response. London: Ministry of Housing, Communities and Local
Government; 2020 [https://assets.publishing.service.gov.uk/government/
uploads/system/uploads/attachment_data/file/929153/Government_Re
sponse_to_Grenfell_Inquiry_Phase_1_Report.pdf].
26 Civil Aviation Authority. Chapter 8: Situational awareness. In: Flight-crew
human factors handbook. CAP 737. Gatwick: Civil Aviation Authority; 2014.
p. 71–9.
27 Liker JK. The 14 principles of The Toyota Way: an executive summary of the
culture behind TPS. In: The Toyota Way: 14 management principles from
the world’s greatest manufacturer. New York, NY: McGraw-Hill; 2004. p.
35–42.
28 The Myers and Briggs Foundation [https://www.myersbriggs.org/myers-and-
briggs-foundation].
29 Arora S, Aggarwal R, Pradmuth S, Moran A, Grantcharov T, Kneebone R,
et al. Mental practice enhances surgical technical skills: a randomised
controlled study. Ann Surg 2011;254:265–70.
30 O’Connor P, Keogh I, Azuara-Blanco A. Teamwork and communication. In:
Flin R, Youngson GG, Yule S, editors. Enhancing surgical performance. a
primer in non-technical skills. Boca Raton, FL: CRC Press; 2016. p. 105–21.
31 McElhatton J, Drew C. Time pressure as a causal factor in aviation accidents.
In Jensen R, editor. Proceedings of the 7th International Symposium on
Aviation Psychology. Columbus, OH: Ohio State University Press; 1993.
ª 2020 Royal College of Obstetricians and Gynaecologists
 DOI: 10.1111/tog.12720 2021;23:67–71
The Obstetrician & Gynaecologist
CPD
http://onlinetog.org

CPD questions for volume 23 issue 1

CPD credits can be claimed for the following questions recognised ways of screening cancers for
online via the TOG CPD submission system in the RCOG characteristics suggestive of the syndrome. ThFh
CPD ePortfolio. You must be a registered CPD participant of 7. the National Institute for Health and Care
the RCOG CPD programme (available in the UK and Excellence endorses universal screening of
worldwide) in order to submit your answers. colorectal cancer patients for
Participants can claim 2 credits per set of questions if at Lynch syndrome. ThFh
least 70% of questions have been answered correctly. CPD 8. most gynaecological cancers found to have
participants are advised to consider whether the articles are aberrant mismatch repair
still relevant for their CPD, in particular if there are more immunohistochemical staining will be in
recent articles on the same topic available and if clinical those with the syndrome. ThFh
guidelines have been updated since publication. 9. the addition of MLH1 promotor
Please direct all questions or problems to the CPD Office. hypermethylation testing in a Lynch
Tel: +44 (0)20 7772 6307 or email: cpd@rcog.org.uk. syndrome diagnostic pathway
The blue symbol denotes which source the questions refer improves specificity. ThFh
to including the RCOG journals, TOG and BJOG, and RCOG
Regarding gynaecological surveillance in women with
guidance, such as Green-top Guidelines (GTGs) and
Lynch syndrome,
Scientific Impact Papers (SIPs). All of the above sources are
available to RCOG Members and Fellows via the RCOG 10. there is strong evidence to recommend its use. T h F h
website. RCOG Members, Fellows and Associates have full 11. this should be offered to women around 25
access to TOG content via the TOG app (available for iOS years of age. ThFh
and Android). 12. counselling should include education on red
flag symptoms of cancer and risk-
TOG Lynch syndrome for the gynaecologist reducing surgery. ThFh

With regard to Lynch syndrome, With regard to risk-reducing strategies for women with
Lynch syndrome,
1. loss of mismatch repair protein expression on
13. hysterectomy is strongly recommended for all
immunohistochemistry of cancer
those with the syndrome. ThFh
is diagnostic. ThFh
14. the timing of risk-reducing surgery depends
2. most carriers of the mutation associated with
on the syndrome gene. ThFh
the syndrome know they have the condition. ThFh
15. where possible, a laparoscopic approach
3. the first cancers associated with the syndrome
is recommended. ThFh
are predominantly endometrial or
16. aspirin is not recommended as a means of
ovarian cancers. ThFh
reducing their overall cancer risk. ThFh
4. when cancers occur, they have in them an
unusually high immune infiltrate. ThFh Regarding Lynch syndrome-associated gynaecological cancers,
With regard to testing for Lynch syndrome, 17. endometrial types that arise as a result of the
syndrome have a poorer prognosis than
5. consent must be sought before definitive sporadic types. ThFh
germline testing for Lynch syndrome by a 18. checkpoint inhibition of the PD-1/PD-L1
trained professional. ThFh pathway has been shown to be very effective
6. immunohistochemical staining of tumours in mismatch repair-deficient cancers. ThFh
for the mismatch repair proteins or 19. vaccination against these cancers is currently
microsatellite instability analysis are the focus of research. ThFh

ª 2021 Royal College of Obstetricians and Gynaecologists 67

 CPD

20. the Manchester International Consensus 18. levels correlate positively with ascitic volume. ThFh
guideline is a useful reference for gynaecologists
With regard to the use of CA125 in the screening of
managing women with these cancers. ThFh
ovarian cancer,
19. guidelines recommend it as part of
TOG Raised CA125 – what we actually know. . . initial investigation. ThFh
20. a one-off serum blood test has been shown to
Carbohydrate antigen 125 (CA125) is, reduce patient mortality. ThFh
1. elevated when the serum level is above 40 U/ml. ThFh
2. expressed in tissues derived from embryonic
coelomic tissue. ThFh TOG Does ovarian cystectomy pose a risk to
3. a mandatory test in follow-up of patients with ovarian reserve and fertility?
ovarian cancer. ThFh
With regard to functional ovarian cysts,
4. a reliable screening biomarker. ThFh
5. normal in 50% of women with stage I 1. they are the most frequently occurring cysts in
ovarian cancer. ThFh adults and children. ThFh
6. elevated in over 70% of women with advanced 2. luteal cysts are observed in 25% of natural
ovarian cancer. ThFh menstrual cycles in fertile women. ThFh
7. only elevated in ovarian epithelial cancers. ThFh 3. women with low ovarian reserve are at
increased risk of developing them. ThFh
With regard to ovarian cancer, 4. luteal cysts result from unruptured follicles. ThFh
8. it is the leading cause of death from any 5. they almost always regress spontaneously
gynaecological malignancy. ThFh within one to three menstrual cycles. ThFh
9. approximately 70% of women present in stage
With regard to dermoid cysts,
I–II. ThFh
10. a risk of malignancy index of over 300 only is 6. they are bilateral in 30–40% of cases. ThFh
a trigger for patient referral to a cancer centre. T h F h 7. they are associated with a reduction in
ovarian reserve. ThFh
In patients with an elevated CA125 and no evidence of
ovarian cancer on imaging, With regard to endometriomas,

11. additional tumour marking testing, such as
for CA19-9 and carcinoembryonic antigen,
is recommended.
With regard to current guidance on the diagnosis of
ovarian cancer,
12. pelvic ultrasound scan is considered the first-
line investigation for women presenting with
symptoms of ovarian cancer.
13. CA125 testing should be done in all
postmenopausal women with a cystic lesion of
1 cm or more on the ovary.
Recent studies relating to ovarian cancer tumour markers
have suggested that,
14. age-specific CA125 cut-offs are less accurate
and increase false-positive results.
With regard to CA125 in ascitic fluid,
15. levels correlate with those in the serum.
16. it is produced by tumour cells.
17. levels are higher than those in blood.
8. women with endometriomas have lower
ovarian reserve (as measured by anti-
ThFh m€ullerian hormone and antral follicle counts)
compared with age matched controls. ThFh
9. cystectomy prior to in vitro fertilisation
treatment has been shown to
improve outcomes. ThFh
10. recurrence rates are similar following either
ThFh cystectomy or drainage and diathermy. ThFh
With regard to benign ovarian cysts in children
and adolescents,
ThFh
11. malignant teratomas account for about 1% of
all teratomas in children. ThFh
12. functional ovarian cysts account for about
one-third of all paediatric adnexal masses. ThFh
ThFh
With regard to ovarian torsion,
13. it accounts for approximately 3% of all
ThFh emergency gynaecological surgery. ThFh
ThFh 14. laparoscopic detorsion appears to preserve
ThFh ovarian function. ThFh

68 ª 2021 Royal College of Obstetricians and Gynaecologists

15. premenarchal girls have elongated
infundibulopelvic ligaments, which increases
their risk.
16. untwisting at the time of surgery should be
followed by cystectomy if circulation returns.
With regard to ovarian reserve assessments,
17. ovarian cystectomy has been associated with a
reduction in the ovarian reserve. ThFh
18. they are recommended before ovarian
cystectomy in women who have severe
endometriosis and bilateral endometrioma. ThFh
With regard to recommendations for ovarian cystectomy,
19. the initial incision on the cyst should be made
close to the mesovarium. ThFh
20. gonadotrophin-releasing hormone agonist
therapy is used for large endometriomas to
reduce the thickness of the cyst wall. ThFh
TOG Very advanced maternal age
Pregnancy following conception via assisted reproductive
technologies in women of advanced maternal age,
1. is significantly more likely to result in a live
birth if a donor embryo rather than an
autologous embryo is used.
2. is associated with a two-fold increase in the
risk of developing pre-eclampsia in
comparison to a pregnancy following
spontaneous conception.
3. is an indication for aspirin (150 mg) from 12
weeks of gestation until delivery to decrease
the risk of pre-eclampsia and small-for-
gestational age.
With regard to early pregnancy in women of very advanced
maternal age,
4. there is an overall 53% risk of miscarriage. ThFh
5. the overall risk of ectopic pregnancy in those
aged 44 years or more is twice that in
younger women. ThFh
6. there is evidence that women aged 40 years
and above are twice as likely to need a blood
transfusion during an admission for an
ectopic pregnancy in comparison to
younger women. ThFh
Women of very advanced maternal age are more likely than
younger women to be,
7. multiparous.
8. overweight or obese.
ª 2021 Royal College of Obstetricians and Gynaecologists
Multiple pregnancy rates in women of very advanced
maternal age,
ThFh
9. have been consistently higher than in any
other age group due to multiple embryos
ThFh
being transferred during assisted
reproductive technology. ThFh
With regard to medical complications in women of very
advanced maternal age,
10. studies have shown that they are three to six
times more likely to develop gestational
hypertension than younger women. ThFh
11. the most significant risk factor for developing
pre-eclampsia is obesity. ThFh
Venous thromboembolism risk in women of very advanced
maternal age,
12. is increased in the first trimester following
assisted reproductive technology. ThFh
13. should be first assessed at 28 weeks’ gestation. T h F h
Regarding placental complications, women of very
advanced maternal age,
14. are three times more likely to have placenta
praevia than younger women. ThFh
15. have a similar risk of placental abruption as
younger women. ThFh
ThFh
Regarding postpartum haemorrhage,
16. it complicates one in four pregnancies in
women of very advanced maternal age. ThFh
ThFh 17. women of very advanced maternal age are
almost twice as likely to need blood products
than younger women. ThFh
Women of very advanced maternal age,
ThFh
18. are 33.5 times more likely to be admitted to
intensive care than younger women. ThFh
Regarding trisomy,
19. the risk of having a child with trisomy 21 is
1:35 at the age of 45. ThFh
20. if a cut off of 1 in 150 is used as a screen-
positive result, one in four women of very
advanced maternal age will screen positive. ThFh
TOG Care in pregnancies subsequent to
stillbirth or perinatal death
In relation to investigation of a stillbirth,
1. histopathological examination of the placenta
ThFh by a pathologist provides useful information
ThFh in less than 10% of cases. ThFh
69
 CPD
2. cytogenetic analysis is the most useful
investigation to identify a cause of stillbirth. ThFh
3. postmortem (autopsy) uptake in the UK has
increased over recent years. ThFh
4. histopathological examination of the placenta
by a perinatal pathologist reduces the
reporting of ‘unexplained’ stillbirth. ThFh
With respect to stillbirths,
5. approximately 80% of those in high-income
countries occur in women who have no
recognised risk factors at booking. ThFh
6. previous occurrence is associated with an
approximately 20-fold recurrence in a
subsequent pregnancy. ThFh
7. detection of fetal growth restriction
antenatally reduces the risk. ThFh
8. stopping smoking before 16 weeks’ gestation
reduces the risk to that of the
background population. ThFh
When a mother has a history of stillbirth in the
previous pregnancy,
9. the likelihood of preterm birth is reduced in a
subsequent pregnancy. ThFh
10. the likelihood of placental abruption is
increased in a subsequent pregnancy. ThFh
11. the recurrence risk is highest when cause of
the index stillbirth was of placental origin. ThFh
12. the likelihood of complications is significantly
influenced by the time interval between the
two pregnancies. ThFh
When caring for patients in a subsequent pregnancy
after stillbirth,
13. the cost to the NHS is comparable to that of a
pregnancy complicated by
gestational diabetes. ThFh
14. women and their families are at increased risk
of intense anxiety, depression, and complex
emotional responses that persist into the
subsequent pregnancy. ThFh
15. most families embark on a subsequent
pregnancy within 12 months of the stillbirth. ThFh
16. women who have a history of stillbirth are less
likely to stop smoking than women who have
had a live birth. ThFh
17. aspirin commenced before 16 weeks’ gestation
has been shown to significantly reduce the risk
of stillbirth in high-risk women. ThFh
18. guidelines exist to standardise the care
provided across the UK to women who have
experienced a stillbirth. ThFh
70
The risk of stillbirth recurrence in a subsequent pregnancy
can be reduced,
19. with the use of serial ultrasound scan
measurements of fetal biometry and uterine
and umbilical artery doppler waveforms. ThFh
With regard to establishing the cause of stillbirth,
20. using the relevant condition at death
(ReCoDe) system is associated with the lowest
unexplained rate. ThFh
TOG Obstetric outcomes of twin pregnancies
presenting with a complete hydatidiform
mole and coexistent normal fetus: A
systematic review and meta-analysis
A single complete hydatidiform mole (CHM),
1. is almost always diploid, with its
chromosomes derived entirely from the
paternal genome. ThFh
A twin pregnancy with a CHM and coexisting normal fetus
is a condition that,
2. contains a CHM and a normal fetus whose
placenta is often partially molar. ThFh
3. has become more common due to the
increasing use of assisted
reproductive techniques. ThFh
4. presents clinically with vaginal bleeding in at
least 70% of cases. ThFh
5. presents unique clinical challenges that should
be managed antenatally by a multidisciplinary
team with expertise in managing high-
risk pregnancies. ThFh
Women presenting with a CHM and coexisting
normal fetus,
6. experience obstetric and/or perinatal
complications in approximately 80% of cases. ThFh
7. have a 10-fold higher risk of clinical
hyperthyroidism than a single CHM. ThFh
8. should be advised that their chance of a live
birth if the pregnancy continues beyond the
first trimester is approximately 50%. ThFh
Following delivery of a twin pregnancy with confirmed
histopathologic diagnosis of CHM and coexisting normal
fetus, women should be advised that,
9. they have a lower risk of gestational
trophoblastic neoplasia compared to those
with a single CHM. ThFh
ª 2021 Royal College of Obstetricians and Gynaecologists
10. they have a one in three chance of developing
gestational trophoblastic disease.
Reference
1 Zilberman Sharon N, Maymon R, Melcer Y, Jauniaux E. Obstetric outcomes of
twin pregnancies presenting with a complete hydatidiform mole and
coexistent normal fetus: a systematic review and meta-analysis. BJOG
2020;127:1450–7.
TOG Controversies in prevention of
spontaneous preterm birth in
asymptomatic women: an evidence
summary and expert opinion
With regard to preterm birth,
1. approximately two-thirds occur in the low-
risk population. ThFh
2. an inter-pregnancy interval of <6 months is a
potentially modifiable risk factor. ThFh
3. universal cervical length screening by
transvaginal ultrasound, if introduced in the
UK, would be estimated to reduce the overall
rate by less than 0.5%. ThFh
With regard to the vaginal microbiome and its influence on
preterm birth,
4. assessment of the vaginal microbiota by 16S
rRNA sequencing in high-risk pregnancies is
likely to become common practice in the next
5 years.
ª 2021 Royal College of Obstetricians and Gynaecologists
5. current National Institute for Health and Care
ThFh Excellence guidelines suggest that women in the
general obstetric population should be screened
and treated for asymptomatic bacterial vaginosis
to reduce the chance of preterm birth. ThFh
6. women with vaginal group B streptococcus
(GBS) colonisation in the antenatal period
should be informed that they have a
significantly increased risk of preterm birth
and offered treatment for GBS. ThFh
With regard to methods for the prevention of preterm birth,
7. a second reinforcing cerclage in women with
progressive cervical shortening following
cerclage has proven effectiveness. ThFh
8. women with a cerclage placed within 10 mm
of a closed external cervical os are likely to be
at a higher risk of preterm birth compared
with those with a more proximally
placed cerclage. ThFh
9. the American College of Obstetrics and
Gynecology currently recommends cervical
length follow-up after cerclage placement. ThFh
10. vaginal progesterone therapy significantly
reduces the risk of preterm birth <33 weeks
when used to treat a short cervix ≤25 mm. ThFh
Reference
1 Goodfellow L, Care A, Alfirevic Z. Controversies in the prevention of sponta-
neous preterm birth in asymptomatic women: an evidence summary and
expert opinion. BJOG 2021;128:177–94.
ThFh
71
 DOI: 10.1111/tog.12721 2021;23:72–4
The Obstetrician & Gynaecologist
http://onlinetog.org
Please note that letters and emails to
the editor should be no more than
500 words with a maximum of five
references.
Re: Laparoscopic cornual resection of interstitial
pregnancy using the Endo GIATM Universal Stapler
Dear Editor
We read with interest work published by Das et al.1
discussing tips and techniques used in minimal access
procedures for treating interstitial pregnancy, primarily
focusing on laparoscopic cornual resection performed with
the Endo GIATM Universal Stapler (Medtronic, Watford UK).
We agree that interstitial pregnancies pose a high risk to the
mother and using a technique that rapidly obtains haemostasis
is of great importance. However, the main aim of preserving
the uterus is to preserve future fertility, and this long-term goal
has to be considered alongside any short-term aims.
Cornual (‘wedge’) resection involves removal of a significant
amount of healthy myometrium. This is unnecessary and goes
against the principles of good surgical practice, which aim to
restore an organ’s normal anatomy and function. Although the
resection succeeds in preserving the patient’s future fertility, it
carries a risk of uterine rupture due to the loss of myometrium
and extensive uterine scarring.2 Liao et al. reported an incidence
of subsequent uterine rupture and dehiscence after wedge
resection of 30%.3 This is considerably higher than uterine
rupture rates post-myomectomies. In our recent review,4 we
concluded that wedge resection should realistically only be
performed in cases of ruptured interstitial pregnancies with
troublesome bleeding. A success rate 99.16% (95% confidence
interval 97.51–100) was reported in patients with interstitial
pregnancies who underwent a cornuostomy, which involves less
myometrial trauma and, in our opinion, is likely to result in less
long-term complications such as uterine rupture and the
morbidity and mortality that this entails, than more aggressive
treatments such as wedge resection.
We note that when using the Endo GIATM Universal
Stapler, the cornua is resected, breaching the myometrium,
and placing two triple-staggered rows of titanium mini-
staples. Although this technique provides a speedy
management option, we have reservations regarding the
long-term effects that performing a wedge resection and
leaving staples in situ has. These staples will not dissolve to
allow tissue healing and will not stretch to allow any future
72
Letters and emails
pregnancy to grow. This is likely to leave an even weaker area
of myometrium than the traditional wedge resection.
In conclusion, although this technique may seem to offer
patients benefit in that it is quick, straightforward to learn, and does
not require advanced laparoscopic skills such as intracorporeal
suturing, the long-term fertility outcomes are likely to be worse
than the traditional wedge resection. Laparoscopic cornuostomy is
safe, effective and because of less trauma to the myometrium, is
likely to have less risk of rupture in future pregnancies. When
managing complex, rare early pregnancy cases, early diagnosis is
important to facilitate onwards referral to centres with the
experience and skills necessary to manage patients safely, both in
the short and long term.
Maximilian Brincat PGcert BSc (Hons) MRes MD MRCOG
Senior Registrar in Obstetrics and Gynaecology, Mater Dei Hospital, Msida,
Malta
Tom K Holland MBBS MRCOG MD(Res)
Early Pregnancy and Gynaecology Assessment Unit, Department of
Obstetrics and Gynaecology, Golden Jubilee Wing, King’s College Hospital,
London SE5 8RX, UK
Joel Naftalin MBBS BSc MD MRCOG
Institute for Women’s Health, EGA wing, University College Hospital, 25
Grafton Way, London WC1E 6DB, UK
Davor Jurkovic MD PhD FRCOG
Consultant Gynaecologist and Director of Gynaecology Diagnostic and
Outpatient Treatment Unit, University College Hospital, 235 Euston Road,
London NW1 2BU, UK
References
1 Das S, Sekar H, Maulod N, Maulod A, Lodhi W, Yoong W. Laparoscopic
cornual resection of interstitial pregnancy using the Endo GIATM Universal
Stapler. The Obstetrician & Gynaecologist 2020;22:227–31.
2 Weissman A, Fishman A. Uterine rupture following conservative surgery for
interstitial pregnancy. Eur J Obstet Gynecol Reprod Biol 1992;44:237–9.
3 Liao CY et al. Cornual wedge resection for interstitial pregnancy and
postoperative outcome. Aust N Z J Obstet Gynaecol 2017;57:342–5.
4 Brincat M, Bryant-Smith A, Holland TK. The diagnosis and management of
interstitial ectopic pregnancies: a review. Gynecol Surg 2019;16:2.
ª 2021 Royal College of Obstetricians and Gynaecologists

Authors’ reply
Dear Editor
We would like to thank Brincat et al. for their interest in
our article ‘Laparoscopic cornual resection of interstitial
pregnancy using the Endo GIATM Universal Stapler’.1 We
feel that the points that our learned colleagues have raised,
while interesting, warrant some friendly rebuttal
and correction.
The main aim of our Tips and techniques article was to
raise awareness about a novel method of laparoscopic
resection using an automatic stapler, therefore enabling
practicing gynaecologists to surgically manage interstitial
pregnancy safely at their base hospital. Our aim was not to
provoke a territorial debate on whether such a pregnancy,
already fraught with a high risk of haemorrhage, should be or
should not be transferred to a tertiary hospital, where the
woman may still need to wait for ‘experts’ on laparoscopic
suturing to perform a cornuostomy or cornuectomy.
We have already emphasised in our series of 12 cases2
that stapling devices do not obviate the need to develop
laparoscopic suturing skills but allow surgeons less skilled
in intracorporeal suturing to avoid a laparotomy when
managing this condition. Interestingly, we found the
technique to be especially useful in cases of ruptured
interstitial pregnancies when the stapler was able to excise
the cornu and rapidly secure haemostasis without recourse
to laparoscopic suturing.2 In fact, the use of the Endo
GIATM Universal Stapler for laparoscopic cornuectomy
appeared to be associated with lower mean blood loss
(300 ml)2 compared with cases managed by more
conventional laparoscopic suturing (460–500 ml),3-5
possibly due to the stapler’s simultaneous action of
excision and haemostasis.
Contrary to the authors’ assertion, cornual (‘wedge’)
resection does not always involve removal of a significant
amount of healthy myometrium, as this depends on the
gestational size of the individual pregnancy. The median
gestational sizes of interstitial pregnancies excised
laparoscopically have ranged in various larger cases series
from 5.4 weeks3 to approximately 8 weeks.2,4,5
With regard to the risk of uterine rupture in subsequent
pregnancies, we humbly suggest that the authors may have
fallen into the trap of selective reporting. Firstly, there is a
paucity of long-term data on pregnancy outcomes following
interstitial pregnancy, particularly on mode of delivery, and
the few authors that have followed up subsequent
pregnancies after cornuectomy have not documented any
increases in complication rates,2,6-8 in particular uterine
rupture. In any case, many clinicians would recommend an
ª 2021 Royal College of Obstetricians and Gynaecologists
Letters and emails
elective caesarean delivery as a full thickness myometrial
incision would have been affected, not dissimilar to that
following a myomectomy where the uterine cavity had been
breached. The 30% uterine rupture rate in 10 women who
subsequently conceived in Liao and colleagues’ study9
represents a single-centre experience of 29 ‘wedge’
resections for interstitial pregnancies, of which 17 were
performed laparoscopically and 12 via laparotomy. This is,
therefore, a heterogenous group, and the high complication
rate may reflect complex confounding variables: one rupture,
for example, occurred in a woman who underwent a repeat
ipsilateral laparoscopic excision of recurrent extrauterine
pregnancy, while another arose in a twin pregnancy at 13
weeks’ gestation.10 Further, excessive use of electrocautery for
haemostasis and inadequate laparoscopic closure of the
myometrial incision may be potential risk factors that can
predispose to uterine rupture, similar to that following
laparoscopic myomectomy.11
Lastly, surgical staples have been in existence since the
1970s, and the Endo GIATM Universal Stapler has been
extensively used by upper gastrointestinal as well as colorectal
surgeons with good long-term outcomes.12 Titanium, one of
the most common materials for in situ operative implants,
produces less immune reaction and, being nonferrous, does
not interfere significantly with Magnetic Resonance
Imaging scanners. More recent publications have also
highlighted the safety of the triple-row stapling device as
well as it being well tolerated.13
Sayantana Patra-Das MRCOG
ST7 Trainee, Department of Obstetrics and Gynaecology, Homerton
Hospital, Homerton Row, London E9 6SR, UK
Hashviniya Sekar MBBCh
ST2 Trainee, Department of Obstetrics and Gynaecology, Barnet Hospital,
Wellhouse Lane, London EN5 3DJ, UK
Narmen Maulod MBBCh
Trust Grade Doctor, Department of Obstetrics and Gynaecology, North
Middlesex University Hospital, London N18 1QX, UK
Aland Maulod
Medical Student, Barts and Royal London School of Medicine and
Dentistry, 4 Newark Street, Whitechapel, London E1 2AT, UK
Wasim Lodhi FRCOG
Consultant Obstetrician and Gynaecologist, Department of Obstetrics and
Gynaecology, North Middlesex University Hospital, London N18 1QX, UK
Wai Yoong MD FRCOG
Consultant Obstetrician and Urogynaecologist, Department of Obstetrics
and Gynaecology, North Middlesex University Hospital, London N18 1QX,
UK
73
 Letters and emails
References
1 Das S, Sekar H, Maulod N, Maulod A, Lodhi W, Yoong W. Laparoscopic
cornual resection of interstitial pregnancy using the Endo GIATM Universal
Stapler. The Obstetrician & Gynaecologist 2020;22:227–31.
2 Yoong W, Neophytou C, de Silva L, Adeyemo A, Lodhi W. Novel
laparoscopic cornual resection of interstitial pregnancy using the Endo GIATM
Universal Stapler (Medtronic): A series of 12 cases. Aust N Z J Obstet
Gynaecol 2020;60:130–4.
3 Tulandi T, Al-Jaroudi D. Interstitial Pregnancy: Results Generated From the
Society of Reproductive Surgeons Registry. Obstet Gynecol
2004;103:47–50.
4 Hwang JH, Lee JK, Lee NW, Lee KW. Open cornual resection versus
laparoscopic cornual resection in patients with interstitial ectopic
pregnancies. Eur J Obstet Gynecol Reprod Biol 2011;156:78–82.
5 Ng S, Hamontri S, Irene Chua I, Chern B, Siow A. Laparoscopic
management of 53 cases of cornual ectopic pregnancy. Fert Steril
2009;92:448–52.
6 Nirgianakis N, Papadia A, Grandi G, McKinnon B, Bolla D, Mueller M.
Laparoscopic management of ectopic pregnancies: a comparison between
interstitial and ‘‘more distal’’ tubal pregnancies. Arch Gynecol Obstet
2017;295:95–101.
74
7 Hoyos LR, Vilchez G, Allsworth JE, Malik M, Rodriguez-Kovacs J, Adekola H,
et al. Outcomes in subsequent pregnancies after wedge resection for
interstitial ectopic pregnancy: a retrospective cohort study. J Maternal-Fetal
& Neonatal Medicine 2019;32:2354–60.
8 Svenningsen R, Staff AC, Langebrekke A, Qvigstad E. Fertility Outcome after
Cornual Resection for Interstitial Pregnancies. J Minim Invasive Gynecol
2019;26:865–70.
9 Liao CY, Tse J, Sung SY, Chen SH, Tsui WH. Cornual wedge resection for
interstitial pregnancy and postoperative outcome. Aust N Z J Obstet
Gynaecol 2017;57:342–5.
10 Liao CY, Ding DC. Repair of Uterine Rupture in Twin Gestation after
Laparoscopic Cornual Resection. J Min Inv Gynecol 2009;16:493–5.
11 Parker WH, Einarsson J, Istre O, Dubuisson JB. Risk factors for uterine
rupture after laparoscopic myomectomy. J Min Inv Gynecol
2010;17:551–54.
12 Delis SG, Bakoyiannis A, Karakaxas D, Athanassiou K, Tassopoulos N,
Manesis E, Ketikoglou I, Papakostas P, Dervenis C. Hepatic parenchyma
resection using stapling devices: peri-operative and long-term outcome.
HPB (Oxford) 2009;11:38–44.
13 Foo CC, Chiu AHO, Yip J, Law WL. Does advancement in stapling technology
with triple-row and enhanced staple configurations confer additional
safety? A matched comparison of 340 stapled ileocolic anastomoses. Surg
Endosc 2018;32:3122–30.
ª 2021 Royal College of Obstetricians and Gynaecologists
 DOI: 10.1111/tog.12718
The Obstetrician & Gynaecologist
http://onlinetog.org
2021;23:76–7
Write for
TOG ratings
Have you recently read a
book or used an app, website
or e-learning resource to
help your O&G practice?
Submit your review to
tog@rcog.org.uk
to be considered for the
next TOG ratings
• Book reviews: 200 words
• Website reviews:
100-150 words
• App reviews: 100 words
76
TOG Ratings ★★★★★
TOG ratings ★★★★★
WEBSITE REVIEW
https://www.arc-uk.org/ WEBSITE REVIEW WEBSITE REVIEW
RCOG eLearning Tutorial: Situational Awareness https://your-
Antenatal Results and Choices (ARC) is a national charity initially formed in 1988
(https://elearning.rcog.org.uk/new-human- healthy-
by a group of healthcare professionals and bereaved parents. The initial aim was to
support patients and their families who had undergone a termination of pregnancy
factors/situational-awareness) pregnancy-
for foetal abnormality. The charity’s focus has widened to cater for the increase in
patients requesting information and support on all aspects of antenatal screening.
The Norfolk and Norwich University Hospital in collaboration with the Royal
tool.tommys.
org/
College of Obstetricians & Gynaecologists has produced an excellent eLearning I trialled the Tommy’s ‘Your healthy
The website has dedicated pages for parents and healthcare professionals. tutorial on situational awareness. The tutorial starts with a fantastic video explaining pregnancy tool’, a short internet-based
For parents, there is a wealth of information for the current pregnancy, decision- what situational awareness is and factors leading to loss of situational awareness. The interactive assessment tool that can
making, future pregnancies and, importantly, previous patients’ stories. For short video provides insight into a typical working day on the labour ward, start- be freely accessed by patients early in
pregnancy. The tool is very user-friendly,
professionals, there are training opportunities, access to publications and a ing with handover and the impact of distraction, being called to an emergency and
can be accessed on a mobile phone or
professional’s forum. The available telephone helpline number is highlighted nicely knowing when to call for assistance when simultaneous emergencies are happening tablet and uses short, focussed questions
on the homepage. and the leader is busy. and clear language throughout. Users are
guided to provide brief information about
I was very impressed by this website. It is an excellent information portal with The eLearning package then provides users with a few short tasks and an example of
sensitive, comprehensive information to hand and access to more detailed
their current pregnancy, their health and
situational awareness simulation that can be easily replicated into any delivery suite. obstetric history. Overall, this takes less
publications. It shows a dedication to improving and individualising patient care. Finally, the authors give some important take home messages regarding situational than 3 minutes to complete. I particularly
Reviewer: Dr Tina Newell MRCOG awareness. liked the way results are provided, with
‘three simple things you could do to start
ST6 Obstetrics &Gynaecology, Belfast Health & Social Care Trust, Belfast I would highly recommend that all maternity staff work through the short eLearning helping you and your baby have a happy
TOG rating: package and watch the video provided. and healthy pregnancy’, provided as
headline information on clickable tabs.
Reviewer: Abdelmageed Abdelrahman MBBCh BAO DIPM DFSRH MRCOG MSc Full results are provided in a separate
Subspecialty Trainee in Urogynaecology, Liverpool Women’s Hospital NHS field using a traffic light system: ‘focus on
Foundation Trust, Liverpool, UK these’, ‘think about these’, ‘you’re fi ne on
WEBSITE REVIEW these’, with the option of receiving further
TOG rating:
www.lynch-syndrome-uk.org
individualised information by email.
In summary, this tool is a positive
Lynch Syndrome UK is an all-volunteer charity with a mission to addition to an expanding array of online
provide support and information for those affected by Lynch syndrome (LS) within information from a highly reputable
the UK. The team of trustees within the charity are from various backgrounds. It source. The tool encourages women to be
proactive about their health and that of
gives the impression of a welcoming group of over 2000 members ready to support their fetus and may help raise awareness
one another. The website provides knowledge and encouragement to patients and about the importance of folic acid and
also their families. vitamin D supplementation, appropriate
The learning section gives the background of LS and more in-depth documents to
use of medications in pregnancy and
optimisation of maternal physical and
download. In addition, there is an opportunity to obtain information leaflets via mental wellbeing to improve outcomes. I
email. Within the home page, there is an information video on the current updates would recommend this tool to GP surgeries
on LS. There is a page dedicated to current research studies and a concise summary and gynaecology doctors to direct women
prior to their booking visits.
page on the 2017 UK LS screening guidelines with a when/who/how approach.
Image credit: Tommy’s.
Th is website provides a learning platform for clinicians to direct patients towards.
It could benefit from more visual references/videos to complement medical Reviewer: Dr Kate Navaratnam MBChB
(hons) PhD MRCOG
descriptions. Overall, it is an easy to navigate, concise website aimed at those NIHR Academic Clinical Lecturer, Centre
affected by LS. It provides clear information at first glance with opportunities to gain for Women’s Health Research, Institute
more knowledge. of Translational Medicine, University of
Reviewer: Dr Tina Newell MRCOG Liverpool, Liverpool, UK
ST6 Obstetrics & Gynaecology, Belfast Health & Social Care Trust, Belfast
TOG rating:
TOG rating:
© 2021 Royal College of Obstetricians and Gynaecologists © 2021 Royal College of Obstetricians and Gynaecologists 77
 DOI: 10.1111/tog.12718
The Obstetrician & Gynaecologist
http://onlinetog.org
2021;23:76–7
Write for
TOG ratings
Have you recently read a
book or used an app, website
or e-learning resource to
help your O&G practice?
Submit your review to
tog@rcog.org.uk
to be considered for the
next TOG ratings
• Book reviews: 200 words
• Website reviews:
100-150 words
• App reviews: 100 words
76
TOG Ratings ★★★★★
TOG ratings ★★★★★
WEBSITE REVIEW
https://www.arc-uk.org/ WEBSITE REVIEW WEBSITE REVIEW
RCOG eLearning Tutorial: Situational Awareness https://your-
Antenatal Results and Choices (ARC) is a national charity initially formed in 1988
(https://elearning.rcog.org.uk/new-human- healthy-
by a group of healthcare professionals and bereaved parents. The initial aim was to
support patients and their families who had undergone a termination of pregnancy
factors/situational-awareness) pregnancy-
for foetal abnormality. The charity’s focus has widened to cater for the increase in
patients requesting information and support on all aspects of antenatal screening.
The Norfolk and Norwich University Hospital in collaboration with the Royal
tool.tommys.
org/
College of Obstetricians & Gynaecologists has produced an excellent eLearning I trialled the Tommy’s ‘Your healthy
The website has dedicated pages for parents and healthcare professionals. tutorial on situational awareness. The tutorial starts with a fantastic video explaining pregnancy tool’, a short internet-based
For parents, there is a wealth of information for the current pregnancy, decision- what situational awareness is and factors leading to loss of situational awareness. The interactive assessment tool that can
making, future pregnancies and, importantly, previous patients’ stories. For short video provides insight into a typical working day on the labour ward, start- be freely accessed by patients early in
pregnancy. The tool is very user-friendly,
professionals, there are training opportunities, access to publications and a ing with handover and the impact of distraction, being called to an emergency and
can be accessed on a mobile phone or
professional’s forum. The available telephone helpline number is highlighted nicely knowing when to call for assistance when simultaneous emergencies are happening tablet and uses short, focussed questions
on the homepage. and the leader is busy. and clear language throughout. Users are
guided to provide brief information about
I was very impressed by this website. It is an excellent information portal with The eLearning package then provides users with a few short tasks and an example of
sensitive, comprehensive information to hand and access to more detailed
their current pregnancy, their health and
situational awareness simulation that can be easily replicated into any delivery suite. obstetric history. Overall, this takes less
publications. It shows a dedication to improving and individualising patient care. Finally, the authors give some important take home messages regarding situational than 3 minutes to complete. I particularly
Reviewer: Dr Tina Newell MRCOG awareness. liked the way results are provided, with
‘three simple things you could do to start
ST6 Obstetrics &Gynaecology, Belfast Health & Social Care Trust, Belfast I would highly recommend that all maternity staff work through the short eLearning helping you and your baby have a happy
TOG rating: package and watch the video provided. and healthy pregnancy’, provided as
headline information on clickable tabs.
Reviewer: Abdelmageed Abdelrahman MBBCh BAO DIPM DFSRH MRCOG MSc Full results are provided in a separate
Subspecialty Trainee in Urogynaecology, Liverpool Women’s Hospital NHS field using a traffic light system: ‘focus on
Foundation Trust, Liverpool, UK these’, ‘think about these’, ‘you’re fi ne on
WEBSITE REVIEW these’, with the option of receiving further
TOG rating:
www.lynch-syndrome-uk.org
individualised information by email.
In summary, this tool is a positive
Lynch Syndrome UK is an all-volunteer charity with a mission to addition to an expanding array of online
provide support and information for those affected by Lynch syndrome (LS) within information from a highly reputable
the UK. The team of trustees within the charity are from various backgrounds. It source. The tool encourages women to be
proactive about their health and that of
gives the impression of a welcoming group of over 2000 members ready to support their fetus and may help raise awareness
one another. The website provides knowledge and encouragement to patients and about the importance of folic acid and
also their families. vitamin D supplementation, appropriate
The learning section gives the background of LS and more in-depth documents to
use of medications in pregnancy and
optimisation of maternal physical and
download. In addition, there is an opportunity to obtain information leaflets via mental wellbeing to improve outcomes. I
email. Within the home page, there is an information video on the current updates would recommend this tool to GP surgeries
on LS. There is a page dedicated to current research studies and a concise summary and gynaecology doctors to direct women
prior to their booking visits.
page on the 2017 UK LS screening guidelines with a when/who/how approach.
Image credit: Tommy’s.
Th is website provides a learning platform for clinicians to direct patients towards.
It could benefit from more visual references/videos to complement medical Reviewer: Dr Kate Navaratnam MBChB
(hons) PhD MRCOG
descriptions. Overall, it is an easy to navigate, concise website aimed at those NIHR Academic Clinical Lecturer, Centre
affected by LS. It provides clear information at first glance with opportunities to gain for Women’s Health Research, Institute
more knowledge. of Translational Medicine, University of
Reviewer: Dr Tina Newell MRCOG Liverpool, Liverpool, UK
ST6 Obstetrics & Gynaecology, Belfast Health & Social Care Trust, Belfast
TOG rating:
TOG rating:
© 2021 Royal College of Obstetricians and Gynaecologists © 2021 Royal College of Obstetricians and Gynaecologists 77
 DOI: 10.1111/tog.12714
The Obstetrician & Gynaecologist
http://onlinetog.org
UKOSS update
The outcome of pregnancy in women with
cystic fibrosis: a UK population-based
descriptive study.1
 Increasing rates of pregnancy amongst women with cystic
fibrosis (CF) mean that obstetricians and midwives are now
more frequently managing their care. However, previous
studies have collected data over many years and do not
necessarily reflect contemporary management and outcomes.
 The aim of this study was to estimate the incidence of
cystic fibrosis in pregnancy and to explore obstetric and
neonatal outcomes using the UK Obstetric Surveillance
System (UKOSS).
 Seventy-one pregnant women with CF were notified over a
2-year period, giving an estimated incidence of CF in
pregnancy as 4.4/100 000 UK maternities (95% confidence
interval 3.3–5.5). No women died.
 There was one early miscarriage, four terminations of
pregnancy and three sets of twins, resulting in the live birth
of 69 infants. One infant died following spontaneous
preterm birth.
 The mean gestation at birth was 36 completed weeks.
 There was a positive correlation between both maternal
lung function (FEV1) and mean gestation at delivery, and
between FEV1 and mean birthweight centile for
gestational age.
 This study shows that pregnancy outcomes are generally
good in women with cystic fibrosis. Successful pregnancy
is possible even in women with FEV1 <60% of predicted,
although such women have higher chance of preterm
delivery and a smaller baby.
The incidence, maternal, fetal and neonatal
consequences of single intrauterine fetal
death in monochorionic twins: A
prospective observational UKOSS study.2
 Monochorionic (MC) twin pregnancies are predisposed to
unique complications, including single intrauterine fetal
death (sIUFD). However, there is little consensus about
the management of sIUFD.
78
2021;23:78–9
UKOSS update
 The aim of this study was to describe maternal, fetal and
neonatal complications associated with single intrauterine
fetal death (sIUFD) in monochorionic twin pregnancies
using UKOSS.
 Eighty-one monochorionic twin pregnancies with sIUFD
after 14 weeks’ gestation were identified; the commonest
aetiology was twin-twin transfusion syndrome (38/81,
47%), ‘spontaneous’ sIUFD (22/81, 27%) was
second commonest.
 Death of the co-twin was common (10/70, 14%). Preterm
birth (<37 weeks’ gestation) was the commonest adverse
outcome (77%): half were spontaneous and
half iatrogenic.
 Only 46/75 (61%) cases had antenatal central nervous
system (CNS) imaging, of which 33 cases had known
results; 7/33 (21%) had radiological findings suggestive of
neurological damage.
 Postnatal CNS imaging revealed an additional 7 babies
with CNS abnormalities, all born at <36 weeks, including
all 4 babies exhibiting abnormal CNS signs.
 Major maternal morbidity was relatively common, with
6% requiring intensive therapy unit admission, all related
to infection.
 This study shows that monochorionic twin pregnancies
with sIUFD are complex and require specialist care.
Further research is required regarding optimal gestation
at delivery of the surviving co-twin, preterm birth
prevention and classifying the cause of death in twin
pregnancies. Awareness of the importance of CNS
imaging, and follow-up, needs improvement.
Marian Knight MA DPhil FFPH FRCP Edin FRCOG
Professor of Maternal and Child Population Health, National Perinatal
Epidemiology Unit, Nuffield Department of Population Health, University
of Oxford, Old Rd Campus, Oxford, OX3 7LF, UK
Email: marian.knight@npeu.ox.ac.uk
References
1 Ashcroft A, Chapman SJ, Mackillop L. The outcome of pregnancy in women
with cystic fibrosis: a UK population-based descriptive study. BJOG 2020
Dec;127:1696–703.
ª 2020 Royal College of Obstetricians and Gynaecologists
 UKOSS update

2 Morris RK, Mackie F, Garces AT, Knight M, Kilby MD. The incidence, maternal, Further information
fetal and neonatal consequences of single intrauterine fetal death in
monochorionic twins: A prospective observational UKOSS study. PLoS One Details of this and other UKOSS study results can be
2020 Sep 21;15:e0239477.
obtained from the UKOSS website http://www.npeu.ox.ac.
uk/ukoss/completed-surveillance. If you would like a reprint
Acknowledgement of any publications please contact ukoss@npeu.ox.ac.uk.
Thank you to all members who contributed information to
these studies.

ª 2020 Royal College of Obstetricians and Gynaecologists 79

 DOI: 10.1111/tog.12713
The Obstetrician & Gynaecologist
2021;23:80
http://onlinetog.org
And now for something completely different
James Drife MD FRCOG FRCPED FRCSED FCOGSA FFSRH
Emeritus Professor of Obstetrics and Gynaecology, Leeds, UK
One of the unnoticed casualties of the pandemic has been the
formal dinner. November 2020 came and went without the
black ties and expensive dresses of the RCOG’s Annual
Dinner. Burns Suppers have been cancelled across the globe.
Our local medical society is now using Zoom for all of its
meetings, including the wine tasting, but the dinner was too
big a challenge. We thought of using Deliveroo, but it
wouldn’t have been the same.
What these grand occasions offered, besides classy food
and good company, was speeches. The last after-dinner
speech I heard was almost a year ago, and I was the one
giving it. My speaking engagements have been dropping off
ever since I retired, but this is the first time I’ve gone a whole
year without one. I’m worried about becoming deskilled.
How (not) to do it
Medical after-dinner speaking is a craft that needs constant
practice. You keep learning by experience. Or, to put it bluntly,
you keep making mistakes. The worst of those – and the easiest to
avoid – is failing to do your homework. Years ago at the RCOG
Annual Dinner, the guest speaker (a famous author) kept
referring to us as a “club”. He wasn’t being satirical: he simply
hadn’t bothered to find out who we were. We took it badly.
Any speech must be tailored to the occasion, and this is
particularly important if you’re trying to be funny. That’s
why touring stand-ups always start with, “Hello, Leeds!” (or
wherever) and some local jokes. Crucially, though, your
geography needs to be accurate. Years ago, in front of a
distinguished audience in Liverpool, I name-checked another
well-known seaport. They were shocked, but not as much as I
was. Memo to self: concentrate!
During fifty-odd years of speaking, I’ve learned many
lessons the hard way. One is that the speech must be literally
‘after dinner’. Long ago an organiser, trying to be kind,
suggested I speak before the meal so that I (and he) could
relax and enjoy the evening. The faces of those hungry
doctors in Harrogate haunted me for years afterwards. I think
of them every time I drive past the Majestic Hotel.
But you can have good times too. Giving an after-dinner
speech is like going on a blind date. Sometimes you and the
80
And finally. . .
audience click from the start and have a great evening
together; other times, the relationship needs work but you can
still part as friends. Just make sure they can hear and see you,
and remember the old surgical aphorism: if in doubt, cut it
out. No audience ever complained that a speech was too short.
Learning to laugh again
If it’s unpredictable and so much trouble, why do it? Well,
you get a buzz when it goes well. And you feel sorry for the
dinner organiser, who may have been traumatised by
discovering what it costs to hire a professional. According
to one website, speakers’ fees range from £ to ££££££. Even £
is too much for a small society, and if they could afford an
eye-watering fee, do doctors want to hear an ageing
sportsperson or (heaven help us) a motivational speaker?
For me, the main reason for doing it is that it’s worthwhile.
Laughter bonds people together, and doctors rarely get the
chance to laugh these days. We’re seen – and we see ourselves
– as authority figures, and laughter is subversive. Royal
Colleges take themselves extremely seriously and daren’t risk
humour at their dinners. It’s increasingly likely that someone
with a mobile phone will take offence and tweet.
Nevertheless, there are still a few of us who believe it’s our
duty to navigate this minefield. Doctors deserve a chance to
relax and enjoy themselves. What’s more, as we’ve learned
over the past year, we need it.
From stand-up to sit-down
Which is why I’ve agreed to give a virtual after-dinner speech at a
Zoom conference next week. The dinner on Thursday evening
has of course been cancelled, but the speech has been moved to
3.30pm on the Friday, just before people wave goodbye.
Yes, I know. This will be the Majestic Hotel all over again.
But I’ll give it my best shot. I’ll forget all my experience and
start from scratch – hence the title above. Memo to self: it’s
from the 1970s! Change it. I’ll need a new role model from the
small screen – Clive James perhaps, or someone who’s still
alive. Could it possibly work? And with the audience on
mute, how will I find out?
ª 2020 Royal College of Obstetricians and Gynaecologists