YOUR PARTNER INDONESIA • 2020

IN PAEDIATRIC, ISSN 2411-0140

OBSTETRIC & VOL. 46 NO. 3
GYNAECOLOGY
PRACTICE JOURNAL OF
PAEDIATRICS,
OBSTETRICS &
GYNAECOLOGY

NEUROLOGICAL DISEASE
IN PREGNANCY

GYNAECOLOGY
Invasive Vulval Cancer

PAEDIATRICS
Gastro-Oesophageal Reflux
in Infancy

CME ARTICLE
Prevention of Spontaneous
Preterm Birth

2020 VOL. 46 NO. 3
Editorial Board
Board Director, Paediatrics
Professor Pik-To Cheung
Associate Professor, Department of Paediatrics and Adolescent Medicine
The University of Hong Kong, Hong Kong
Board Director, Obstetrics and Gynaecology
Professor Pak-Chung Ho
Director, Centre of Reproductive Medicine
The University of Hong Kong - Shenzhen Hospital, China
Professor Biran Affandi
University of Indonesia, Indonesia
Professor Hextan
Yuen-Sheung Ngan
The University of Hong Kong, Hong Kong
Professor Kenneth Kwek
KK Women’s and Children’s Hospital,
Singapore
Professor Kok Hian Tan
KK Women’s and Children’s Hospital,
Singapore
Professor Dato
Dr Ravindran Jegasothy
MAHSA University, Malaysia
Associate Professor Daisy Chan
Singapore General Hospital, Singapore
Associate Professor Raymond
Hang Wun Li
The University of Hong Kong, Hong Kong
Adjunct Associate Professor
Ng Kee Chong
Chairman Medical Board &
Senior Associate Dean, c/o KK Women’s &
Children’s Hospital, Singapore
Professor Seng-Hock Quak
National University of Singapore, Singapore
MIMS JPOG 2020 VOL. 46 NO. 3 i
CONFERENCE COVERAGE
European Society of Human Reproduction and
Embryology (ESHRE 2020) Virtual 36th Annual
Meeting, July 5-8
89
• Cerebral palsy risk in IVF babies
halved in past 20 years
Adjunct Associate Professor
• Linzagolix reduces HMB in
Tan Ah Moy women with uterine fibroids
KK Women’s and Children’s Hospital,
Singapore
Dr. Catherine Lynn Silao
University of the Philippines Manila,
Philippines
90
Dwiana Ocviyanti, MD, PhD
Universitas Indonesia, Indonesia • Emotion-focused strategies may help women cope
Dr. Karen Kar-Loen Chan with recurrent pregnancy loss
The University of Hong Kong,
Hong Kong
Dr. Kwok-Yin Leung
Queen Elizabeth Hospital, Hong Kong
JOURNAL WATCH
Dr. Mary Anne Chiong
University of the Philippines Manila,
Philippines
Dr. Wing-Cheong Leung
Kwong Wah Hospital, Hong Kong
91
Adjunct Associate Professor • Severe hearing loss in childhood
Tan Lay Kok cancer survivors: What’s the link?
Singapore General Hospital, Singapore
• Cannabis use during
pregnancy ups autism risk?
92
• Younger women with PCOS at increased risk for CVD
 MIMS JPOG 2020 VOL. 46 NO. 3 iii

2020 VOL. 46 NO. 3

REVIEW ARTICLE
OBSTETRICS
CEO Yasunobu Sakai
Managing Editor Elvira Manzano
Medical Editor Elaine Soliven
Cover Peggy Tio
93
Designer Sam Shum
Production Agnes Chieng Neurological Disease in Pregnancy
Circulation Christine Chok
Finance Manager Jessie Seow
Neurological disease encompasses a
Advertising Coordinator Pannica Goh broad spectrum of conditions which
may be affected by pregnancy, present
Published by:
MIMS (Hong Kong) Limited de novo in pregnancy, or are caused
37th Floor, Citicorp Centre, 18 Whitfield Road, Causeway Bay, Hong Kong
Tel: (852) 2559 5888 | Email: enquiry@mimsdoctor.com
by the pregnancy itself. It is important
than any women of childbearing age
with a neurological condition receive
Enquiries and Correspondence appropriate pre-pregnancy counselling and that during
China Philippines pregnancy they are managed by an experienced multidisciplinary
Yang Xuan Wilma Calderon, Gracia Cruz, team including a neurologist, specialist nurse or midwife, maternal
Tel: (86 21) 6157 3888 Dr Ryan Cua, Noriel Escueta,
Email: enquiry.cn@mims.com Ned Manalili, Marvin Osea medicine obstetrician or obstetric physician, and obstetric
Tel: (63 2) 886 0333
Hong Kong Email: enquiry.ph@mims.com anaesthetist.
Wing Leung Tsui
Tel: (852) 2559 5888 Singapore Felicity Coad; Catherine Nelson-Piercy
Email: enquiry.hk@mims.com Jackson Tu, Warren Tan, Melanie
Chia, Jasmine Tan, Kerwin Tan
India Tel: (65) 6290 7400
Monica Bhatia Email: enquiry.sg@mims.com
Tel: (91 80) 2349 4644
Email: enquiry.in@mims.com Thailand
Nawiya Witayarithipakorn
Indonesia Tel: (66 2) 741 5354
Ruth Theresia
Tel: (62 21) 729 2662
Email: enquiry.th@mims.com GYNAECOLOGY
Email: enquiry.id@mims.com Vietnam
Nguyen Thi Lan Huong,
Malaysia
Xavier Wee, Kam Zhi Yan,
Nguyen Thi My Dung 106
Tel: (84 8) 3829 7923
Sugalia Santhira, Krystle Lim,
Rathika Nagarajan
Email: enquiry.vn@mims.com Invasive Vulval Cancer
Tel: (60 3) 7623 8000
Email: enquiry.my@mims.com Vulval cancer is a rare gynaecological
cancer, predominantly seen in
postmenopausal women. It accounts
for about 4% of gynaecological
malignancies. Most women present
with vulval symptoms such as a painful
PUBLISHER: MIMS Journal of Paediatrics, Obstetrics & Gynaecology (JPOG) is published 4 times a year by MIMS Pte Ltd. CIRCULATION:
lump, ulcer, or itching, although some
JPOG is a controlled circulation for medical practitioners in South East Asia. It is also available on subscription to members of allied
professions. SUBSCRIPTION: The price per annum is US$42 (surface mail, students US$21) and US$48 (overseas airmail, students US$24);
women may be asymptomatic. It is best managed in experienced
back issues US$8 per copy. EDITORIAL MATTER published herein has been prepared by professional editorial staff. Views expressed are not
necessarily those of MIMS Pte Ltd. Although great care has been taken in compiling and checking the information given in this publication cancer centres where relevant expertise and experience is
to ensure that it is accurate, the authors, the publisher, and their servants or agents shall not be responsible or in any way liable for the
continued currency of the information or for any errors, omissions or inaccuracies in this publication whether arising from negligence available to provide multidisciplinary, individualized care for
or otherwise howsoever, or for any consequences arising therefrom. The inclusion or exclusion of any product does not mean that the
publisher advocates or rejects its use either generally or in any particular field or fields. COPYRIGHT: © 2020 MIMS Pte Ltd. All rights these women.
reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic,
mechanical, photocopying, recording or otherwise, in any language, without written consent of copyright owner. Permission to reprint
must be obtained from the publisher. ADVERTISEMENTS and ADVERTORIALS are subject to editorial acceptance and have no influence on
Vandna Verma; Krishnayan Haldar
editorial content or presentation. MIMS Pte Ltd does not guarantee, directly or indirectly, the quality or efficacy of any product or service
described in the advertisements or other material which is commercial in nature. Philippine edition: Entered as second-class mail at the
Makati Central Post Office under Permit No. PS-326-01 NCR, dated 9 Feb 2001. Printed by Tung Hing Binding Co., Rm 1001, 10/F., Hong Man
Ind. Centre, 2 Hong Man St., Chai Wan, Hong Kong Tel: 2897 1990 Fax: 2898 2343.
iv MIMS JPOG 2020 VOL. 46 NO. 3

2020 VOL. 46 NO. 3

REVIEW ARTICLE CME Accreditation

The Journal of Paediatrics, Obstetrics and Gynaecology is now
PAEDIATRICS accredited for CME points by the Singapore Medical Council (SMC).

Doctors can submit claims for self-reading, authorship or peer

115 review of articles through the SMC website at www.smc.gov.sg.
Gastro-Oesophageal Reflux in Infancy
CME points will be awarded as follows:
Gastro-oesophageal reflux (GOR) is
• 1 non-core CME point per article for self-reading
very common in infancy. It is important
to differentiate benign physiological • 5 non-core CME points for being a main author of a published
paper
reflux from gastro-oesophageal reflux
disease (GORD), which is associated • 2 non-core CME points for being a subsidiary author of a
with significant morbidity. This review published paper
summarizes the approach to infants • 2 non-core CME points for reviewing a published paper
with symptoms and signs of reflux, differential diagnosis,
investigations and management including non-pharmacological, For more information, contact us at enquiry@mimsjpog.com.
pharmacological, and surgical treatments. Severe cases require a
careful diagnostic work, treatment of associated conditions, and
aggressive medical management of the reflux. Involvement of
the multidisciplinary team is essential and in persistent refractory
reflux surgical intervention may need to be considered.
Vinod Kolimarala; R Mark Beattie; Akshay Batra

CONTINUING
MEDICAL EDUCATION
125
Prevention of Spontaneous Preterm Birth
This review highlights the various phenotypes of spontaneous
PTB, risk factors, and pathophysiological pathways associated
with the syndrome. It also discusses the various screening
and preventative measures currently employed by clinicians,
such as transvaginal sonographic screening for a short cervix,
progesterone therapy, placement of cervical cerclage, insertion
of cervical pessary, antibiotic treatment for lower genital tract
infections, and tocolytic therapy, while exploring professional
guidelines in the prevention of spontaneous PTB.
Kubi Appiah; Piya Chaemsaithong; Liona Chiu Yee Poon
The Cover:
Neurological Disease in Pregnancy
©2020 MIMS Pte Ltd
CONFERENCE COVERAGE
European Society of Human Reproduction and Embryology (ESHRE 2020) Virtual 36th Annual
Meeting, July 5-8
Cerebral palsy risk in IVF babies
halved in past 20 years
The incidence of cerebral palsy among
children conceived through in vitro fertili-
zation (IVF) has been halved over the past
two decades, although the risk of cerebral
palsy remains higher than children who
are conceived naturally, according to a
Nordic study presented at the ESHRE
2020 Meeting.
The decline was largely attributed to
a reduction in twin births in IVF, pointed out
presenting author Dr Anne Lærke Spang-
mose from Rigshospitalet, Copenhagen
University Hospital, Copenhagen, Denmark.
The results thus provide strong ev-
idence that limiting the number of twin
births following IVF can lower the risk
of cerebral palsy in children conceived
through assisted reproductive technolo-
gy, highlighted Spangmose.
“[While] multiple embryo transfer is
still standard care in many countries …
our findings emphasize that single em-
bryo transfer and singleton births should
be encouraged worldwide,” she said.
The registry-based cohort study in-
cluded 111,844 children from three national
IVF birth cohorts in Denmark (1990–2010),
Finland (1990–2010), and Sweden (1990–
2014). The children were followed until
2014 (or 2018 for the Swedish cohort). Their
health records were compared against
those of 5 million naturally-conceived chil-
dren. [ESHRE 2020, abstract O-144]
Among the IVF population, the overall
prevalence of cerebral palsy consistently
dropped from 12.5 cases per 1,000 births
in the initial years (1990–1993) to 3.4 per
1,000 births in later years (2011–2014).
In contrast, the prevalence of cerebral
palsy declined only slightly from 4.3 to 2.1
per 1,000 births in children who were con-
ceived naturally during the same period.
Nonetheless, the risk of cerebral
palsy remained evident in children con-
ceived through IVF vs natural means,
Spangmose noted.
The risk of cerebral palsy was almost
doubled among children conceived through
IVF vs natural means (adjusted odds ratio
[adjOR] 1.93), after adjusting for maternal
age, parity, offspring’s sex, and birth country
and year. The risk remained elevated after
further controlling for plurality (adjOR, 1.18).
When the analysis was stratified
based on multiplicity of birth, the research-
ers found that among singletons, the
prevalence of cerebral palsy has declined
from 8.5 to 2.8 per 1,000 births – which is
similar to the background population rate.
On the other hand, the rate of cer-
ebral palsy remained stable at 10.9 per
1,000 births for IVF twins during the study.
Compared with naturally conceived
children, the corresponding adjOR of
cerebral palsy was higher for IVF twins
(adjOR, 1.32) but similar for IVF singletons.
According to Spangmose, the birth
rates of twins following IVF have declined
considerably in Europe, particularly in the
Nordic countries whereby IVF twin rates
have dropped from ~25 percent in the
1990s to <5 percent currently – similar to
the twin rate of 2 percent in the population
of naturally conceived pregnancies.
– PEARL TOH
The risk of cerebral palsy in ART children has more than halved
over two decades – a Nordic collaborative study on 55,233
liveborn children, abstract O-144.
Linzagolix reduces HMB in
women with uterine fibroids
The use of linzagolix, a new oral gonad-
otropin-releasing hormone (GnRH) an-
tagonist, with or without add-back ther-
apy (ABT) significantly reduces heavy
MIMS JPOG 2020 VOL. 46 NO. 3 89
menstrual bleeding (HMB) in women with
uterine fibroids, according to the PRIM-
ROSE 2* trial presented at ESHRE 2020.
“[Linzagolix] is the only GnRH an-
tagonist being developed with two dose
options for both treatment of endometri-
osis associated pain and HMB in women
with uterine fibroids,” said lead author Dr
Hugh Taylor from Yale School of Medicine
in New Haven, Connecticut, US.
This phase III trial evaluated 501 wom-
en (mean age 42.9 years, mean BMI 27.02
kg/m2) who had a baseline menstrual blood
loss (MBL) of 218 mL due to uterine fibroids.
Participants were randomly assigned to re-
ceive placebo (n=102), linzagolix 100 mg
alone (n=97) or with ABT (n=101), or lin-
zagolix 200 mg alone (n=103) or with ABT
(n=98) daily for 24 weeks. ABT consisted of
oestradiol 1 mg and norethindrone acetate
0.5 mg. [ESHRE 2020, abstract O-027]
At 24 weeks, a higher percentage of
women treated with linzagolix 100 mg with
or without ABT had significantly reduced
MBL compared with placebo (77.2 percent
and 56.7 percent vs 29.4 percent; p<0.001
for both).
Similarly, those on linzagolix 200 mg
with or without ABT demonstrated a sig-
nificantly reduced MBL than those on pla-
cebo at 24 weeks (93.9 percent and 77.7
percent vs 29.4 percent; p<0.001 for both).
“[Of note,] the linzagolix 200 mg with ABT
resulted in a remarkable 94 percent de-
creased in HMB,” said Taylor.
A significantly higher percentage of
women on either dose of linzagolix with or
without ABT also achieved a higher rate
of amenorrhoea vs placebo (63.4 per-
cent and 34.0 percent; p<0.001 for 100
mg and 80.6 percent and 70.9 percent;
p<0.001 for 200 mg vs 11.8 percent).
Among subjects with anaemia (de-
fined as haemoglobin [Hb] <12 g/dL at
baseline), a significant increase in Hb lev-
90 MIMS JPOG 2020 VOL. 46 NO. 3
els was observed in the linzagolix 100 mg
with or without ABT group (difference vs
placebo, 1.6 g/dL; p<0.001 and 0.9 g/
dL; p=0.002) and linzagolix 200 mg with
or without ABT group (1.9 and 1.7 g/dL;
p<0.001 for both) than the placebo group.
A significant decrease in uterine
volume was observed in all linzagolix
groups (median change from baseline,
p=0.004 and p=0.003 for linzagolix 100
mg and both p<0.001 for linzagolix 200
mg with or without ABT, respectively),
whereas a significant decrease in fibroid
volume was only noted in the linzago-
lix 200 mg without ABT group (median
change from baseline, p<0.001).
Linzagolix recipients achieved a
significant improvement in pain (0–10
NRS** score; p≤0.002) and quality of life
(UFS-QoL*** total score; p≤0.003) at 12
and 24 weeks compared with the place-
bo recipients.
As ABT reduces bone mineral den-
sity (BMD) loss, all linzagolix treatment
groups were associated with a 1–2 per-
cent BMD loss, mainly in the lumbar
spine, except with the linzagolix 200 mg
without ABT treatment group. “Of note, in
this study, we did not give supplemental
calcium or vitamin D [to either treatment
groups],” said Taylor, who added that the
“effects on BMD of calcium or vitamin D
supplementation with linzagolix in uterine
fibroids are not known”.
Treatment-emergent adverse event
was noted in 50.5 percent of participants
in both the linzagolix 100 mg without ABT
arm and the linzagolix 200 mg with ABT
arm, ”which was expected … [and this]
gives the most profound reduction in
oestradiol levels,” Taylor noted.
“In conclusion, [either] linzagolix 100
or 200 mg with or without ABT significant-
ly decreased HMB, 57 percent respond-
ed with linzagolix 100 mg without ABT,
… which has the potential for long-term
treatment, … and 94 percent responded with
linzagolix 200 mg with ABT,” Taylor noted.
*PRIMROSE 2: Efficacy and safety of OBE2109 in subjects with
heavy menstrual bleeding associated with uterine fibroids
**NRS: Numerical Rating Scale
***UFS-QoL: Uterine fibroid symptom and quality of life
— ELAINE SOLIVEN
Efficacy and safety of linzagolix on heavy menstrual bleeding
(HMB) due to uterine fibroids (UF): Results from a placebo-con-
trolled, randomized, Phase 3 trial, abstract O-027.
Emotion-focused strategies
may help women cope with
recurrent pregnancy loss
Meditation and mindfulness interventions
may reduce perceived stress in women
who had recurrent pregnancy loss (RPL; ie,
≥3 consecutive losses), according to data
presented at ESHRE 2020.
“[Our findings show that] a 7-week
meditation and mindfulness programme
significantly reduced perceived stress [vs]
a standard supportive care programme for
women with RPL,” said Karen Kirchheiner
from Hvidovre Hospital in Denmark, who
presented the findings.
Seventy-six women were randomized
1:1 to receive supportive care alone (con-
trol arm) or with a 7-week* meditation and
mindfulness programme facilitated by an
authorized instructor (intervention arm).
Women in the intervention arm were also
instructed to undergo daily guided audio
meditation for 10–20 minutes. Women in
the control arm were instructed against
meditation. [ESHRE 2020, abstract O-184]
At 7 weeks, mean perceived stress sig-
nificantly dropped from baseline in both the
intervention (from 20 to 15 points; p<0.001)
and the control arms (from 20 to 18 points;
p=0.006). Between-group comparison showed
that the intervention outweighed the control
protocol in terms of perceived stress reduc-
tion (mean, 15 vs 18 points; p=0.027).
CONFERENCE COVERAGE
Based on COMPI-FPSS** scores at
week 7, women in the intervention arm had
a significant reduction in personal stress
from baseline (from 10.5 to 9.9 points;
p=0.04). No significant differences were
seen in the other two domains despite
the reduced scores (from 9.2 to 8.9 points
[marital] and 7.9 to 7.0 points [social]).
Consistent numerical reductions were
seen across all COMPI-FPSS domains with
the intervention protocol at 12 months, but
only the social domain score reduction
was statistically significant (p=0.04).
Two women in the intervention arm
reported depression at baseline, dropping
to none at week 7. At 12 months, only one
had depression. However, these reduc-
tions did not equate to statistical signifi-
cance (p=0.50 and p=1.0 for week 7 and
12 months, respectively). “[Between-group
comparisons] in all three timelines [also did
not reveal] any significant decrease in de-
pression,” noted Kirchheiner. However, she
underlined that the study was not powered
to detect differences in MDI***.
It is unclear whether control arm par-
ticipants followed the no-meditation proto-
col, or whether those in the intervention arm
meditated as instructed, as “meditation and
mindfulness can be an overload for women
experiencing RPL since seven participants
left the intervention arm,” said Kirchheiner.
“[Nonetheless, our findings suggest
that] guided self-administered meditations
could be a useful tool in the care for women
experiencing RPL … We now have a doc-
umented tool to reduce perceived stress.
The question now is how to implement this
in our clinical practice,” she concluded.
*Three 3-hour courses of learning meditation with 2–3-week
intervals
**COMPI-FPSS: COpenhagen Multi-centre Psychosocial Infer-
tility-Fertility Problem Stress Scale
***MDI: Major Depression Index
— AUDREY ABELLA
Meditation and mindfulness reduce stress in women with recurrent
pregnancy loss: A randomized controlled trial, abstract O-184.
JOURNAL WATCH PEER REVIEWED
P according to normal hearing (n=946),
Paediatrics
Severe hearing loss in
childhood cancer survivors:
What’s the link?
Severe hearing loss among survivors
of childhood cancer is associated with
neurocognitive deficits, a cross-sectional
study in the US has shown.
In this large cohort of childhood
cancer survivors, more than one-third of
those treated with ototoxic therapy had
severe hearing impairment. Compared
with survivors who had normal or mild
hearing impairment, those with severe
hearing impairment were at an increased
risk for neurocognitive deficits independ-
ent of neurotoxic therapy.
Researchers measured hearing
and neurocognitive function – the prima-
ry endpoints – among 1,520 childhood
cancer patients who survived 5 years
or longer after their cancer diagnosis
and participating in the St. Jude Life-
time Cohort Study. They were grouped
mild hearing impairment (n=221), or
severe hearing impairment (n=353),
and stratified by treatment exposure
(platinum chemotherapy only, n=307;
cochlear radiotherapy with or without
platinum-based chemotherapy, n=473;
and no exposure to treatment, n=740).
Hearing outcomes were coded us-
ing the Chang Ototoxicity Grading Scale.
The prevalence and risk for severe
hearing impairment were higher among
survivors who received platinum chemo-
therapy only (34.9 percent; relative risk
[RR], 1.68) or cochlear radiotherapy (38.3
percent; RR, 2.69) vs those who had no
exposure (8.8 percent).
Compared with normal hearing or
mild hearing impairment, severe hearing
impairment appeared associated with
deficits in verbal reasoning skills: plati-
num-only group, RR, 1.93; cochlear ra-
diotherapy group, RR, 2.0; no-exposure
group, RR, 1.11; verbal fluency: plati-
num-only, RR, 1.83; cochlear radiother-
apy, RR, 1.45; no exposure, RR, 1.86;
visuomotor speed: platinum-only, RR, 3.1;
cochlear radiotherapy, RR, 1.4; no expo-
sure, RR, 1.87; and mathematic skills:
platinum-only, RR, 1.63; cochlear radio-
therapy, RR, 1.58; no exposure, RR, 1.9.
More studies are warranted to de-
termine whether neurocognitive deficits
identified in childhood cancer survivors
with severe hearing impairment can be
remediated through audiologic inter-
ventions or, more importantly, wheth-
er these neurocognitive deficits could
be prevented through early audiologic
screening and intervention, comment-
ed Associate Professor Wendy Landier
from the Division of Paediatric Haema-
tology-Oncology, The University of Ala-
bama, Birmingham, Alabama, US in an
accompanying editorial.
MIMS JPOG 2020 VOL. 46 NO. 3 91
“The importance of early identi-
fication of hearing deficits, which has
always been crucial for optimizing
language and communication skills
in affected children, may take on new
significance as discovery in this area
continues,” she said. “In the meantime,
findings highlighted by this study re-
garding the poor uptake of audiologic
interventions among childhood cancer
survivors should speak volumes to the
clinicians caring for them.”
Bass JK, et al. With Neurocognition in Survivors of Childhood
Cancer. JAMA Oncol 2020;doi:10.1001/jamaoncol.2020.2822;
Landier W. Seeing (Hearing Loss) With Fresh Eyes. JAMA Oncol
2020;doi:10.1001/jamaoncol.2020.2639.
O
Obstetrics
Cannabis use during
pregnancy ups autism risk?
Children of mothers who reported canna-
bis use during pregnancy are at a higher
risk for autism vs children of mothers who
are nonusers, research has shown.
“Despite these warnings, there is ev-
idence that more people are using can-
nabis during pregnancy,” said one of the
study authors Dr Mark Walker, chief of the
Department Of Obstetrics, Gynecology
and Newborn Care at The Ottawa Hos-
pital in Ottawa, Ontario, Canada. “This
is concerning because we know so little
about how cannabis affects pregnant
women and their babies.”
Using health administrative data-
bases containing pregnancy and birth
information, Walker and his team retro-
spectively analysed all live births in On-
tario, Canada, from April 2007 through
March 2012.
92 MIMS JPOG 2020 VOL. 46 NO. 3
There were 508,025 live births includ-
ed in the study, 497,821 of whom were
analysed for autism spectrum disorder
(ASD) and neurodevelopmental disorder.
Cannabis use during pregnancy was at 0.6
percent. Among children with cannabis ex-
posure in utero, 2.2 percent had ASD.
The incidence of ASD per 1,000 per-
son-years in children exposed to canna-
bis in utero was 4.00 vs 2.42 among un-
exposed children. The adjusted hazard
ratio for ASD in children with cannabis
exposure during pregnancy was 1.51.
The incidence of intellectual disa-
bility and learning disorders were also
higher in children with prenatal canna-
bis exposure (11–22 percent increase),
although these were not statistically
significant.
It is of researchers hope that the
findings could help women and their
healthcare providers make informed
decisions with regard to cannabis use
during pregnancy. However, they also
emphasized caution when interpreting
the results given the likelihood of resid-
ual confounding.
JOURNAL WATCH PEER REVIEWED
Corsi DJ, et al. Maternal cannabis use in pregnancy and child than women without PCOS (adjusted
neurodevelopmental outcomes. Nat Med. 2020;doi:10.1038/
s41591-020-1002-5. hazard ratio [adjHR], 1.2). The difference
persisted despite further adjustment
for year of first ART treatment, baseline
parity, gestational diabetes, relationship
status, and education (adjHR,1.19), and
G adjustment for BMI, smoking, and alco-
hol use (adjHR, 1.49).
Gynaecology In women 50 years or older, there
was no difference in CVD risk between
those who had PCOS and those who
Younger women with PCOS
at increased risk for CVD had none.
“On average, women with PCOS
Women younger than 50 years with pol- have a worse CVD risk profile than wom-
ycystic ovary syndrome (PCOS) are at en without PCOS, but these differences
increased risk for CVD than younger may diminish with age,” said Oliver-Wil-
women without the hormonal disorder, liams. “Some PCOS symptoms are only
according to a study. present during the reproductive years, the
However, no link was observed raised chance of heart disease might dis-
between PCOS and CVD in women 50 appear later in life.”
years or older. She added that small lifestyle
“Heart health appears to be a par- changes, such as eating more fruits and
ticular problem for young women with vegetables and doing more exercise,
PCOS,” said investigator Clare Oli- can help reduce CVD risk in women with
ver-Williams, junior research fellow in PCOS.
the Cardiovascular Epidemiology Unit,
Department of Public Health and Prima-
ry Care at the University of Cambridge,
UK. “This may be because they are
more likely to be overweight and have
high blood pressure and diabetes com-
pared to their peers.”
Oliver-Williams and colleagues ana-
lysed data of 60,574 women (median age
33 years at baseline) from a Danish as-
sisted reproductive technology (ART) co-
hort from 1994 to 2015. The women were
followed from their first ART visit until
CVD onset, death, emigration from Den-
mark or the end of 2015, whichever came
first. Median follow-up was 8.9 years.
Among the cohort, 10.2 percent had
Oliver-Williams C, et al. Risk of cardiovascular disease for
PCOS at baseline and 4.8 percent devel- women with polycystic ovary syndrome: results from a national
Danish registry cohort study. Eur J Prev Cardiol 2020;doi:10.11
oped CVD during follow-up.
77/2047487320939674.
After adjustment for age, women
with PCOS were at greater risk for CVD
OBSTETRICS PEER REVIEWED MIMS JPOG 2020 VOL. 46 NO. 3 93

Neurological Disease
in Pregnancy
Felicity Coad BSc MBBS MRCP; Catherine Nelson-Piercy MA FRCP FRCOG

Neurological disease encompasses a broad spectrum of conditions which may

be affected by pregnancy, present de novo in pregnancy, or are caused by
the pregnancy itself. In the UK, 9.8 women in 100,000 died during pregnancy
or up to 42 days after delivery (Mothers and Babies Reducing Risk through
Confidential Enquiry (MBRRACE) report 2018). Neurological diseases, including
epilepsy and stroke, continues to be the second leading indirect cause of
maternal mortality and the numbers have not changed since reporting began
in 1985, despite the availability of easily accessible Green-top Guidelines on
the management of epilepsy through the Royal College of Obstetricians and
Gynaecologists (RCOG). It is important than any women of childbearing age with
a neurological condition receive appropriate pre-pregnancy counselling and
that during pregnancy they are managed by an experienced multidisciplinary
team including a neurologist, specialist nurse or midwife, maternal medicine
obstetrician or obstetric physician, and obstetric anaesthetist. Additional
benefits in care will come with improving awareness in the general public and
community doctors so that appropriate support is provided to enable the safest
possible pregnancy.
94 MIMS JPOG 2020 VOL. 46 NO. 3
Table 1. Seizures in Pregnancy
Other causes of seizure Potential distinguishing features
Eclampsia High blood pressure; proteinuria; fever, low
Thrombotic platelets, microangiopathic haemolytic
thrombocytopenic anaemia, thrombosis causing renal and
purpura (TTP) neurological impairment
ADAMTS13 - <5–10%
Cerebrovascular accident Ongoing neurological impairment and CT/
MRI evidence of an infarct or haemorrhage
Cerebral venous or sinus Identified on CT venogram; often a history
thrombosis of severe headache
Hypoglycaemia Neurological impairment should resolve
once glucose corrected, although this may
depend on the period of hypoglycaemia
Electrolyte imbalances Typically, hyponatraemia and
hypocalcaemia
Posterior reversible Associated visual symptoms. Can be
leukoencephalopathy associated with high blood pressure;
syndrome identified on MRI and symptoms usually
resolve 1–2 weeks later
Reversible cerebral Typical history of thunder-clap headache;
vasoconstriction syndrome identified on CT/MR angiography;
presents post­partum, symptoms usually
resolve within 3 weeks
Space-occupying lesion Possible focal neurological deficit
(SOL) depending on site of SOL; CT/MRI will
identify
EPILEPSY
Classification
Epilepsy affects approximately 0.5–1% of wom-
en of childbearing age and is the commonest
neurological disorder seen in pregnancy. An
estimated 2,500 infants are born to women with
epilepsy (WWE) every year in the UK. Epilepsy
is the third most frequent cause of indirect ma-
ternal deaths and the risk of death is increased
10-fold in pregnant WWE. The majority of deaths
in WWE have been attributed to SUDEP (sud-
den unexplained death in epilepsy). The chal-
lenge of managing WWE is combining optimal
seizure control with lowest effective dose of an-
tiepileptic drugs (AEDs) in order to minimize in
utero exposure to the foetus and the associated
OBSTETRICS PEER REVIEWED
risks of neurodevelopmental delay and structural
defects.
Classifying epilepsy is important as it guides
the neurologist in choosing appropriate AEDs
and counselling about prognosis during preg-
nancy. Epilepsy is classified according to the
clinical type of seizure or specific encephalo-
graphic (EEG) features.
Seizures can be focal (previously simple par-
tial – conscious, or complex partial – conscious-
ness impaired) or generalized (petit-mal or grand-
mal). A specific type of focal seizure is temporal
lobe epilepsy, often associated with an aura, a
duration of one or more minutes, and confusion
after the event. Generalized tonic-clonic seizures
are associated with variable periods of hypoxia in
the mother and foetus. This seizure-type carries
the highest risk of SUDEP.
About one-third of patients with epilepsy
have a positive family history of epilepsy, al-
though most cases are idiopathic, with no un-
derlying cause found. Secondary epilepsy may
occur in patients who have had previous brain
surgery or trauma, an intracranial mass lesion or
antiphospholipid syndrome. Table 1 lists other
causes of seizures in pregnancy.
The diagnosis of epilepsy and epileptiform
seizures should be made by a physician, usual-
ly a neurologist, with expertise in epilepsy. De
novo seizures in women in the second half of
their pregnancy should not be assumed to be
epilepsy, and the pre-­eclampsia pathway should
be initiated until further neurological assessment
can be made. Investigation including MRI or CT
imaging should not be withheld because the
woman is pregnant. The diagnosis of non-epi-
leptic attack disorder can be difficult and should
be made when other causes of seizure have
been excluded (see Table 1). They often coexist
in WWE.
WWE require specific care throughout their
pregnancy. Guidelines have been developed by
the RCOG and were published in June 2016 to
help improve the care of WWE who are or wish to
become pregnant.
OBSTETRICS PEER REVIEWED MIMS JPOG 2020 VOL. 46 NO. 3 95

Table 2. Rates of Major Congenital Malformations in Four Different Epilepsy Registries (Adapted from a review article
by Kevat and Mackillop, 2013)

Carbamazepine Clonazepam Lamotrigine Levetiracetam Phenobarbital Phenytoin Topiramate Sodium

valproate
International - - 2.2% - - - - -
Lamotrigine (of 1,558)
Pregnancy
Registry (2011)
UK Pregnancy 2.6% - 2.3% - - - - 6.7%
and Epilepsy (of 1,718) (of 2,198) (of 1,290)
Register (2014)
North American 2.78% 2.00% 2.05% 2.00% 6.12% (of 2.58% 5.34% 8.18%
AED Pregnancy (of 1,080) (of 100) (of 2,143) (of 999) 201) (of 427) (of 468) (of 341)
Registry (2018)
International 5.5% - 2.9% 2.8% 6.5% (of 294) 6.4% 3.9% 10.3%
Registry of (of 1,957) (of 2,514) (of 599) (of 125) (of 152) (of 1,381)
Antiepileptic Drugs
and Pregnancy
(EURAP) (2018)
Data show the total number of women exposed to monotherapy AED and the percentage of these who have a baby with an MCM.

PRECONCEPTION CARE of AEDs (ie, teratogenesis and neurodevelop-

WWE should be referred to a neurologist before
getting pregnant. A re-evaluation of the need for
AED treatment should include whether the diag-
nosis is correct and whether the epilepsy has
spontaneously remitted. As part of pre-pregnan-
cy counselling, women should be given informa-
tion on the following:
1. The impact of AEDs on the foetus including
structural and neurodevelopmental effects.
2. The change in metabolism of AEDs during
pregnancy and potential changes in seizure
frequency.
3. The importance of good preconception sei-
zure control and pregnancy planning includ-
ing taking high-dose folic acid (5 mg) for at
least 3 months prior to conception.
ANTIEPILEPTIC MEDICATION
AEDs cross the placenta and are teratogenic.
The benefits of seizure control (ie, the reduction
of seizure-related harm, including SUDEP) need
to be balanced against the detrimental effects
mental delay). Major congenital malformations
(MCMs) include neural tube defects, orofacial
clefts, congenital heart defects, and hypospa-
dias. Minor malformations include dysmorphic
features, hypertelorism, hypoplastic nails and
distal digits, and midface hypoplasia. WWE
not exposed to AEDs during pregnancy have a
similar incidence of MCM to the background
population.
The risk of major congenital
malformations
A 15-year prospective observational study look-
ing at the MCM risk of AED monotherapies in
pregnancy in UK and Ireland, showed that the
MCM risk with valproate monotherapy was 6.7%
compared to 2.6% with carbamazepine and 2.3%
with lamotrigine. A significant dose effect was
seen with valproate and carbamazepine-exposed
pregnancies. High-dose lamotrigine (>400 mg
daily) was associated with fewer MCMs than low-
dose valproate (<600 mg daily).
96 MIMS JPOG 2020 VOL. 46 NO. 3
A recently published pregnancy cohort
study looked at women taking topiramate and
the risk of oral clefts in the foetus. It found that
WWE taking higher doses of topiramate as mon-
otherapy (>100 mg) during the first trimester had
a relative risk of 5.16 of cleft lip vs 1.64 in the
lower dose group (<100 mg). The UK and Ire-
land Epilepsy and Pregnancy Register from 2013
showed that levetiracetam as monotherapy was
relatively low-risk for MCM in foetuses exposed
from the first trimester, but when used in combi-
nation with another AED conferred an increased
risk of MCM. Levetiracetam and lamotrigine given
together were lower risk for MCM compared with
levetiracetam and sodium valproate.
Data taken from the North American AED
Pregnancy Registry showed that among infants
exposed to carbamazepine as polytherapy, the
risk of MCM was 15.4% for carbamazepine plus
valproate, and 2.5% for carbamazepine plus any
other AED. The risk of MCM in infants exposed to
lamotrigine plus valproate was 9.1%, and 2.9%
for lamotrigine plus any other AED.
These studies suggest that appropriate
counselling should be based on the specific AED
combinations, and monotherapy is preferable
where possible. Table 2 summarizes data from
four Epilepsy in Pregnancy registries, showing
the percentage of MCM in foetuses born to wom-
en taking different AEDs.
Long-term neurodevelopmental
outcomes
A study looking at the cognitive function at
6 years of age after foetal exposure to AEDs
showed a statistically significant decrease in IQ
scores of children whose mothers were exposed
to valproate in utero compared to carbamazepine
and lamotrigine. These data support the need to
avoid valproate in pregnancy where possible.
Valproate must no longer be prescribed to wom-
en or girls of childbearing potential unless they
are on the pregnancy prevention programme
(PPP). Periconception folic acid has, for a num-
ber of years, been known to reduce the incidence
OBSTETRICS PEER REVIEWED
of NTDs, but recently it has also been shown to
increase IQ at 6 years of age in children whose
mothers took folic acid compared with those chil-
dren whose mothers did not.
A Cochrane review in 2014 demonstrated
no significant differences in neurological devel-
opment in children exposed to carbamazepine,
lamotrigine, and phenytoin AEDs vs children
born to epileptic mothers not on AED or the gen-
eral non-epileptic population. In utero exposure
to carbamazepine and lamotrigine does not ap-
pear to adversely affect neurodevelopment of the
children, but this is based on limited data. There
is also little evidence for levetiracetam and phe-
nytoin so parents should be aware of the limita-
tions on advising the use of these agents.
Measures to minimize risk to mother
and foetus
Discontinuation of AEDs in seizure-free women
should be discussed before conception, although
women with juvenile myoclonic epilepsy should
not discontinue their medication. The aim is to treat
with one AED at the lowest effective dose. Folic
acid 5 mg should be commenced 3 months before
conception and should be continued throughout
pregnancy. The risk of the child developing epilep-
sy (4–5% if either parent has epilepsy, with mater-
nal epilepsy associated with a higher risk) should
also be discussed with the woman.
ANTENATAL MANAGEMENT
Once pregnancy is confirmed, WWE should book
early so they can be referred to an obstetrician, ob-
stetric physician, or ideally a joint obstetric epilepsy
clinic. WWE should be provided with information
about the UK Epilepsy and Pregnancy Register
and encouraged to participate. Any unplanned
pregnancies in WWE warrant urgent referral to a
neurologist. These women should be discouraged
from abruptly stopping or changing their medica-
tions until they see a neurologist and have an in-
formed discussion of the risks and benefits.
In addition to regular antenatal care and first
trimester ultrasound screening, a detailed anom-
OBSTETRICS PEER REVIEWED
aly scan at 18–20 weeks, including foetal echo-
cardiography should be performed. WWE taking
AEDs have an increased risk of small-for-gesta-
tional-age babies and therefore require serial
growth scans from 28 weeks of gestation.
Effect of pregnancy on seizures
A review of seizure control in pregnancy from the
EURAP (International Registry of Anti-epileptic
Drugs and Pregnancy) database shows that sei-
zure frequency of 1 year prior to pregnancy is the
best predictor of seizure frequency during preg-
nancy. A meta-analysis showed that freedom
from seizures for 9 months to 1 year prior to preg-
nancy is associated with a 72–92% likelihood of
remaining seizure-free during pregnancy.
In a cohort study (n=3,784), 66.6% of the
women were seizure-free during their pregnan-
cies. Worsening seizure control in the second and
third trimester was more common in women tak-
ing lamotrigine than those taking carbamazepine
or valproate. Several studies have documented
an increase in plasma clearance of levetiracetam
and lamotrigine during pregnancy. A study in 2013
found that in a cohort of 115 pregnancies, WWE
showed a peak clearance increase of 207% for le-
vetiracetam and 191% for lamotrigine. Interesting-
ly, in this same cohort, women undergoing subse-
quent pregnancies did not necessarily follow the
same pattern of plasma clearance making it difficult
to predict drug dosing. Routine serum AED levels
are not currently recommended by the RCOG due
to paucity of evidence about whether levels im-
prove seizure control. Data from the EMPiRE study
(2018) have suggested that regular therapeutic
drug monitoring (TDM) does not improve seizure
control or alter maternal or foetal outcomes. How-
ever, we still use TDM in selected patients, for ex-
ample those women in whom we are concerned
about adherence, toxicity, or increased seizure
frequency. Seizure deterioration during pregnancy
may be a result of increased plasma clearance but
other causes include poor adherence (often due to
fears of teratogenesis), vomiting or lack of gastro-
intestinal absorption, and lack of sleep.
MIMS JPOG 2020 VOL. 46 NO. 3 97
Green-top RCOG guidelines recommend
that babies born to mothers taking enzyme-in-
ducing AEDs should be offered 1 mg of intra-
muscular vitamin K to help prevent haemorrhagic
disease of the newborn. There is insufficient evi-
dence to support giving routine oral vitamin K to
women antenatally to prevent haemorrhagic dis-
ease of the newborn.
RCOG guidelines suggest that WWE who
are not considered to have a high risk of un-
provoked seizures can be managed as low-risk
women in pregnancy.
INTRAPARTUM MANAGEMENT
Most WWE have normal vaginal deliveries and
Caesarean section is only required for obstet-
ric reasons or if there are recurrent generalized
seizures in late pregnancy or labour. The risk of
seizures increases around the time of delivery so
women with major convulsive seizures should
deliver in hospital. Women should not stop their
oral AEDs during labour. An early epidural can
be offered in order to limit the risk of precipitat-
ing a seizure because of pain and anxiety. For
women with poor seizure control, such as those
with recent convulsive seizures or recent stress/
sleep-deprivation provoked seizures or a histo-
ry of seizure during labour, long-acting benzo-
diazepines such as clobazam can be initiated
prophylactically during the peripartum period.
The risk of neonatal respiratory depression must
be balanced against the benefit of seizure pre-
vention. In the event of a seizure, which is not
self-limiting, facial oxygen, and intravenous
lorazepam, or rectal or intravenous diazepam
should be administered.
A recent systematic review identified 38
studies looking at pregnancy in WWE and out-
comes. There was a small but statistically signif-
icant increase in obstetric risk including sponta-
neous miscarriage, antepartum haemorrhage,
hypertensive disorders, induction of labour, Cae-
sarean section, and post­
partum haemorrhage.
Babies born to WWE on AEDs were more likely
to require neonatal intensive care.
98 MIMS JPOG 2020 VOL. 46 NO. 3
A population-based cohort study in Den-
mark looked at pregnancies between 1997
and 2008 and identified WWE. 4,700 women
used AEDs during pregnancy and compared to
non-AED-using WWE, they had no statistically
significant increased incidence of spontaneous
miscarriage or stillbirth.
POSTPARTUM CARE
The risk of having a seizure in the first 24 hours
after delivery is approximately 1–2%, so women
should not be left unattended. Sleep deprivation
during the postpartum period lowers seizure
threshold so additional support is advised dur-
ing this time. To minimize the risk to the baby in
the event of a major convulsive seizure, strate-
gies including changing nappies on the floor, and
bathing the baby in very shallow water or under
supervision should be employed.
The neonate should be given 1 mg of in-
tramuscular vitamin K to prevent haemorrhagic
disease of the newborn. WWE should be encour-
aged to breastfeed as most AEDs only cross into
the breast milk in minimal amounts (3–5% of ma-
ternal levels). However, women taking lamotrigine
or phenobarbitone should breastfeed prior to tak-
ing their medication in order to minimize neonatal
exposure, as these drugs cross into breast milk
in much larger amounts (30–50%). If the mother's
dose of AED was increased during pregnancy,
the AED dose should be reviewed within 10 days
of delivery to avoid postpartum toxicity.
HEADACHE
Headache accounts for one-third of all neurolog-
ical problems in pregnancy. A careful history and
neurological examination should be performed
in order to distinguish between the different
causes and exclude focal signs, papilloedema,
and neck stiffness. Primary headache disorders
include migraine and tension headache. Other
acute causes of headache include CNS infec-
tions such as meningitis, encephalitis, vascular
disease (eg, subarachnoid and other intrac-
ranial haemorrhage, cerebral venous sinus
OBSTETRICS PEER REVIEWED
thrombosis and arterial dissection), and other
intracranial diseases (eg, raised and reduced
intracranial pressure and pituitary apoplexy).
Obstetric causes include pre-eclampsia and
post-dural puncture headache. It is also impor-
tant not to forget some drug side-effects, for
example, vasodilators such as nifedipine and
hydralazine, as well as analgesia overuse, can
cause headaches.
Migraine
Migraine is common in women of childbearing
age. It may present de novo in pregnancy and
may be difficult to differentiate from a tension
headache, as migraine may present with or with-
out aura. Migraine is thought to be caused by
vasodilatation of cerebral blood vessels, possi-
bly related to platelet aggregation and seroto-
nin release with stimulation of nociceptors. MRI
during a migraine attack shows episodic cerebral
oedema, dilatation of intracerebral vessels, and
reduced water diffusion not respecting vascular
territories, so the primary event may be neurolog-
ical, rather than vascular.
Migraine with aura (classical) and without
aura (non-classical) may represent separate
clinical entities. In pregnancy, 50–90% of women
with pre-existing classical migraine improve with
a reduction in frequency and severity of attacks.
Improvement is most marked in the second and
third trimesters, and in those with premenstrual
and non-classical migraine.
A careful history is essential and features of
headache that make migraine a likely diagnosis
include a throbbing, unilateral severe headache
which may be made worse by movement, light
(photophobia), or sound (phonophobia). There
may be associated nausea and vomiting, and ep-
isodes generally last from 4–72 hours. Aura occur
in around 20% of patients and consist of visual
disturbances (eg, flashes of lights or zigzag lines
in front of the eyes), paraesthesia, or other neu-
rological symptoms. Hemiplegic migraine may
mimic a transient ischaemic attack, particularly
if there is no headache. In the absence of known
OBSTETRICS PEER REVIEWED
hemiplegic migraine, the presence of focal neu-
rological signs should be urgently investigated
with cerebral imaging. Pre-existing migraine is
associated with an increased risk of gestational
hypertension or pre-eclampsia, predominantly
in women whose headaches do not improve in
pregnancy.
The mainstay of the management of mi-
graines in pregnancy includes the avoidance
of triggers, treatment of acute attacks, and pre-
vention of future attacks. Non-pharmacological
measures to avoid migraine such as adequate
sleep and stress management may be of ben-
efit. In an acute attack, simple analgesics may
be used with antiemetics (eg, buclizine or cy-
clizine). Non-steroidal anti-inflammatory agents
such as ibuprofen are effective but should not
be used in the third trimester due to the risk of
premature closure of the ductus arteriosus and
oligohydramnios. Many women who experience
severe migraine have been managed at one time
or another with 5-HT1 agonists (triptans, eg, su-
matriptan, naratriptan), which are useful in treat-
ing acute attacks but are of limited benefit in pre-
venting further migraines. Triptans bind to 5-HT
receptors, causing vasoconstriction and inhibi-
tion of neuronal inflammation. Recent data from
an international registry suggest no teratogenic
effects; only minimal amounts of triptans have
been measured in breast milk and they are there-
fore considered to be safe during breastfeeding.
If frequent migraine attacks occur (two or
more attacks per month), 75 mg aspirin daily
should be used as a first-line agent. ᵝ-blockers
(propranolol) are effective in more than 80%
of cases and can be used in patients without
contraindications if aspirin is ineffective. Tricy-
clic anti-depressants (amitriptyline 25–50 mg
at night), calcium channel blockers (verapamil
40–80 mg at night), and cyproheptadine (2–4
mg at night) are safe in pregnancy and may be
useful in resistant cases. There are insufficient
data regarding safety of pizotifen (a serotonin
antagonist) for prevention of migraine in preg-
nancy, however, its use is justified after the first
MIMS JPOG 2020 VOL. 46 NO. 3 99
trimester, if first- and second-line prophylactic
agents are ineffective. Topiramate is avoided
where possible due to increased risk of MCM
(see epilepsy section).
Cerebral vein thrombosis
Cerebral vein thrombosis (CVT) has an inci-
dence of 1 in 10,000, but if untreated carries a
high mortality rate. The majority of cases are
seen in pregnant or puerperal women. The
pathogenesis relates to the hypercoagulable
pregnant state exacerbated by dehydration or
maternal sepsis, although underlying thrombo-
philias may contribute. Possible trauma to the
endothelial lining of cerebral sinuses and veins
during labour may also play a role. Common
presentations include headache, vomiting, sei-
zures, photophobia, and signs of raised intrac-
ranial pressure, along with focal signs such as
hemiparesis. Maternal pyrexia and leucocytosis
may be present.
Diagnosis is made using CT or MR venous
angiography. The differential diagnosis includes
subarachnoid haemorrhage, herpes encephali-
tis, and eclampsia. Management includes rehy-
dration, anticoagulation, and anticonvulsants (if
seizures are present).
Other causes of headache
Pre-eclampsia may also present with a head-
ache which may be associated with visual scintil-
lations, visual loss, or jitteriness. Headache in this
condition is thought to be secondary to vasocon-
striction and/or cerebral oedema. Severe head-
ache in a woman with pre-eclampsia suggests
the possibility of intracerebral haemorrhage es-
pecially if the blood pressure is very high.
Subarachnoid haemorrhage (SAH) oc-
curs in 20 per 100,000 pregnancies; this is two to
threefold higher than non-pregnant rates. It may
occur due to rupture of an arterial (berry) aneu-
rysm or an arteriovenous malformation (AVM).
The patient may present with a sudden-onset
severe ‘thunderclap’ headache, with nausea and
vomiting. There may be altered consciousness,
100 MIMS JPOG 2020 VOL. 46 NO. 3
neck stiffness, papilloedema, and focal neuro-
logical signs. Clipping and endovascular treat-
ment of aneurysms has been successful during
all stages of pregnancy. The risk of re-bleeding
from an AVM in the remainder of the pregnan-
cy may be 50% with the greatest risk in the
post-haemorrhagic period.
Postpartum angiopathy is a member of
a group of reversible cerebral vasoconstriction
syndromes (RCVS) with similar clinical and radi-
ologic features that are characterized by ‘thun-
derclap’ headache and diffuse, segmental, re-
versible vasospasm. It usually presents in the first
week postpartum after a previously uncomplicat-
ed pregnancy, with a severe ‘thunderclap-type’
headache with or without focal neurological
signs. Fifty to 70% of cases are associated with
the patient being given ergot derivatives. There
may be associated seizures and the presentation
may mimic an SAH or transient ischaemic attack.
It is associated with atypical SAH. The diagno-
sis is by CT angiography or MR angiography,
which shows smooth narrowing and dilatation of
multiple segments of intracranial arteries (string
of beads appearance). It is important to note,
however, that the imaging may be normal if done
early. Treatment includes analgesia and nimodip-
ine. There is usually complete resolution within
months.
Posterior reversible encephalopathy syn-
drome (PRES) is a transient neurological distur-
bance causing occipital lobe-related symptoms
commonly headache, seizures, and cortical
blindness of acute or subacute onset. In preg-
nant patients, it is usually related to pre-eclampsia
or eclampsia and there is severe impairment of
vision limited to distinguishing light and dark
with normal optic fundi and a normal pupillary
reflex. Blurred vision, photophobia, and nausea
and vomiting can also be present, with symp-
toms and signs recovering relatively rapidly. It is
thought to be caused by vasogenic brain oede-
ma. MRI shows characteristic bilateral involve-
ment of white and grey matter in the posterior
regions of cerebral hemispheres.
OBSTETRICS PEER REVIEWED
Idiopathic intracranial hypertension
(IIH) often presents with a retro-orbital head-
ache worse after laying flat (eg, first thing in
the morning). Other symptoms include visual
obscuration and intracranial noises such as tin-
nitus. Classically, it is associated with obesity
or women who have had recent rapid weight
gain and can form part of an obesity hypoventi-
lation syndrome with associated sleep apnoea.
The diagnosis of IIH is made from the combi-
nation of papilloedema and raised intracranial
pressure without CT or MRI evidence of hydro-
cephalus or a space-occupying lesion. A lum-
bar puncture should be performed to measure
the cerebrospinal fluid (CSF) opening pressure
(>25 cm H2O). Pre-existing IIH tends to wors-
en in pregnancy, and is seen more commonly
in the second trimester. Management of IIH in-
cludes limitation of weight gain. Acetazolamide
can be used from the second trimester onwards,
and thiazide diuretics can be administered, al-
though should be avoided in the third trimester,
as they can cause neonatal thrombocytopenia.
Repeated lumbar punctures over a period of
time may be needed to reduce the CSF pres-
sure. Women with IIH should fill out an Epworth
Sleepiness Scale questionnaire and be referred
for overnight pulse oximetry testing.
Post-dural puncture headache (PDPH)
arises due to loss of CSF and a reduction in
cerebrospinal pressure. Up to 38% of PDPH
can arise after a seemingly uneventful proce-
dure. It is commonly associated with a dural
tap (most common with epidural but may occur
after a spinal). Onset is usually within 24 hours
(but can be up to 72 hours) after epidural/spinal
anaesthesia/analgesia and often presents as a
fronto-occipital throbbing headache which oc-
curs abruptly on standing and improves almost
immediately on lying flat again. Associated fea-
tures include nausea and vomiting, visual symp-
toms, and rarely seizures. An anaesthetic review
is required and effective treatment includes an
epidural blood patch, which can cure in approx-
imately 50%.
OBSTETRICS PEER REVIEWED
CEREBROVASCULAR DISORDERS
Stroke is an important cause of severe mater-
nal morbidity and mortality in the UK. The in-
creasing age of women at childbirth, along
with the physiological changes of pregnancy
such as thromboembolic, immunological, and
connective tissue changes, may lead to an in-
crease in the incidence of haemorrhagic stroke
associated with pregnancy and all strokes dur-
ing the puerperium. The incidence of stroke in
non-pregnant women aged between 15 and
49 is approximately 25.0 per 100,000. This
becomes 9-fold higher in the peripartum and
3-fold higher in early postpartum, so although
the background risk in this population is low,
pregnancy significantly increases the relative
risk. Stroke contributes to more than 12% of
maternal deaths, with pre-­
eclampsia and ec-
lampsia associated with 25–45% of pregnan-
cy-related stroke, including haemorrhagic and
non-­haemorrhagic causes.
ISCHAEMIC (NON-HAEMORRHAGIC)
STROKE
Most strokes associated with pregnancy occur
in the distribution of the middle cerebral arteries
and the majority of pregnancy-related strokes
occur in the third trimester or postpartum. The
common risk factors for stroke outwith preg-
nancy, including hypertension, diabetes, and
smoking are less common in pregnancy, so rar-
er causes, for example, cardiac causes of arte-
rial emboli or arrhythmias, mitral valve disease,
paradoxical embolus through an atrial septal
defect or patent foramen ovale, antiphospholip-
id syndrome, or an underlying vasculitis need
to be considered. MRI or CT with angiography
is appropriate to confirm stroke and differenti-
ate haemorrhage from infarction. If the stroke
is ischaemic, an echocardiogram and carotid
Doppler studies are indicated. Management de-
pends on the underlying cause, and includes
75 mg aspirin daily, which should be contin-
ued postpartum. Some patients require anti-
coagulation. Thrombolysis or thrombectomy
MIMS JPOG 2020 VOL. 46 NO. 3 101
should not be withheld because of pregnancy
and multidisciplinary discussion about optimal
timing of delivery should take into considera-
tion stabilization of the mother and minimizing
bleeding risk.
HAEMORRHAGIC STROKE
Haemorrhagic stroke is rare in women of child-
bearing age outside pregnancy but is as com-
mon as ischaemic stroke during pregnancy.
Management of haemorrhagic stroke is similar to
non-pregnant women and often involves neuro-
surgical intervention, including clipping or end-
ovascular treatment. These interventions have
been performed in all trimesters of pregnancy
and are associated with low foetal and maternal
mortality. With regards to delivery, epidural is
contraindicated only if the intracranial pressure
is elevated and Caesarean section should only
be performed for obstetric indications. The most
pressing need is to treat hypertension (especial-
ly systolic hypertension) quickly and effectively
to prevent haemorrhagic stroke.
MULTIPLE SCLEROSIS
Multiple sclerosis (MS) is an inflammatory demy-
elinating disorder of the central nervous system,
which typically presents in the second or third
decade of life and is twice as common in females
as in males. Three main clinical subtypes are rec-
ognized which are relapsing-remitting, primary
progressive or secondary progressive. There are
Revised McDonald Criteria for diagnosing MS,
which involve a combination of clinical and radi-
ological signs suggesting at least two separate
episodes of demyelination. The pathogenesis
of MS is incompletely understood but involves
a maladaptive T-cell-mediated immune response
to an unknown antigen. Common presentations
include optic neuritis, diplopia, sensory symp-
toms, or weakness of the limbs.
Consensus guidelines have been published
regarding the management of women with mul-
tiple sclerosis. MS does not affect fertility, so ap-
propriate contraception and a planned pregnan-
102 MIMS JPOG 2020 VOL. 46 NO. 3
cy after pre-pregnancy counselling are advised.
Key points to cover during such counselling
include:
1. 
Do not defer disease modifying drug treat-
ment because of a wish to have children in the
future.
2. Pregnancy does not increase the risk of wors-
ening long-term disability, although some
symptoms may worsen such as fatigue, bal-
ance, and bladder symptoms.
Women with advanced MS may experience
deterioration in their mobility and worsening spas-
ticity as pregnancy advances, which may be due
to increasing weight and an altered centre of grav-
ity. Patients with a pre-existing neuropathic blad-
der are at increased risk of recurrent urinary tract
infections, which require prompt treatment with
antibiotics, or more frequent self-catheterizations.
Drugs used to relieve spasticity (baclofen), parox-
ysmal pain or dysaesthesiae (carbamazepine and
gabapentin) may also be used.
3. 
Whilst relapses during pregnancy are felt to
reduce in frequency, a postpartum relapse in
subsequent 3 months is not uncommon (25%).
4. The Pregnancy in Multiple Sclerosis (PRIMS)
study reported a reduction in MS relapse
during pregnancy, particularly in the third tri-
mester (70% reduction), and an increase in
relapse rates in the first 3 months postpartum
(40% relapse rate), with a subsequent decline
in relapse rates to pre-pregnancy levels by 10
months postpartum.
Despite the increased risk of relapse
postpartum, there is no evidence to suggest
that pre-emptive methylprednisolone or immu-
noglobulin therapy will prevent this. Relapses
should be treated with corticosteroids as per the
non-pregnant population.
Severe, acute relapses may warrant treat-
ment with high-dose corticosteroids during preg-
nancy and breastfeeding.
5. Medication should not be stopped abruptly
should a woman become pregnant – urgent
referral to the MS team is advised to discuss
the risks and benefits of each medication.
OBSTETRICS PEER REVIEWED
There are now many options available to
reduce the relapse rate of MS. There are data
available regarding the safe use of interferon B
and glatiramer acetate (eg, Copaxone) and they
should be continued at least until conception.
Copaxone is licenced for use in pregnancy.
Some women will need to continue these treat-
ments throughout pregnancy and as yet there is
no evidence of harm to the foetus.
Natalizumab (Tysabri) is licenced for women
with rapidly evolving severe MS. These women
are less likely to benefit from the relatively immu-
nosuppressed state of pregnancy and may need
to continue this treatment during pregnancy. Na-
talizumab does not cross the placenta in the first
trimester, but it does cross the placenta in the
second and third trimester. The recommenda-
tions to minimize foetal exposure suggest taking
a last dose around 34 weeks. Breastfeeding is
possible with natalizumab as oral bioavailability
is felt to be negligible.
Fingolimod should be taken with contracep-
tion and stopped 2 months prior to conceiving.
In an unplanned pregnancy, fingolimod should
be stopped and referral for foetal medicine scan-
ning made. There are no data regarding safety in
breastfeeding and it should be avoided.
Teriflunomide is teratogenic and women tak-
ing this medication should be on a reliable form
of contraception. Unplanned pregnancy requires
urgent referral to an obstetrician and neurologist
and accelerated clearance of this medication.
Dimethyl fumarate (Tecfidera) has limited
data but has been continued in pregnancy where
benefit outweighs the risk, but ideally a medica-
tion switch should be arranged. Women on this
medication should not breastfeed due to paucity
of data about breast milk excretion.
6. Vitamin D supplementation of 4000 IU (100
µg) vitamin D per day is advised to all MS pa-
tients regardless of pregnancy status.
MS is not a contraindication to vaginal de-
livery or epidural anaesthesia, however, care-
ful documentation of pre-existing neurological
deficit in the legs is necessary to avoid any
OBSTETRICS PEER REVIEWED
postpartum MS exacerbation being wrongly at-
tributed to the regional block.
Women with MS should be encouraged to
breastfeed. A recent meta-analysis of 12 stud-
ies showed that women who did not breast-
feed were almost twice as likely to have at least
one postpartum relapse compared with those
women who exclusively breastfed, although it
remains uncertain whether exclusive breast-
feeding can truly reduce postpartum relapse
rate.
There is evidence of an increased risk of
postpartum depression in both men and women
with MS, and therefore the local MS team and
midwives must monitor carefully for this and offer
appropriate support if required.
MYASTHENIA GRAVIS
Myasthenia gravis (MG) is a rare autoimmune
condition caused by antibodies against the nico-
tinic acetylcholine receptor (AChR) and other post-
synaptic antigens, for example, muscle-specific
kinase (MuSK). There is a female to male pre-
ponderance of 2:1 with onset usually in the sec-
ond and third decades. Clinical features include
fatigable painless muscle weakness leading to
diplopia, ptosis, and dysphagia, and in severe
cases, respiratory muscle weakness. Diagnosis
is confirmed by serum autoantibody analysis
and EMG evidence of disordered neuromuscu-
lar transmission.
Forty percent of women with MG have an
exacerbation in pregnancy; in 30% there is no
change in symptoms and 30% go into remis-
sion. Exacerbation in pregnancy is less likely
if the woman has undergone previous thymec-
tomy, as 10% have an associated thymoma.
Postpartum exacerbations occur in 30% of
women. Pyridostigmine (a long-acting anticho-
linesterase drug) is the mainstay of treatment,
and larger or more frequent doses may be re-
quired as the pregnancy advances. When MG
symptoms are not satisfactorily controlled, cor-
ticosteroids, azathioprine, and in some cases
intravenous immunoglobulin or plasmaphere-
MIMS JPOG 2020 VOL. 46 NO. 3 103
sis have been used. Respiratory insufficiency
may occur during pregnancy or postpartum, so
close monitoring by a multidisciplinary team is
necessary.
A UK multispecialty working group recom-
mend that pre-pregnancy counselling should be
offered to all women of childbearing age with
MG, and specific advice about the safety of dif-
ferent therapies in pregnancy should be offered
with clear instructions not to discontinue safe
immunosuppressive agents or pyridostigmine in
pregnancy.
Initial evaluation of pregnant woman with
MG should include pulmonary function tests, a
baseline ECG, and thyroid function tests (due
to the association with other autoimmune con-
ditions). MG women with dyspnoea or cough
could be promptly evaluated for the possibility
of a myasthenic flare with diaphragm and res-
piratory muscle weakness. Infections should be
treated promptly as they can also precipitate MG
flares.
Monitoring of foetal movements should
be encouraged because transplacental pas-
sage of AChR antibodies may rarely cause
arthrogryposis multiplex congenita, where
the foetus develops contractures due to lack
of movement. There is a high incidence of
preterm delivery and intrauterine growth re-
striction (40%). Since the uterus has smooth
muscle, the first stage of labour is unaffected
by MG, however, the second stage which uti-
lizes maternal voluntary striated muscle may
be impaired.
Referral to an obstetric anaesthetist should
be made early in the pregnancy, to plan for all
delivery eventualities and regional/general an-
aesthesia. Certain drugs should be avoided or
used with caution in women with MG including
magnesium sulphate for eclampsia prophylaxis
(which may precipitate a crisis), depolarising
muscle relaxants such as suxamethonium, and
drugs that impair or block neuromuscular trans-
mission such as gentamicin and ᵝ-blockers,
particularly propranolol.
104 MIMS JPOG 2020 VOL. 46 NO. 3
Up to 10% of neonates born to mothers
with MG may be affected by neonatal myas-
thenia due to transplacental passage of IgG
antibodies. This is characterized by difficulty
feeding, crying, a floppy baby and respiratory
difficulties and is usually apparent in the first 48
hours after birth. Newborn babies should have
rapid access to neonatal high-dependency sup-
port in the event they have transient myasthenic
weakness. This resolves within 2 months cor-
responding to the disappearance of maternal
antibodies in the neonate and is treated with
anticholinesterase drugs.
CEREBRAL TUMOURS
Cerebral tumours are uncommon in pregnant
patients. However, primary tumours of the cen-
tral nervous system and metastatic cancer may
present during pregnancy with signs and symp-
toms including headache, nausea and vomiting,
and visual symptoms that are often unremitting.
The headache is generally exacerbated by ma-
noeuvres that increase intracranial pressure,
such as coughing. Other symptoms depend on
the site and size of the tumour and may include
an altered mental state, focal neurological defi-
cits, or seizures. Meningiomas and pituitary tu-
mours are more common among women and
tumour size may be influenced by the vascular
and hormonal changes that accompany preg-
nancy. Neuroimaging will aid diagnosis and
guide further investigations.
MYOTONIC DYSTROPHY
Myotonic dystrophy (MD) is a rare degenerative
neuromuscular and neuroendocrine disease. The
most common form is myotonic dystrophy type
I which is inherited in an autosomal dominant
pattern. It is a trinucleotide repeat disorder with
the affected gene located on chromosome 19,
making the condition amenable to pre-implan-
tation genetic diagnosis (PGD) to avoid bearing
an affected child. The characteristic features in-
clude a progressive muscular dystrophy, muscle
weakness, and myotonia. Cataracts, cognitive
OBSTETRICS PEER REVIEWED
impairment, cardiac conduction defects, dyspha-
gia, and respiratory compromise may become
evident later in life.
In pregnancy, MD can worsen, particu-
larly in the third trimester with the associated
extra weight and diaphragmatic splinting from
a gravid uterus. However, symptoms improve
rapidly after delivery. There are a number of
pregnancy-related complications associated
with MD including increased risk of miscar-
riage, polyhydramnios (which may lead to
premature labour), dysfunctional labour, intra-
partum and postpartum haemorrhage which
can be managed with uterotonics. These com-
plications are more likely when the baby has
congenital MD.
Congenital MD occurs in some pregnan-
cies and is characterized by severe generalized
hypotonia and weakness of the neonate, diffi-
culties in breathing, sucking and swallowing,
talipes, and neurodevelopmental problems.
Women with MD should be referred to an
obstetric anaesthetist experienced in managing
these patients. When required, Caesarean sec-
tions can be performed under either regional or
general anaesthesia, but the drugs used for the
latter can cause complications in these patients
and women should be counselled regarding
this.
BELL’S PALSY
This is a unilateral lower motor neurone lesion
of the facial (VIIth cranial) nerve which causes a
unilateral facial weakness. Involvement of fron-
talis muscle on the affected side distinguishes
this from an upper motor neurone lesion. The
incidence of Bell’s palsy is approximately 45 in
100,000 pregnancies with the condition having
a 10-fold increase compared with the non-preg-
nant state. Most cases in pregnancy occur
around term, either in the 2 weeks before or after
delivery. Peripartum Bell’s palsy may be related
to swelling of the facial nerve within the petrous
temporal bone, which may be related to oede-
ma. Ramsay Hunt syndrome (herpes zoster of
OBSTETRICS PEER REVIEWED
the geniculate ganglion) should be excluded
in women presenting with Bell’s palsy, in which
herpetic vesicles may be visualized in the exter-
nal auditory meatus or soft palate. Bell’s palsy
resolves spontaneously in most cases, but re-
covery may take several months. If the patient
presents within 72 hours of onset of symptoms,
a 7-day course of 60–80 mg of prednisolone
once a day is associated with reduced risk of
unfavourable recovery. There is limited evidence
that combined antiviral and glucocorticoid treat-
ment achieves improved outcomes. Aciclovir,
ideally within 72 hours of symptoms, is used for
Ramsay Hunt syndrome instead of steroids.
ENTRAPMENT NEUROPATHIES
Carpal tunnel syndrome affects 2–3% of preg-
nant women and arises due to median nerve
compression at the flexor retinaculum. It presents
in later pregnancy with paraesthesia and numb-
ness of the thumb and lateral two and a half fin-
gers, and can sometimes be painful. More severe
symptoms can occur at night and in the domi-
nant hand, and motor loss of the median nerve
can occur, resulting in wasting of the thenar em-
inence. Relief can occur by vigorous shaking of
the affected hand. Wrist splints and physiothera-
py may offer symptomatic relief during pregnan-
cy and carpal tunnel syndrome usually improves
after delivery.
Nerves arising from the lumbosacral plex-
us may become damaged during delivery, par-
ticularly following a long second stage, due
to foetal head compression. Foot drop due to
compression of the sciatic nerve (L4–S3), the
lumbosacral trunk (L4–5) or the common pero-
neal nerve (L4–5) is the commonest presenta-
tion. The latter occurs due to pressure on the
common perineal nerve at the neck of the fib-
ula, usually with the woman in the lithotomy or
squatting position. Numbness or pain in the an-
terolateral aspect of the thigh, in the distribution
of the lateral cutaneous nerve of the thigh, may
arise in pregnancy due to nerve compression at
the lateral aspect of the inguinal ligament. It is
MIMS JPOG 2020 VOL. 46 NO. 3 105
Practice Points
• 
A thorough history and physical examination of the patient
should be performed, and specialist advice sought early when
looking after pregnant women with neurological disease.
• 
Women should be managed by a multidisciplinary team,
ideally including a neurologist with expertise in pregnancy or
an obstetric physician, specialist nurse or midwife, maternal
medicine obstetrician, and an obstetric anaesthetist.
• The risks and benefits of continuing medication in pregnancy
need to be discussed with the patient and an informed decision
made.
more common in obese patients and resolves
spontaneously following delivery.
FURTHER READING
1. Allais G, Gabellari IC, Borgogno P, de Lorenzo C, Benedetto C. The
risks of women with migraine during pregnancy. Neural Sci 2010; 31:
S59–61.
2. Campbell E, Kennedy F, Russell A, et al. Malformation risks of anti­
epileptic drug monotherapies in pregnancy: updated results from
the UK and Ireland Epilepsy and Pregnancy Registers. J Neural Neu-
rosurg Psychiatry, 2014 Feb 3; https://doi.org/10.1136/ jnnp-2013-
306318 [Epub ahead of print].
3. Dobson R, Dassan P, Roberts M, et al. UK consensus on pregnancy
in multiple sclerosis: 'Association of British Neurologists' guidelines.
Pract Neural 2019; 19: 106–14.
4. Ephross SA, Sinclair SM. Final results from the 16-year sumatriptan,
naratriptan, and treximet pregnancy registry. Headache J Head Face
Pain, 2014.
5. Hernandez-Diaz S, Huybrechts KF, Desai RJ, et al. Topiramate use
early in pregnancy and the risk of oral clefts. Neurology, 2017; https:/
/doi.org/10. 1212//WNL.0000000000004857.
6. Holmes LB, Mittendorf R, Shen A, Smith CR, Hernandez-Diaz S. Fetal
effects of anticonvulsant polytherapies: different risks from different
drug combinations. Arch Neural 2011; 68: 1275–81.
7. Kevat D, Mackillop L. Neurological diseases in pregnancy. J R Coll
Phys Edinb 2013; 43: 49–58.
8. KJ1 Meador, Baker GA, Browning N, et al. NEAD Study Group. Fetal
antiepileptic drug exposure and cognitive outcomes at age 6 years
(NEAD study): a prospective observational study. Lancet Neural 2013;
12: 244–52.
9. Royal College of Obstetrician and Gynaecology Green Top Guidelines
No.68 epilepsy in pregnancy, June 2016.
10. Thangaratinam S, Marlin N, Newton S, et al. AntiEpileptic drug Moni-
toring in PREgnancy (EMPiRE): a double-blind randomised trial on ef-
fectiveness and acceptability of monitoring strategies. Health Technol
Assess 2018; 22.
11. Vossler DG. Comparative risk of major congenital malformations with
8 different antiepileptic drugs: a prospective cohort study of the EU-
RAP registry. Epilepsy Curr 2019; 19: 83–5.
12. Vukusic S, Hutchinson M, Hours M, Moreau T, Cortinovis-Toumiaire
P, Adeleine P. Confavreux C, and the Pregnancy in Multiple Sclerosis
Group. Pregnancy and multiple sclerosis (the PRIMS study): clinical
predictors of post-partum relapse. Brain 2004; 127: 1353–60.
© 2019 Elsevier Ltd. All rights reserved. Initially published in Obstetrics,
Gynaecology and Reproductive Medicine 2019;29(11):306–313.
About the authors
Felicity Coad is a Medical Registrar in Acute Medicine at Guy's and St
Thomas' Hospital working as a Clinical Fellow in Obstetric Medicine, UK.
Conflicts of interest: none.
Catherine Nelson-Piercy is Professor of Obstetric Medicine at Guy's and
St Thomas' Hospitals NHS Foundation Trust, London, UK. Conflict of in-
terest: none.
106 MIMS JPOG 2020 VOL. 46 NO. 3 GYNAECOLOGY PEER REVIEWED

Invasive Vulval Cancer

Vandna Verma MS MRCOG; Krishnayan Haldar MD FRCOG

Vulval cancer is a rare gynaecological cancer, predominantly seen in postmen-

opausal women. It accounts for about 4% of gynaecological malignancies. Most
women present with vulval symptoms such as a painful lump, ulcer, or itching,
although some women may be asymptomatic. It is best managed in experienced
cancer centres where relevant expertise and experience is available to provide
multidisciplinary, individualized care for these women. The majority of vulval can-
cers are squamous cell cancers. Wide local excision of the lesion, usually with sur-
gical staging of groin nodes, through separate incisions is recommended for early
disease. Locally advanced vulval cancers require complex and highly individual-
ized treatment, which may be a combination of radical excision with reconstruction
with or without radiotherapy. Sentinel lymph node dissection is now becoming a
standard of care instead of en-bloc inguino-femoral lymphadenectomy for surgical
staging of smaller, early stage tumours. Radiotherapy is often required as adjuvant
treatment following surgery, or for treatment of recurrent disease.

INTRODUCTION per 100,000 cases per year in the UK. It

Invasive vulval cancer is a rare malig- constitutes only 4% of all gynaecological
nancy with an annual incidence of 3 malignancies. Most GPs will see only
GYNAECOLOGY PEER REVIEWED
one or two cases throughout their career, while
general gynaecologists will come across one or
two cases in a year. It is mainly a disease of the
postmenopausal women, and 80% cases are
seen in women over the age of 55 years.
The incidence of vulval cancer has risen over
the last few decades due to an ageing popula-
tion and increasing incidence amongst younger
women. The increasing risk in younger women is
due to changing sexual behaviours, human papil-
loma virus (HPV) infection, and smoking. Judson,
et al, reviewed the trend over a 28-year period
from 1973 to 2000 and found that the incidence
of invasive vulval cancer increased by 20% over
this period. The risk of invasive cancer increases
steadily with age, rising from 2 per 100,000 at 50
years to 20 per 100,000 after 80 years.
Pathology
The majority of primary vulval cancers are squa-
mous cell carcinomas, accounting for about 90%
of the cases. Other less common histological
subtypes include malignant melanomas, basal
cell carcinoma, adenocarcinoma, sarcomas, and
verrucous carcinoma. Secondary carcinomas of
the vulva most frequently spread from the cervix
or endometrium.
AETIOLOGY
The exact aetiology of vulval cancer remains un-
certain, but it has been associated with a large
number of risk factors. These include underlying
vulval skin disorders such lichen sclerosus, lichen
planus, Paget’s disease of the vulva, and vulval
intraepithelial neoplasia (VIN). Other risk factors
include persistent HPV infection, smoking, multi-
ple sexual partners, and immunosuppression (eg,
transplant patients). HPV infection is reported in
20–60% of women with invasive vulval cancer.
The malignant potential of treated VIN is approxi-
mately 5% and the lifetime risk of developing can-
cer within lichen sclerosis is 3–5% (Box 1).
There are two proposed pathways for devel-
oping vulval squamous cancer. The first is related
to chronic inflammation and skin disorders such
MIMS JPOG 2020 VOL. 46 NO. 3 107
Box 1. Risk Factors for Vulval Cancer
• Smoking
• Multiple sexual partners
• HPV infection
• VIN
• Lichen sclerosis
• Immunosuppression (eg, transplant patients)
• Paget’s disease of the vulva
the vulvar dystrophies. The other is related to HPV
infection.
VIN is the usual precursor lesion to squa-
mous cell vulval cancer. VIN is subdivided into
two types, reflecting the underlying aetiology:
1. Type 1: Mainly seen in younger women and is
associated with HPV infection, smoking, and
may be basaloid or warty VIN. This is often
multifocal.
2. Type 2: Predominantly, a disease of postmen-
opausal women, unrelated to HPV infection,
or smoking but with a higher incidence in
women with lichen sclerosis. It is usually uni-
focal and unicentric.
CLINICAL PRESENTATION
Women with vulvar cancer usually present with a
vulval lesion, noticed by the patient or a clinician.
The most common presentation is a vulval lump
or ulcer. Symptoms such as pain, bleeding, dis-
charge or itching may occur, although few women
may report no particular symptoms. Often, there
is a long history of pruritus with a background of
vulvar dystrophy. Rarely, a metastatic nodal mass
in the groin may be the first presenting symptom.
On clinical examination, the lesion is usually raised
and may be fleshy, ulcerated, or warty in appear-
ance. Most commonly, it involves the labia majora
but can sometimes be seen on labia minora, clit-
oris, and perineum. Lesions can be multifocal in
a minority of cases, therefore a thorough exami-
nation of the entire vulva, perineum and perianal
skin is essential. Clinical assessment of a suspect-
ed case of vulval cancer must include a thorough
108 MIMS JPOG 2020 VOL. 46 NO. 3
Box 2. Revised FIGO Staging for Carcinoma of Vulva (2008)
Stage Description
I Tumour confined to the vulva
IA Lesions ≤2 cm in size, confined to the vulva or
perineum, and with stromal invasion ≤1 mm, no
nodal metastasis
IB Lesions >2 cm in size or with stromal invasion >1 mm,
confined to the vulva or perineum, with negative nodes
II Tumour of any size with extension to adjacent perineal
structures (a third of lower urethra, a third of the lower
vagina, anus) with negative nodes
III Tumour of any size with or without extension to adjacent
perineal structures (a third of lower urethra, a third of the
lower vagina, anus) with positive inguino-femoral lymph
nodes
IIIA1 With one lymph node metastasis (≥5 mm), or
IIIA2 One or two lymph node metastases (<5 mm)
IIIB1 With two or more lymph node metastases (≥5 mm), or
IIIB2 Three or more lymph node metastases (5 mm)
IIIC With positive nodes with extracapsular spread
IV Tumour invades other regional (upper two-third urethra,
upper two-third vagina) or distant structures
IVA1 Tumour involves the upper urethral and/or vaginal
mucosa, bladder mucosa, rectal mucosa, or fixed to
the pelvic bone, or
IVA2 Fixed or ulcerated inguino-femoral lymph nodes
IVB Any distant metastasis including pelvic lymph nodes
pelvic examination, inspection of the cervix, and an
evaluation of groin lymph nodes.
DIAGNOSIS
Any suspicious vulval lesion should be biopsied
to evaluate for possible malignancy. Whenever
malignancy is possible, an incisional or wedge
biopsy should be taken from the edge of the le-
sion. The biopsy should be planned to include
a section of normal tissue. Ideally, the biopsy
specimen will include underlying the dermis and
connective tissue for adequate evaluation of the
depth and nature of stromal invasion by the pa-
thologist.
GYNAECOLOGY PEER REVIEWED
Excisional biopsy must be avoided wherever
possible, as complete removal of the malignant
lesion will have a significant impact on future
treatment options for the patients. In some cases,
excision may be unavoidable. In these situations,
it is essential to keep meticulous records of the
site and size of the lesion, with photographs (with
the patient’s consent) wherever practical.
Most biopsies can be undertaken in the out-
patient setting using local anaesthesia. However,
in some cases, an examination under anaesthetic
with ‘mapping biopsies’ may be needed, particu-
larly in larger lesions where the patient is experi-
encing severe pain on examination, or in cases
where biopsies have previously been inconclusive
due to the presence of tumour necrosis.
INVESTIGATIONS
• Cervical cytology and assessment of cervix
and vagina should be considered as vulval
cancer can be associated with other malig-
nancies of the lower genital tract.
• Cross-sectional imaging to evaluate disease
spread is recommended, either with CT or
MRI. This is to detect any enlarged groin and/
or pelvic lymph nodes, erosion into the un-
derlying bone, or other metastases.
• 
Ultrasound scan is sometimes useful for
guided biopsy of suspicious lymph nodes,
especially in obese patients.
ROUTES OF SPREAD
Vulval cancer spreads by direct extension, lym-
phatic embolization and haematogenous routes.
Lymphatic metastasis occurs early relatively
early in the disease and initially involves the in-
guino-femoral lymph nodes and subsequently
spreads to the pelvic lymph nodes, particularly
the external iliac group. The risk of lymph node
involvement is related both to the depth of inva-
sion as well as to the clinical stage of the disease
and increases from 8% at 1–2 mm to around 30%
with a 3–5 mm depth of invasion. Metastasis to
pelvic lymph nodes is uncommon, and only 20%
of patients with positive groin nodes have positive
GYNAECOLOGY PEER REVIEWED MIMS JPOG 2020 VOL. 46 NO. 3 109

pelvic nodes. Haematogenous spread occurs late Box 3. Five-year Survival Rates vs FIGO Stage and Lymph Node Status
in the course of vulval cancer and is rare in the
absence of lymph node metastasis. Local spread
FIGO 5-yr Lymph node 5-yr
can be extensive and involve the perineum, vagi-
stage survival rate (%) status survival rate (%)
na, bowel, and bone.
I 90.4 Negative 80.7

STAGING II 77.1 1 positive 62.9

Vulvar cancer is typically staged using the FIGO III 51.3 2 positives 30.4
2008 surgical staging system (Box 2). An alter-
IV 18.0 3 positives 19.2
native staging system is the TNM (tumour, node,
metastasis) system. Overall 69.7 4 positives 13.3

PROGNOSIS
With appropriate management, the prognosis of
vulval cancer is generally good in early stage dis-
ease. Box 3 show the overall 5-year survival rates
published by FIGO.
The 5-year survival rate in operable cases
is approximately 70%. The survival rate depends
upon the FIGO stage and in particular the status of
lymph node involvement. The 5-year survival rate
for patients with negative lymph nodes is around
80%, which reduces to 13% for patients with four
or more positive lymph nodes.
Metastatic disease in the regional ingui-
no-femoral lymph nodes is the single most impor-
tant prognostic factor. Patients with one microscop-
ically positive lymph node have a good prognosis
regardless of the FIGO stage of the disease. Ext-
racapsular spread carries a poor prognosis, and
5-year survival rate for patients with positive pel-
vic nodes is approximately 11%. Other important
prognostic factors are depth of stromal invasion,
tumour size, and tumour ploidy. Age is not a signifi-
cant prognostic variable. Box 4 summarizes rele-
vant prognostic factors for survival in vulval cancer.
TREATMENT
Appropriate management of vulval cancer re-
quires the involvement of an experienced multi-
disciplinary team in a tertiary centre, which has
the required expertise and caseload volume to
provide the most appropriate and bespoke care
to these patients. This specialist approach has
been shown to improve the prognosis and the
Box 4. Prognostic Factors
• Inguino-femoral lymph node metastases
• FIGO stage
• Depth of stromal invasion
• Tumour size
• Tumours ploidy
• Performance status of the patient
outcome for women with vulval cancer. When
considering the treatment approach at presenta-
tion, it is important to consider how to manage the
primary lesion as well as how to assess and treat
potentially involved inguinal nodes.
MANAGEMENT OF THE PRIMARY
TUMOUR IN EARLY VULVAL CANCER
(Stage I and II)
Surgery is the mainstay of treatment for patients
with early vulval cancer. Treatment should be in-
dividualized as there is no ‘standard’ operation
suitable for every patient. The most conservative
surgery, which gives the best cure for the disease,
should be performed. The main aim of surgery is
complete resection of the primary tumour with
adequate disease-free surgical margins togeth-
er with appropriate management of the regional
lymph nodes.
Traditionally, radical vulvectomy was regard-
ed as the standard treatment for primary vulval
110 MIMS JPOG 2020 VOL. 46 NO. 3
Cervical cytology and assessment of cervix and vagina should be considered,
as vulval cancer can be associated with other malignancies of the lower
genital tract.
tumour, but it has been replaced by a conserv-
ative surgical approach to reduce the long-term
psychosexual and functional disturbances. Mod-
ern surgeons advocate radical local excision of
the primary lesion, rather than radical vulvectomy
for all early stage vulval cancers. The term radical
means that the abnormal lesion should be resect-
ed together with a ‘safety margin’ of normal tissue
all around the lesion. A histopathological margin
of at least 8 mm is optimal to minimize the risk of
local disease recurrence after resection. In prac-
tice, this usually requires the surgeon to excise a
tumour-free margin of at least 15 mm at the time
of surgery, as tissue shrinkage occurs following
histological fixation and the reported pathological
margins are closer.
Radical local excision is suitable for lesions
on the lateral or posterior part of the vulva as the
clitoris can often be preserved. Anterior lesions
that involve clitoris or lie close to it, will usually re-
quire excision of the clitoris. Surgical resection is
the standard recommended treatment, however a
more conservative approach may be considered
GYNAECOLOGY PEER REVIEWED
in individual cases for women with small lesions
and for whom sexual function is important. For
perianal lesions, it may be difficult to achieve ade-
quate surgical margin due to proximity of the rec-
tum and anus, and preoperative and postoperative
radiotherapy may be considered in such cases. In
lesions close to the urethra, resection of the distal
1 cm of the urethra can be usually be undertaken
without a significant impact on continence.
MANAGEMENT OF GROIN LYMPH
NODES IN EARLY VULVAL CANCER
(Stage I and II)
Appropriate management of the groin lymph
nodes is the single most important factor in im-
proving the outcome in early vulval cancer. Groin
recurrence, in a patient who had not had lym-
phadenectomy in the first place, carries a poor
outcome.
Before planning treatment of the groin nodes,
it is important to evaluate for any evidence of
spread. In additional to clinical examination, im-
aging is also helpful to evaluate the groin nodes.
Either ultrasound scan or cross-sectional imaging
can be used. If the nodes have a suspicious ap-
pearance, it is helpful to biopsy the nodes prior
to planning treatment. Additionally, where there is
any suggestion that groin lymph nodes may be in-
volved by malignancy, it is important to evaluate for
metastatic spread, usually with a CT scan.
Surgical staging is considered to be the man-
agement of choice for groin lymph nodes in early
vulval cancer (apart from stage IA where the risk of
lymph node metastasis is very low), unless there
is already evidence of nodal involvement on pre-
operative investigations. Surgical staging is a tech-
nique to further assess the involvement of local
lymph nodes and involves removing either all of
the nodes (groin node dissection/inguino-femoral
lymphadenectomy), or just the ‘sentinel nodes’
and sending them to the pathologists for further
assessment/ultrastaging.
Surgical staging of the nodes is not required
for patients with FIGO stage IA tumour as the risk
of groin lymph node metastases is <1%. All pa-
GYNAECOLOGY PEER REVIEWED
tients with stage IB and stage II tumour require
surgical groin lymph node assessment. For lat-
eralized lesions (tumour edge separated from
midline structure by at least 1 cm of macroscop-
ically normal tissue), ipsilateral inguino-femoral
lymphadenectomy should be performed, and if
nodal metastasis is present, then consideration
should be given to contralateral inguino-femoral
lymphadenectomy. The femoral nodes should be
removed to reduce the risk of lymph node recur-
rence in the groins.
En bloc removal of inguino-femoral lymph
nodes can cause significant morbidity with
wound breakdown, lymphocyst, and lymphede-
ma formation and long-term psychosexual issues
are common. Sentinel lymph node detection has
been developed to reduce the incidence of these
significant postoperative morbidities while not
compromising on cure rates. The technique aims
to biopsy the first lymph nodes that the tumour
drains into, known as ‘the sentinel nodes’, and
thus spares removal of the majority of the nodes.
The technique is associated with fewer side ef-
fects as the majority of lymph nodes are spared.
Sentinel node biopsy is only recommended for
women who fulfil strict criteria which includes: a
unifocal tumour, <4 cm in maximum dimension,
and where no suspicious nodes are identified by
clinical and radiological examination. The detec-
tion rates for sentinel nodes per groin, using radi-
ocolloid and blue dye, in centres with appropriate
expertise, is above 90%. The false-negative rate
for sentinel node biopsy is about 4–6%, while the
recurrence rate with sentinel node biopsy and en
bloc groin lymphadenectomy is 2.8% and 1.4%,
respectively. Full groin dissection is standard
practice at present for women with positive sen-
tinel node biopsy; however, the trial outcome for
radiotherapy in such patients is awaited.
Primary radiotherapy to treat groins may be
associated with lower morbidity but a higher rate
of groin recurrence and reduced survival. Stud-
ies looking at primary radiotherapy, however, are
criticized for low numbers, and non-standardized
approach to RT, especially the depth of radiother-
MIMS JPOG 2020 VOL. 46 NO. 3 111
apy applied. Until outcomes from larger trials are
available, primary radiotherapy should be consid-
ered only in patients not able to undergo surgical
clearance.
MANAGEMENT OF ADVANCED
DISEASE (Stage III and IV)
Management of more advanced cancer also
needs to be individualized, and multidisciplinary
assessment with the involvement of clinical on-
cologists, urologists, colorectal surgeons, and
plastic surgeon is required to formulate the ap-
propriate treatment plan. Reconstructive surgery
at the time of radical excision may improve func-
tion and cosmetic outcome as well as shorten
the convalescence period. The most suitable
treatment should again be determined inde-
pendently for the primary tumour and groin and
pelvic lymph nodes.
Management of the primary tumour in
advanced vulval cancer
Primary surgical resection is the recommend-
ed treatment option whenever possible, and
depending upon the size of the tumour, radi-
cal vulvectomy or modified radical vulvectomy
should be considered. For tumours which in-
volve the distal vagina and/or urethral orifice,
primary surgical resection can be performed
without a stoma. In cases where the primary
lesion is extensive, involving the anus, rectum,
rectovaginal septum, or proximal urethra, ad-
equate surgical clearance requires pelvic ex-
enteration along with radical vulvectomy and
bilateral groin dissection. This approach may
not be suitable for these elderly patients and is
associated with high psychological morbidity.
Evidence is now accumulating in favour of the
use of preoperative radiotherapy with or without
chemotherapy as the first-line treatment for pa-
tients with advanced vulval cancer with exten-
sive lesions who would otherwise require pelvic
exenteration.
Radical vulvectomy can lead to large vulval
defects, and primary closure of the skin may not
112 MIMS JPOG 2020 VOL. 46 NO. 3
Box 5. Postoperative Complications
Early complications Late complications
• Lymphocyst formation • Chronic leg oedema
• W
 ound dehiscence or • Recurrent lymphadenitis
breakdown
• Urinary stress continence
• Wound infection or cellulitis • Introital stenosis
• UTIs • Femoral hernia
• Deep vein thrombosis • Pubic osteomyelitis
• Pulmonary embolism • R
 ectovaginal or rectoperineal
• Haemorrhage fistulae
• Osteitis pubis
be possible. Secondary closure for smaller areas
may be acceptable, and this is particularly use-
ful for defects around the urethra. Reconstructive
techniques may be necessary after radical exci-
sion and the following techniques may be used:
Full-thickness skin flaps may be developed
1. 
which are suitable for covering large defects
on posterior vulva.
Unilateral or bilateral myocutaneous grafts
2. 
can be devised to cover an extensive area
from mons pubis to perineal area.
Tensor fascia lata myocutaneous flaps are
3. 
suitable for large defects in the groin and vulva.
Management of groin and pelvic lymph
nodes in advanced vulval cancer
Clinical assessment, along with CT scan of the
groin, pelvis, and abdomen, is employed to de-
termine the status of the groin and pelvic lymph
nodes. Patients can be differentiated into three
types:
Patients with no clinically or radiologically
1. 
suspicious nodes: Bilateral inguino-femo-
ral lymphadenectomy is undertaken through
separate groin incisions. If there is one mac-
rometastasis (>5 mm tumour deposit, ≥3 mi-
crometastases, or extracapsular spread), then
adjuvant pelvic and groin radiation is recom-
mended.
2. 
Patients with clinically or radiological-
ly suspicious nodes: All enlarged lymph
GYNAECOLOGY PEER REVIEWED
nodes should biopsied and positive nodes
removed surgically. Surgical debulking of
involved nodes is usually followed by full
pelvic and groin irradiation. Debulking of
enlarged nodes has been shown to improve
outcome after radiotherapy in retrospective
reviews.
Patients with fixed, unresectable groin
3. 
nodes: Primary groin and pelvic radiation
with or without chemotherapy should be
considered.
POSTOPERATIVE COMPLICATIONS
(Box 5)
Despite the age and associated medical con-
ditions of women with vulval cancer, surgery is
usually the treatment of choice wherever pos-
sible. Surgery is associated with a significant
risk of postoperative complications. Wound
dehiscence or breakdown used to be a major
early complication in the past with the use of
single ‘butterfly’ incision, but it has reduced
considerably with modification to triple incision
technique, although the rates remain high. A
very common postoperative complication of
full groin node lymphadenectomy is lympho-
cyst formation, which is seen in about 40% of
cases. Early mobilization and long walks in
the early postoperative period increase the
risk of lymphocyst formation. Sentinel node
biopsy is associated with a significantly lower
risk of complications and should be offered as
an alternative wherever suitable. Other early
postoperative complications include cellulitis,
urinary tract infections, deep vein thrombosis,
pulmonary embolism, myocardial infarction,
haemorrhage and rarely, osteitis pubis.
A major late complication of groin node
dissection is chronic leg oedema which is re-
ported in up to 69% of cases, and the onset is
within 3 months in 50% of the patients. Recur-
rent lymphangitis occurs in 10% of patients and
is usually treated with oral antibiotics. Conse-
quences of vulval surgery also include urinary
stress incontinence, introital stenosis, and sex-
GYNAECOLOGY PEER REVIEWED
ual dysfunction. Other late complications that
are uncommon include femoral hernias, pubic
osteomyelitis, and rectovaginal or rectoperineal
fistulae.
RADIOTHERAPY IN VULVAL CANCER
Squamous cell cancer of the vulva is usually sen-
sitive to radiotherapy treatment, although there
are usually significant severe side effects on the
vulval skin. Radiotherapy is rarely used as a pri-
mary treatment and is most commonly used for
adjuvant treatment following surgery.
Indications for adjuvant radiotherapy follow-
ing surgery are as follows:
• Positive surgical resection margins when fur-
ther surgery to re-excise the involved margin
is not feasible
• Positive groin nodes
Primary radiotherapy may be used in ex-
ceptional cases for locally advanced tumours to
shrink the tumour with the aim of then proceed-
ing to sphincter-sparing surgery. Women who
have comorbidities that make them unfit for any
form of surgical intervention may also be consid-
ered for primary radiotherapy.
CHEMOTHERAPY
Primary chemotherapy has a very limited role
in the management of vulval cancer. It is in-
creasingly used together with radiotherapy to
increase radiosensitivity. It is sometimes used in
recurrent or metastatic disease but responses
are variable.
RECURRENT VULVAL CANCER
The overall recurrence rate of vulval cancer is
30%. Most recurrences are seen on the vulva and
occur at a median interval of 2 years. Local recur-
rence is managed surgically whenever possible.
Radiotherapy can also be used to treat local vul-
val recurrences with good effect for women who
have not already received radiation treatment. Re-
gional and distant recurrences are not common,
but are more difficult to manage and carry a par-
ticularly poor prognosis. Radiation therapy with
MIMS JPOG 2020 VOL. 46 NO. 3 113
or without surgery may be used for groin recur-
rences, whereas chemotherapy may be offered
for distant recurrences.
Vulval recurrence can be difficult to treat,
and extremely challenging to palliate.
NEW/EXPERIMENTAL TREATMENT
MODALITIES
Electrochemotherapy (ECT) has been tried as palli-
ative treatment of locally advanced vulval cancer as
well as in preoperative settings to reduce the radi-
cality of excision. Trials are ongoing, and ECT could
be a therapeutic option for local disease control
where standard treatment options are not suitable.
RARE VULVAL MALIGNANCIES
Vulvar melanoma
Vulval melanoma is the second most common
vulval cancer. It is seen predominantly in post-
menopausal white women and most commonly
involves the clitoris or labia minora. Most pa-
tients with vulvar melanoma are asymptomatic
except for the presence of a pigmented lesion.
Any pigmented vulvar lesion should be biopsied
or excised unless it has been present for some
years and remained unchanged. The FIGO stag-
ing system is not applicable for melanomas as
the prognosis is related to the depth of pen-
etration rather than the diameter of the lesion.
Instead, the Clark or Breslow modification of the
staging system, as proposed by the American
Joint Committee on Cancer (AJCC) and based
on the depth of invasion, should be used for
staging these lesions as it correlates with surviv-
al and recurrence.
Surgery is the mainstay of treatment of the
primary lesion. The current trend favours a con-
servative approach with radical wide local exci-
sion as there is no survival difference in patients
undergoing local excision versus those with radi-
cal vulvectomy. The role of groin node dissection
is controversial, and there is a lack of strong ev-
idence to show any survival advantage for ingui-
nal lymphadenectomy.
114 MIMS JPOG 2020 VOL. 46 NO. 3
Practice Points
• Vulval cancer is a rare gynaecological cancer, predominantly
seen in postmenopausal women and accounts for about 4% of
gynaecological malignancies.
• Risk factors include smoking, HPV infection, VIN, lichen sclerosis,
immunosuppressed women, and Paget’s disease of the vulva.
• Most common presentation is a vulval lump or a mass, often
associated with a long history of pruritus in the background of
vulvar dystrophy.
• Metastatic disease in the regional inguino-femoral lymph nodes
is the single most important prognostic factor.
• Modern surgical approach has become more conservative to
reduce the long-term psychosexual and functional disturbances
associated with the traditional radical vulvectomy and radical
local excision is the surgery of choice for early vulval cancer.
• Groin lymphadenectomy is not required in patients with FIGO
stage IA tumour but all patients with stage IB and stage II require
appropriate groin lymph node dissection.
• Sentinel node biopsy is recommended for women with a unifocal
tumour, <4 cm in maximum dimension, and where no suspicious
nodes are identified by clinical and radiological examination.
• 
Radical vulvectomy or modified radical vulvectomy is the
recommended treatment option for advanced vulval cancer with
or without reconstructive surgery depending upon the size of the
tumour.
• Management options for lymph nodes in advanced vulval cancer
are bilateral inguino-femoral lymphadenectomy and/or groin and
pelvic radiation with or without chemotherapy.
Vulval melanomas should be managed by
the melanoma MDT with input from the gynae-
cological team. The patients are often suitable
for treatment with the newer biological systemic
therapies.
Bartholin gland carcinoma
Bartholin gland cancer is a rare form of vulvar ma-
lignancy, accounting for 5% of vulval cancers. His-
tologically, they may be a transitional cell or squa-
mous cell carcinoma that arises from the duct or
adenocarcinomas deriving from the gland them-
selves or sometimes adenoid cystic carcinomas.
The diagnosis is often made after resection of a
persistent or recurrent Bartholin cyst. Treatment is
mainly surgical and includes radical hemivulvec-
tomy with bilateral groin dissection. However, as
these lesions are located deep in the ischiorectal
fossa, it is difficult to achieve adequate surgical
GYNAECOLOGY PEER REVIEWED
margins, and postoperative radiation to the vulva
may reduce the risk of local recurrence.
Basal cell carcinoma
Basal cell carcinoma constitutes 2–4% of vulvar
cancers and usually affects postmenopausal
white women. Most lesions are smaller than 2
cm, typically appear as a ‘rodent ulcer’ with rolled
edges and are commonly seen on anterior labia
majora. They are locally aggressive tumours, and
local excision is the treatment of choice. They
respond well to radiation and radiotherapy may
be useful in selective cases. Metastasis to groin
lymph nodes is rare.
Verrucous carcinoma
Verrucous carcinomas usually occur in postmen-
opausal women and have a typical cauliflow-
er-like appearance. They are slow-growing but
locally destructive tumours and may even invade
the bone. Metastasis to regional lymph nodes is
rare. Radical local excision is the basic treat-
ment. Radiotherapy is contraindicated in ver-
rucous carcinoma due to the risk of anaplastic
transformation with subsequent regional and
distant metastases.
FURTHER READING
1. Covens A, Vella ET, Kennedy EB, Reade CJ, Jimenez W, Le T. Sentinel
lymph node biopsy in vulvar cancer: systematic review, meta-anal-
ysis, and guideline recommendations. Gynecol Oncol 2015 May 1;
137: 351–61.
2. Hacker NF. Vulval cancer. In: Berek JS, Hacker NF, eds. Berek and
Hacker’s gynecologic oncology. Lippincott Williams & Wilkins, 2010;
576–92.
3. Royal College of Obstetricians and Gynaecologists. Guidelines for the
diagnosis and management of vulval carcinoma. London: RCOG, 2014.
4. Shafi M, Bolton H, Gajjar K, eds. Gynaecological oncology for the
MRCOG. Cambridge University Press, 2018 Apr 19.
5. te Grootenhuis NC, Van Der Zee AG, Van Doorn HC, et al. Sentinel
nodes in vulvar cancer: long-term follow-up of the groningen interna-
tional study on sentinel nodes in vulvar cancer (GROINSS-V) I. Gyne-
col Oncol 2016 Jan 1; 140: 8–14.
© 2020 Elsevier Ltd. All rights reserved. Initially published in Obstetrics,
Gynaecology and Reproductive Medicine 2020;30(7):213–218.
About the authors
Vandna Verma is a Clinical Fellow in the Department of Obstetrics and
Gynaecology at Cambridge University Hospitals NHS Foundation Trust,
Cambridge, UK. Conflicts of interest: none declared.
Krishnayan Haldar is Consultant Gynaecologist and Gynaecological On-
cologist in the Department of Gynaecological Oncology at Cambridge
University Hospitals NHS Foundation Trust, Cambridge, UK. Conflicts of
interest: none declared.
PAEDIATRICS PEER REVIEWED MIMS JPOG 2020 VOL. 46 NO. 3 115

Gastro-Oesophageal
Reflux in Infancy
Vinod Kolimarala MBBS MRCPCH; R Mark Beattie MBBS BSc (Hons) FRCPCH MRCP; Akshay Batra MBBS MD MRCPCH

Gastro-oesophageal reflux (GOR) is very common in infancy. It is important to

differentiate benign physiological reflux from gastro-oesophageal reflux disease
(GORD), which is associated with significant morbidity. This review summarizes
the approach to infants with symptoms and signs of reflux, differential diagnosis,
investigations and management including non-pharmacological, pharmacological,
and surgical treatments. Most infants with physiological GOR do not require
any medical management if the infant is thriving. Severe cases require a careful
diagnostic work, treatment of associated conditions, and aggressive medical
management of the reflux. Involvement of the multidisciplinary team is essential
and in persistent refractory reflux surgical intervention may need to be considered.

GASTRO-OESOPHAGEAL Most episodes, in healthy individuals,

REFLUX
GOR is the involuntary passage of the
gastric contents into the oesophagus.
It is a normal physiological phenom-
enon, particularly common in infancy.
last less than 3 minutes, occur in the
postprandial period, and cause few or
no symptoms. It is a very common pres-
entation; both in primary and secondary
care setting and can affect nearly 50%
116 MIMS JPOG 2020 VOL. 46 NO. 3
of infants less than 3 months old. Major factors
include the high volume of milk ingested com-
pared with older children/adults, posture, and
the functional immaturity of the lower oesopha-
geal sphincter.
The natural history of GOR is generally of
improvement with age, with less than 5% of chil-
dren with vomiting or regurgitation in infancy
continuing to have symptoms after the age of 14
months. This is due to a combination of growth
in length of the oesophagus, a more upright pos-
ture, increased tone of the lower oesophageal
sphincter, and a more solid diet.
GASTRO-OESOPHAGEAL REFLUX
DISEASE
GORD is defined as GOR associated with trou-
blesome symptoms or complications, although
the authors caution that this definition is com-
plicated by unreliable reporting of symptoms
in young children. Gastrointestinal sequelae
include oesophagitis, haematemesis, oesopha-
geal stricture formation, and Barrett’s oesopha-
gus. Extra-intestinal sequelae can include acute
life-threatening events and apnoea, chronic otitis
media, sinusitis, secondary anaemia, and chron-
ic respiratory disease (chronic wheezing/cough-
ing or aspiration), as well as failure to thrive.
Oesophagitis can develop as a result of acid
or non-acid reflux and presents with symptoms of
crying and irritability in infants and can lead to food
aversion. This is likely to be a significant factor in
faltering growth seen in some children with GORD.
EPIDEMIOLOGY
GORD is a significant problem for infants in the
community and in hospital setting. Determina-
tion of the exact prevalence of GORD at any age
is difficult because of a lack of specific symp-
toms but approximately 33% of infants seek
medical attention for symptoms suggestive of
reflux, of whom up to 20% require diagnostic
evaluation. The problem is more pronounced
in certain groups like infants born prematurely,
infants with neurodisability, with congenital mal-
PAEDIATRICS PEER REVIEWED
formations like repaired oesophageal atresia or
congenital diaphragmatic hernia, and those with
chronic lung disease. Over 50% of children with
neurodisability have GORD, due to oesopha-
geal dysmotility and a poorly functioning lower
oesophageal sphincter. They have trouble ex-
pressing their symptoms, and may also have co-
morbidities, which may impact on the ability to
perform investigations.
PATHOPHYSIOLOGY
The physical barrier between the oesophagus
and stomach is provided by the lower oesoph-
ageal sphincter (LOS) and the diaphragm. The
LOS, or internal sphincter, is a specialised part
of the circular smooth muscle of the distal oe-
sophagus. Both components work together to
stop refluxing of gastric contents into the oe-
sophagus. The major mechanism of reflux is
transient lower oesophageal sphincter relaxation
(TLOSR). This is a normal phenomena. Relax-
ation of LOS occurs in response to swallowing
but this is brief and lasts less than 10 seconds.
In contrast, in infants with GORD, TLOSR is pro-
longed (more than 10 seconds) and accounts for
75–90% episodes of reflux in infants.
Other causes for GORD include abnormal
position of LOS as seen in hiatus hernia. This
results in inability of diaphragm to contribute to
lower oesophageal tone and contraction to pre-
vent reflux. Delayed gastric emptying is felt to be
a contributing factor in worsening of reflux and is
especially seen in children with neurodisability. It
exacerbates GOR by prolonging gastric disten-
sion and increasing the frequency of transient
LOS relaxation. There is an associated delay in
clearance of reflux contents from oesophagus in-
creasing oesophageal exposure to gastric con-
tents, leading to oesophagitis.
SYMPTOMS, SIGNS, AND HISTORY
GORD can be oesophageal or extra-oesophage-
al depending on the presenting symptoms. The
symptoms, signs, and typical historical features
of GORD are summarized in Tables 1 and 2.
PAEDIATRICS PEER REVIEWED
DIFFERENTIAL DIAGNOSIS
Given the frequency of GOR, it is easy to forget
that other conditions can present with similar
features. The commoner alternative diagnoses
include:
• Infection, eg, urinary tract infection, gastro-
enteritis, peptic ulcer disease
• 
Intestinal obstruction, eg, pyloric stenosis,
malrotation, intestinal atresia,
• Food allergy and intolerances, eg, cow’s milk
allergy, soy allergy, coeliac disease
• Eosinophilic oesophagitis
• Metabolic disorders, eg, diabetes, inborn er-
rors of metabolism
• Intestinal dysmotility
• Drug-induced vomiting, eg, cytotoxic agents
• 
Primary respiratory disease, eg, asthma,
cystic fibrosis
• Factitious induced illness
• Child neglect or abuse
It is important to remain vigilant for other
diagnoses.
MANAGEMENT
Physiological reflux is common in infancy and
is a clinical diagnosis. For most parents, reas-
surance that the condition will resolve without
treatment is all that is needed. It is important to
carefully consider the differential diagnosis, par-
ticularly if symptoms persist or worsen.
Full assessment of infants is essential in-
cluding a full feeding history to explore possi-
bility of overfeeding or difficulty with feeding.
Careful attention needs to be paid to severity
of symptoms, faltering growth, and relevant
social factors, eg, parental anxiety and stress.
Severe cases need further assessments and
investigation. These may include barium study,
pH study, impedance study, gastro-oesophage-
al scintigraphy, gastroscopy, and biopsy (de-
scribed below).
Difficult cases require assessment by multi-
disciplinary team including dietician, speech and
language therapist, paediatric gastroenterolo-
gist, and paediatric surgeon.
MIMS JPOG 2020 VOL. 46 NO. 3 117
Table 1. Symptoms and Signs that may be Associated with GORD
Atypical symptoms Wheeze/intractable asthma
Cough/stridor
Cyanotic episodes
Generalised irritability
Sleep disturbance
Neurobehavioural symptoms – breath holding,
dystonia, seizure-like events
Worsening of pre-existing respiratory disease
Apnoea/apparent life-threatening events/
sudden infant death syndrome
Typical symptoms Excessive regurgitation/vomiting
Nausea
Weight loss/faltering growth
Irritability with feeds, arching, colic/food refusal
Dysphagia
Chest/epigastric discomfort
Excessive hiccups
Haematemesis/anaemia – iron deficient
Aspiration pneumonia
Oesophageal obstruction due to stricture
Signs Oesophagitis
Oesophageal stricture
Barrett’s oesophagus
Laryngeal/pharyngeal inflammation
Recurrent pneumonia
Anaemia
Dental erosion
Sandifer syndrome
INVESTIGATIONS
Oesophageal pH monitoring
Acid reflux into the oesophagus occurs in all in-
fants as a physiological phenomenon and is only
significant when it occurs in excess. The pH probe
is designed to measure acidity (ie, acid reflux) in
the lower oesophagus and monitors the frequen-
cy and duration of reflux into the oesophagus. It
is a microelectrode passed through the nose and
down the back of the throat to sit 3–5 cm above
118 MIMS JPOG 2020 VOL. 46 NO. 3 PAEDIATRICS PEER REVIEWED

Table 2. History Required in an Infant with Suspected GORD 4. Common parameters obtained from pH moni-
toring include the total number of reflux episodes,
the number of reflux episodes lasting more than
Pattern of vomiting (predominant symptom)
5 minutes, the duration of the longest reflux epi-
Frequency/amount
sode, and the reflux index which is the percent-
Associated pain/discomfort
age of time when pH was less than 4.
Is the vomit forceful? Specific indications for pH Study include di-
Does the vomit contain blood or bile agnostic uncertainty in presence of extra oesoph-
Are there any associated constitutional symptoms, eg, fever, lethargy, ageal symptoms, poor response to medical treat-
diarrhoea
ment, or to quantify the degree of reflux (Figure 1).
Feeding and dietary history
Amount/frequency (overfeeding) Interpretation of oesophageal pH
Preparation of formula studies
Recent changes in feeding type or technique The North American Society of Pediatric Gas-
Position during feeding troenterology, Hepatology and Nutrition (NASP-
Burping GHAN) consensus recommendation is that a
Behaviour during feeding reflux index greater than 7% is abnormal. In gen-
Choking, gagging, cough, arching, discomfort, food refusal eral, reflux index up to 10% is mild, 10–20% is
moderate which is usually controlled by medical
Medical history
therapy and more than 30% is severe and may
Prematurity require surgical intervention. When interpreting
Birth weight, growth, and development studies, it is important to consider the following:
Past surgery, hospitalizations • It is useful to correlate symptoms (eg, cough,
Respiratory illnesses, especially croup, pneumonia, asthma chest pain) with acid reflux episodes and to
Other respiratory symptoms including hoarseness, hiccups, apnoea select those infants and children with wheez-
Features of atopy ing or respiratory symptoms in whom GOR is
Other chronic conditions a causative/aggravating factor.
• The sensitivity, specificity, and clinical utility
Medications
of pH monitoring for diagnosis and manage-
Current, recent, prescription, non-prescription
ment of possible extra oesophageal compli-
Family psychosocial history and family set up cations of GOR are not well established.
Sources of stress There are several limitations to pH studies.
Postpartum depression These include:
Maternal or paternal drug use • pH studies are unable to detect anatomical
abnormalities (eg, stricture, hiatus hernia,
Family medical history
malrotation) or aspiration.
Significant illnesses
• 
Non-acid reflux will not be detected. This
Family history of gastrointestinal disorders
should be borne in mind with non-acidic
Family history of atopy
feeds such as infant formula and in particular
Growth chart including height, weight, and head circumference when infants are continuously fed.
• The changes in environment, diet, and be-
haviour as a result of investigation and ad-
the lower oesophageal sphincter and records for mission to hospital may impact on the result.
a set period, usually 24 hours. A reflux episode is • There is potential for technical difficulties and
defined as the drop in oesophageal pH less than reproducibility is poor.
PAEDIATRICS PEER REVIEWED MIMS JPOG 2020 VOL. 46 NO. 3 119

• pH studies provide no objective measures of

inflammation, and thus are less useful than
endoscopy and biopsies for the diagnosis
and grading of oesophagitis.
• The severity of pathologic acid reflux does
not correlate consistently with symptom se-
verity or demonstrable complications.

Combined multiple intraluminal im-

pedance (MII) and pH monitoring
Some of the limitations of the pH study in de-
Figure 1. An example of a pH study in an infant showing moderate reflux.
tecting non-acid reflux and proximal reflux can
be overcome by combining it with intraluminal
impedance monitoring. This measures changes
in the electrical impedance (ie, resistance) be-
tween multiple electrodes located along an oe-
sophageal catheter. Oesophageal impedance
tracings are then analysed for the typical chang-
es caused by liquid, solid, air, or mixed bolus
and can differentiate between antegrade and
retrograde flow.
MII reflux episodes can be categorized
as acidic (pH less than 4 lasting 4 seconds or
more), weakly acidic (pH 4–7) or weakly alka-
line (pH ≥7). Studies on the normal values in
infants and children are lacking. Normal values
are results of consensus agreements, data ex-
trapolation, and studies on symptomatic chil-
dren. ESPGHAN EURO-PIG suggests up to 100
reflux episodes in infants aged less than 1 and Figure 2. Combined MII and pH monitoring demonstrating acid reflux in an infant.
oesophageal acid exposure time up to 10% and
up to 70 episodes in children more than 1 year Radiological investigations
and oesophageal exposure time less than 3% is Barium swallow: assesses the patient over only
regarded as normal. short periods and may therefore miss patholog-
The indications are the same as those ical reflux or overdiagnose physiological reflux.
for pH monitoring. MII-pH recording provides It is therefore neither a sensitive or specific test.
more information than simple pH measurement Its main role is in detecting anatomical abnor-
because it allows the study of non-acid reflux, malities such as hiatus hernia, intestinal malro-
extent of reflux, and the temporal association tation, oesophageal stricture or web, atypical
between symptoms and reflux. MII still has the pyloric stenosis, gastric web, duodenal web, or
following limitations: high cost; limited contri- volvulus.
bution to medical therapeutic implications; and
lack of evidence-based parameters for the as- Gastro-oesophageal scintigraphy: uses continu-
sessment of GOR and especially symptom asso- ous evaluation for up to an hour after radiolabelled
ciation in children (Figure 2). meal. Food or milk labelled with 99Technetium is
120 MIMS JPOG 2020 VOL. 46 NO. 3
given to the infant and stomach and oesophagus
are scanned. The standards for interpretation of
this test are poorly established and it is not rec-
ommended for the routine evaluation of paediat-
ric patients with suspected GORD.
Its main role is in the assessment of gas-
tric emptying times to identify the group of chil-
dren with foregut dysmotility and delayed gastric
emptying. It also has a limited role in diagnosis
of pulmonary aspiration in patients with chronic
and refractory respiratory symptoms. Delayed
gastric emptying is especially common in chil-
dren with cerebral palsy in whom vomiting may
reflect an overall gut dysmotility rather than
GORD.
Oesophageal manometry: measures the pres-
sures and peristaltic contractions in the oesoph-
agus. It is now increasingly used to help in the
diagnosis of pathological reflux and has a role
in identifying the position of lower oesophage-
al sphincter and assessing its morphology and
function. The transient relaxation of the sphinc-
ter can be better defined with high resolution
manometry and provocative tests with multiple
swallows help assess severity.
Its main role lies in looking for conditions,
which can mimic GORD, eg, achalasia or other
motor disorders of the oesophagus such as dif-
fuse oesophageal spasm, Chagas disease, iso-
lated hypertensive lower oesophageal sphincter.
Gastroscopy and biopsy: used in children with
suspected oesophagitis. Upper gastrointestinal
endoscopy is a useful investigation and should
be considered in all children with severe sympto-
matic reflux. Presence of active oesophagitis ei-
ther macroscopically or on histology is the most
specific test for GORD though normal oesopha-
geal histology does not exclude significant GOR.
The histological features include an increased
eosinophil count, intrapapillary blood vessel
dilatation, intraepithelial bleeding, basal cell hy-
perplasia, dilated intercellular spaces, and en-
hanced cellular proliferation. Endoscopic biopsy
PAEDIATRICS PEER REVIEWED
is important to identify or rule out other causes of
oesophagitis and to diagnose and monitor Bar-
rett oesophagus.
The indications for endoscopy in GORD
include:
• Gastrointestinal bleeding which can present
as haematemesis or melena
• Failure of resolution of symptoms beyond 1
year of age despite medical therapy
• Faltering growth
• Food aversion
• Suspected Sandifer’s syndrome
MANAGEMENT
Most patients with physiological GOR are man-
aged in primary care by the health visitor and
general practitioner and do not require any
specific treatment. Non-pharmacological meas-
ures include:
• Review of feeding and feeding practice –
checking for overfeeding, trial of smaller more
frequent feeds, too small or too large a teat
(both of which can cause air swallowing).
Review of feeding posture – infants have
• 
significantly less reflux when placed in the
prone position than in a supine position. How-
ever, prone position is associated with a higher
rate of sudden infant death syndrome (SIDS).
In infants from birth to 12 months of age with
reflux, the risk of SIDS generally outweighs the
potential benefits of prone sleeping. In chil-
dren more than 1 year, it is likely that there is
a benefit to right side positioning during sleep
and elevation of the head of the bed.
Use of feed thickeners and use of anti-re-
• 
gurgitation milks – these are useful in re-
ducing the symptoms of GOR and should be
considered in children with persistent symp-
tomatic reflux impacting on nutrient intake or
through excessive vomiting on lifestyle. They
should not be used for healthy children who
regurgitate.
• 
Extensively hydrolysed or amino ac-
id-based formula – infants with persistent
symptoms with associated red flags like
PAEDIATRICS PEER REVIEWED
blood in stools, history of eczema or atopy
could have non IgE mediated cow’s milk
protein intolerance and may benefit from a
2–6 week trial of elimination diet. This can
be done by elimination of cow’s milk in ma-
ternal diet in breastfed infants. In bottle-fed
infants, extensively hydrolysed formula
should be used. Soya formulae should be
avoided as there is significant cross reactivi-
ty between cow’s milk and soya protein and
because of the presence of phytoestrogens
in soya milk they are not recommended in
infants less than 6 months.
DRUG TREATMENT
Drug treatment is indicated in children with se-
vere symptomatic reflux or signs and symptoms
suggestive of GORD.
The major pharmacological agents current-
ly used for treating GORD in children are gastric
acid–buffering agents, mucosal surface barriers,
and gastric anti-secretory agents. Acid suppres-
sant agents are the mainstay of treatment for all
but the patient with occasional symptoms. The
potential adverse effects of acid suppression,
including increased risk of community-acquired
pneumonias and GI infections, need to be bal-
anced against the benefits of therapy.
Compound alginates: (eg, Gaviscon Infant-Rick-
ett Benckiser) are effective for symptomatic treat-
ment for GOR. Infant gaviscon works by reacting
with gastric acid to form a viscous gel. Infant
Gaviscon comes in a dual sachet and each half
is a dose. One dose for babies weighing less
than 4.5 kg and two doses for those more than
4.5 kg given at a maximum of 6 times a day.
Infant gaviscon can be added to formu-
la feed or for breastfed infants dissolved in
cooled boiled water and given by spoon after
a feed. Chronic use of alginates is not rec-
ommended for GORD. Occasionally, they can
cause constipation and bloating. They should
be used with caution in children with renal im-
pairment as the product contains sodium and
MIMS JPOG 2020 VOL. 46 NO. 3 121
can cause hypernatraemia. An overdose can
lead to a bezoar formation which may require
surgical removal.
Acid suppression agents: include H2-receptor
blockers and proton pump inhibitors (PPIs).
H₂ receptor blockers are widely used in the
• 
management of reflux. They are safe and
well tolerated and can be considered before
any further investigation in children who are
thriving and in whom the diagnosis is robust.
There are several studies that have suggest-
ed that H₂-antagonists are efficacious in chil-
dren. Ranitidine is the most commonly used
H₂-receptor blocker. Ranitidine is well toler-
ated and has a low incidence of side-effects
(common side-effects include fatigue, dizzi-
ness, or diarrhoea). Oral ranitidine provides
symptomatic relief and endoscopic improve-
ment of oesophagitis in children with GORD.
Dosage for neonates is between 2 and 3 mg/
kg TDS. Child 1–5 months 1–3 mg/kg TDS.
Child 6 months to 2 years 2–4mg/kg BD.
• PPIs such as omeprazole and lansoprazole
are a group of drugs that irreversibly inacti-
vate H+/K+ ATPase: the parietal cell mem-
brane transporter. This increases the pH of
gastric contents and decreases total volume
of gastric secretion, thus facilitating empty-
ing. Side effects reported with long-term use
include hypomagnesemia, gastric fundal pol-
yps, and small increase in risk of osteoporot-
ic fractures.
Omeprazole is the most commonly used
PPI and is shown to be effective in children
with GORD resistant to ranitidine. For healing
of erosive oesophagitis and relief of symp-
toms, PPIs are superior to H₂-receptor blockers.
Omeprazole is available as dispersible tablets
or capsules given once daily. The tablet can
be gently mixed or dispersed (not crushed) or
the capsule broken for ease of administration
in children. Dosage is 0.7–1.4 mg/kg per day,
although higher doses can be used, up to 3
mg/kg. When acid suppression is required, the
122 MIMS JPOG 2020 VOL. 46 NO. 3
smallest effective dose should be used. Most
patients require only once-daily PPI. Lansopra-
zole is the other commonly used PPI. Dosage
0.5–1 mg/kg OD, a maximum dose of 15 mg OD
can be used.
Prokinetic drugs: can be helpful in some cir-
cumstances. Gastroesophageal reflux is pri-
marily a motility disorder, and the use of phar-
macologic agents that improve oesophageal
and gastric motility are conceptually attractive
as therapies. Unfortunately, the currently avail-
able prokinetic medications have only modest
efficacy in relieving GORD symptoms, and
the side-effect profile makes them less useful
clinical practice. Examples include metoclopr-
amide, domperidone, and erythromycin.
Domperidone is a dopamine-receptor (D2)
blocker that has relatively fewer side effects,
but case reports of extrapyramidal side effects
exist, as well as an effect on the QT interval
(prolongation). Domperidone acts to increase
lower oesophageal sphincter pressure, improve
oesophageal clearance, and promote gastric
emptying. Domperidone is commonly used
in clinical practice either as part of empirical
medical therapy of GORD or if delayed gastric
emptying has been demonstrated on nuclear
scintigraphy.
In view of a small increased risk of cardi-
otoxicity, it is advisable to use domperidone in
lower doses and only in cases with overt vomit-
ing secondary to reflux. All infants should have
an ECG to rule out prolonged QT interval before
starting treatment and should be referred to a
specialist if treatment is required for greater than
3 months.
Buffering agents (magnesium hydroxide and
aluminium hydroxide) and sucralfate: are useful
for occasional heart burn. Buffering agents carry
significant risk of toxicity and are not recommend-
ed for long-term use. Sucralfate binds to inflamed
mucosa and forms a protective layer that resists
further damage from gastric acid.
PAEDIATRICS PEER REVIEWED
ENTERAL FEEDING
In infants with faltering growth who are not
responding to usual medical treatments, a
period of enteral tube feeding (ETF) should
be considered. This ensures slow delivery of
feeds and thus reduced distension of stom-
ach and subsequent reflux. When tube feed-
ing is started small, oral stimulation in the form
of small amount of oral feeds (milk or solids)
should be continued.
Post-pyloric feeding, is reserved for severe
cases not responding to other forms of manage-
ment and associated with complications. As the
stomach is bypassed, there is no distension of
stomach and there is reduction in reflux of gastric
contents. This is particularly helpful in children with
failure to thrive, severe oesophagitis, and reflux-re-
lated pulmonary aspiration. Continuous post-py-
loric feeding is most commonly used in children
with neurodisability where the volume of feed is lim-
ited because of discomfort associated with feeding.
SURGERY
The commonest operative intervention is fundo-
plication done laparoscopically or via open pro-
cedure. Children with comorbidities, particu-
larly neurodisability, who have the most severe
GORD are at the highest risk for operative mor-
bidity and postoperative failure. Before surgery,
it is essential to rule out non-GORD causes of
symptoms and ensure that the diagnosis of
chronic-relapsing GORD is firmly established.
Indications for surgery include:
• Failure of optimal medical therapy
• 
Extra oesophageal manifestation (asthma,
cough, chest pain, recurrent pulmonary aspi-
ration of refluxate)
• Complication of GORD (eg, Barrett’s oesoph-
agus or oesophageal stricture)
It is important to provide families with
appropriate education and a realistic under-
standing of the potential complications of
surgery, which include recurrence of reflux
(10%), retching, bloating, dumping, and intes-
tinal obstruction.
PAEDIATRICS PEER REVIEWED
Some children have a high risk of need-
ing surgery. These include children with neu-
rodisability, those with respiratory disease with
intractable reflux (eg, oesophageal atresia,
bronchopulmonary dysplasia). Children with
complication of oesophagitis such as stricture
or Barrett’s oesophagus and those who have
had a tracheo-oesophageal fistula repair.
GASTRO-OESOPHAGEAL REFLUX
AND NEURODISABILITY
Paediatric neurodisability is an umbrella term
for conditions associated with impairment
of the nervous system, including conditions
such as cerebral palsy, and epilepsy. Potential
causes of feeding difficulties include bulbar
weakness, primary or secondary aspiration,
reflux oesophagitis, widespread gut dysmotil-
ity, mobility and posture problems, poor nutri-
tional state, and constipation. These children
require careful multidisciplinary assessment
by a feeding team including dietetics, speech
and language therapy, occupational therapy,
and the neurodevelopmental paediatrician.
Attention to nutrition is of key importance
and many children with feeding difficulties
benefit from a feeding gastrostomy. A fundopli-
cation is required if reflux is severe, although in
some cases, improved nutritional status will re-
sult in improvement of the reflux.
The motility of the gut is a key factor in feed
tolerance in children with cerebral palsy who
may have delayed gastric emptying, which im-
pact significantly on the ability to feed, particu-
larly if nutrition is dependent upon nasogastric
or gastrostomy feeding. Therapeutic strategies
include explanation and reassurance, trial of
anti-reflux therapy, prokinetic agents such as
domperidone, and in some cases with marked
dysmotility, it may be necessary to give feeds
by continuous infusion via gastrostomy or gas-
trojejunal route. A milk-free diet for a trial pe-
riod of 2–4 weeks can be helpful. Hydrolysed
protein formula feeds/MCT predominant feeds
may be given as a milk substitute.
MIMS JPOG 2020 VOL. 46 NO. 3 123
GASTRO-OESOPHAGEAL REFLUX
AND RESPIRATORY DISEASE
GOR has been associated with significant res-
piratory symptoms in infants and children. There
is a complex relationship between asthma and
GOR, manifested by a bidirectional cause and
effect.
One postulated mechanism for GOR medi-
ated airway disease involves micro-aspiration of
gastric contents that leads to inflammation and
bronchospasm. However, experimental evidence
also supports the involvement of oesophageal
acid–induced reflex bronchospasm, in the ab-
sence of frank aspiration. In such cases, GOR
therapy using either H₂-blockers or PPIs has been
shown to benefit patients with steroid-dependent
asthma, nocturnal cough, and reflux symptoms.
Similarly, intrinsic lung disease may through ex-
cessive coughing result in reflux.
The association between GOR and appar-
ent life-threatening events is somewhat contro-
versial and probably only relevant if the infant
vomits, chokes, or goes blue during or immedi-
ately after feeds.
BARRETT’S OESOPHAGUS
This refers to the presence of metaplastic co-
lumnar epithelium in the lower oesophagus
thought to be a consequence of long-standing
GORD.
There is an increased risk of adenocarcino-
ma of the oesophagus.
It is rare in childhood and requires aggres-
sive medical treatment of the GOR and regular
endoscopic surveillance. Surgery (fundoplica-
tion) is often considered.
CASE STUDY 1
A 7-week-old formula-fed baby presented with
history of vomiting after most feeds and excessive
crying. Vomiting was variable quantity, non-pro-
jectile and non-bilious. The child was thriving
very well. There was no abnormality seen on
examination. A careful feed history revealed that
he was having nearly 200 mL/kg of formula feed.
124 MIMS JPOG 2020 VOL. 46 NO. 3
Practice Points
• 
Functional reflux is very common in infancy and resolve
spontaneously.
• GORD is defined as GOR associated with troublesome symptoms or
complications.
• Physiological reflux is a clinical diagnosis and does not warrant
further investigation. It is important to consider appropriate
differential diagnoses during history taking and examination.
• Most reflux will respond to simple strategies including reassurance
and explanation, feeding advice, feed thickeners, and anti-reflux
milk.
• It is important to carefully consider cow’s milk protein allergy and
a trial of 2–4 weeks of extensively hydrolysed or amino acid-based
formula can be considered before starting medical treatment.
• Medical therapy is by a step-up approach with use of H₂ blockers,
prokinetics, PPIs, and consideration of a trial of hydrolysed formula.
• Surgery is required in cases resistant to medical treatment and
those with extra oesophageal complications such as recurrent
aspiration.
• Children with cerebral palsy are at increased risk of reflux, although
many other factors are relevant in the assessment of feeding
problems in children with neurodisability.
Parents were reassured and the volume of feeds
was reduced. Symptoms resolved in 3 weeks. He
continued to thrive and was discharged from fol-
low-up. Over feeding is frequently seen in formu-
la-fed infants and a careful feeding history allows
for an accurate diagnosis and helps in avoiding
unnecessary treatments.
CASE STUDY 2
An 11-month-old with cerebral palsy and seizure
disorder presented with history of poor weight
gain, recurrent vomiting, and episodic crying.
She was born at 25 weeks of gestation and had
periventricular leukomalacia. She was particu-
larly distressed at meal times as if she was in
pain. Further investigations revealed signifi-
cant reflux (reflux index 14% and endoscopic
findings of oesophagitis). She was treated with
PPIs with improvement in her symptoms. Her
symptoms were secondary of acid reflux in her
oesophagus in response to gastric acid secre-
tion associated with meal times. Her feeding
improved with treatment of the reflux.
PAEDIATRICS PEER REVIEWED
CASE STUDY 3
A 4-month-old presented with feed refusal, retch-
ing, constipation, and eczema. Her symptoms
failed to improve with anti-reflux therapy and her
weight was static. She was referred to a specialist
clinic and was started on extensively hydrolysed
formula. At 6 months, she was started on a dairy-
free diet. Symptoms improved and she showed
good catch-up growth. Cow’s milk was gradually
introduced in her diet from the age of 12 months.
Cow’s milk allergy is the commonest food allergy
in infancy and usually resolves by 2 years of life
and almost always by 5 years of age. GOR can
coexist but poor response to anti-reflux therapy
should prompt consideration of cow’s milk allergy.
FURTHER READING
1. Beattie RM, Dhawan A, Puntis JWL, Batra A, Kyrana E. Oxford special-
ist handbook in paediatric gastroenterology, hepatology and nutrition.
Oxford University Press, 2018.
2. Mutalib M, Rawat D, Lindley K, et al. BSPGHAN Motility working Group
position statement: paediatric multichannel intraluminal pH imped-
ance monitoring eindications, methods and interpretation. Front Gas-
troenterol 2017; 8: 156–62.
3. Nelson SP, Chen EH, Syniar GM, Christoffel KK. Prevalence of symp-
toms of gastroesophageal reflux during infancy. A pediatric prac-
tice-based survey. Pediatric Practice Research Group. Arch Pediatr
Adolesc Med 1997 Jun; 151: 569–72.
4. Rosen R, Vandenplas Y. Paediatric gastroesophageal reflux clinical
practice guidelines: joint recommendations of the North American so-
ciety for paediatric Gastroenterology, Hepatology, and nutrition and the
European society for pediatric gastroenterology, hepatology, and nutri-
tion. J Pediatr Gastroenterol Nutr 2018; 66: 516–54.
5. Rudolph CD, Vandenplas Y. Paediatric gastro-oesophageal reflux clini-
cal practice guidelines: joint recommendation of NASPGHAN and ES-
PGHAN – J Pediatr Gastroenterol Nutr 49;498-547.
6. Sherman PM, Hassall E, Fagundes-Neto U. A global, evidence-based
consensus on the definition of gastro-oesophageal reflux disease in the
pediatric population. Am J Gastroenterol, 2009; https://doi. org/10.1038/
ajg.2009.129.
7. Tighe M, Afzal NA, Bevan A, Hayen A, Munro A, Beattie RM. Phar-
macological treatment of children with gastro-oesophageal reflux.
Cochrane Database Syst Rev 2014 Nov 24; 11.
8. Tighe MP, Beattie RM. Managing gastro-oesophageal reflux in infancy.
Arch Dis Child 2010; 95: 243–4.
9. Tighe MP, Cullen M, Beattie RM. How to use: a pH study. Arch Dis Child
Educ Pract Ed 2009; 94: 18–23.
© 2019 Elsevier Ltd. All rights reserved. Initially published in Paediatrics
and Child Health 2019;29(9):377–383.
About the authors
Vinod Kolimarala is a Speciality Trainee in Paediatric Gastroenterol-
ogy, Department of Paediatric Gastroenterology, University Hospital
Southampton NHS Trust, Southampton, UK. Conflicts of interest: none
declared.
R Mark Beattie is a Professor in Paediatric Gastroenterology and Nu-
trition, Department of Paediatric Gastroenterology, University Hospital
Southampton NHS Trust, Southampton, UK. Conflicts of interest: none
declared.
Akshay Batra is a Consultant in Paediatric Gastroenterology, Department
of Paediatric Gastroenterology, University Hospital Southampton NHS
Trust, Southampton, UK. Conflicts of interest: none declared.
CONTINUING MEDICAL EDUCATION MIMS JPOG 2020 VOL. 46 NO. 3 125

Prevention of Spontaneous
Preterm Birth
Kubi Appiah, MD; Piya Chaemsaithong, MD, PhD; Liona Chiu Yee Poon, MBBS, MD(Res), MRCOG, Cert RCOG

ABSTRACT
Preterm birth (PTB) is birth that occurs be-
fore 37 weeks’ gestation, and it is a leading
cause of perinatal morbidity and mortali-
ty.1 Babies born before 34 weeks’ gesta-
tion are particularly associated with high
rates of morbidity and mortality.2 They are
also at risk of long-term medical and so-
cial sequelae.3 It is therefore important to
institute preventative measures that can
help mitigate the occurrence of PTB in
pregnant women. This review highlights
the various phenotypes of spontaneous
PTB, risk factors, and pathophysiological
pathways associated with the syndrome. Currently, the use of cervical cerclage and progesterone for the prevention of spontaneous
It also discusses the various screening PTB is recommended by professional bodies.
and preventative measures currently em-
ployed by clinicians, such as transvaginal ciated complications include respiratory usually emanates from serious complica-
sonographic screening for a short cervix, distress syndrome, necrotizing enter- tions in pregnancy such as preeclampsia
progesterone therapy, placement of cervi- ocolitis, intraventricular haemorrhage, and foetal growth restriction. Given the
cal cerclage, insertion of cervical pessary, and developmental brain disorders, inverse association between the risk of
antibiotic treatment for lower genital tract such as cerebral palsy, intellectual dis- perinatal morbidity and mortality and ges-
infections, and tocolytic therapy, while ex- abilities, and vision impairment. In adult tational age at birth, PTB is further strati-
ploring professional guidelines in the pre- life, those who are born preterm are fied according to gestational age at deliv-
vention of spontaneous PTB. challenged with noncommunicable dis- ery: extreme PTB (<28 weeks), early PTB
eases including obesity, diabetes melli- (28–33+6 weeks), and late PTB (34–36+6
INTRODUCTION tus, and hypertension.4 weeks).1 This review would focus on pre-
PTB is defined as birth that occurs be- vention strategies for spontaneous PTB.
fore 37 weeks’ gestation. It is the leading CLASSIFICATIONS OF
cause of death in neonates and the sec- PRETERM BIRTH STRATEGIES FOR
ond cause of death in children aged <5 PTB is classified as spontaneous or iat- PREVENTION OF PRETERM
years.1 PTB alone is estimated to cause rogenic. Spontaneous preterm labour LABOUR
over a million neonatal deaths per year and preterm premature rupture of mem-
worldwide. The highest risk of perinatal branes (PPROM) account for about 70% Risk factors
mortality occurs in babies born before and 40% of all PTBs in singleton and twin Multiple risk factors are identifiable be-
32 weeks’ gestation. Prematurity-asso- pregnancies, respectively. Iatrogenic PTB fore and during pregnancy. Increased
126 MIMS JPOG 2020 VOL. 46 NO. 3
Figure 1. Transvaginal ultrasonographic identification of a short cervix.
risk of spontaneous PTB has been as-
sociated with the following risk factors:
history of PTB, maternal age at >40
years, teenage pregnancy, obesity,
poor weight gain during pregnancy, Af-
rican ethnicity, a short inter-pregnancy
interval of <6 months, conception by
assisted reproductive technology, mul-
tiple pregnancies, substance abuse,
cigarette smoking, low socioeconomic
status, bacterial vaginosis, periodontal
disease, and a history of excision of the
cervical transformational zone.5
Methods for identification of
high-risk women
Spontaneous PTB is a complex syn-
drome, making it difficult to prevent. One
major challenge for the prevention of this
adverse outcome relates to the ability to
effectively identify high-risk women. Al-
though PTB history is the most important
risk factor, this alone has been shown to
have limited predictability, with detection
rates (DR) ranging from 15–30%. De- 6
spite this limitation, it is the only method
of screening recommended by most pro-
fessional obstetrical societies.7 A cohort
CONTINUING MEDICAL EDUCATION
1.39 cm
study including 34,025 singleton preg-
nancies has reported that a prior episode
of spontaneous preterm delivery increas-
es the risk of spontaneous PTB in the in-
dex pregnancy by 6-fold, and the risk is
increased by 20-fold when there are two
prior episodes of spontaneous preterm
delivery. However, screening by mater-
nal risk factors can only detect 38.2% of
preterm deliveries in women with previ-
ous pregnancies at or beyond 16 weeks
and 18.4% in those without, at 10% false
positive rate.8 There is a need to consider
other screening methods.
Transvaginal ultrasonographic as-
sessment of cervical length at 16–24
weeks’ gestation (Figure 1) was shown
to be a useful predictor of spontaneous
PTB, 9
either alone or in combination
with maternal risk factors. A study of
6,819 women with singleton pregnancy
reported that 111 women (1.6%) had a
short cervix of <15 mm and 294 women
(4.3%) had funnelling at 22–24 weeks’
gestation. The prevalence of funnelling
decreased (from 98% to 25% and <1%)
with increasing cervical length from ≤15
mm to 16–30 and >30 mm, respectively.
Women with funnelling showed a sig-
nificantly higher rate of preterm deliv-
ery at <33 weeks’ gestation than those
without (6.9% vs 0.7%; p=0.0001).10 A
large prospective observational study of
58,807 singleton pregnancies demon-
strated that the combination of cervical
length at 20–24 weeks’ gestation and
maternal risk factors achieved DR of
80.6%, 58.5%, 53.0%, and 28.6% for ex-
treme (<28 weeks), early (28–30 weeks),
moderate (31–33 weeks), and mild (34
weeks) spontaneous PTB, respectively.11
In relation to multiple pregnancies,
a different cut-off for the measurement of
cervical length is required for the predic-
tion of spontaneous PTB. A study of 215
women with twin pregnancies demon-
strated that a cervical length of ≤25 mm
at 23 weeks’ gestation achieved DR of
100%, 80%, 47%, and 35%, respectively,
for spontaneous delivery at <28, <30,
<32, and <34 weeks’ gestation. The
respective DR for cervical length of ≤15
mm was 50%, 40%, 24%, and 11%.12 In a
study of 51 triplet pregnancies, a cervical
length of ≤25 mm at 15–20 weeks’ gesta-
tion had DR of 100%, 72%, and 25% for
spontaneous delivery at ≤28, <30, and
≤32 weeks’ gestation, respectively.13
The cervicovaginal fluid (CVF) re-
flects the biochemical environment and
physiological changes of the vagina,
cervix, and adjacent overlying foetal
membranes. Therefore, it has been the
main biological fluid used to determine
biomarkers that could predict spontane-
ous PTB. Two CVF biomarkers – foetal
fibronectin and phosphorylated insu-
lin-like growth factor binding protein – are
used as point-of-care tests to predict PTB
in women presenting with threatened
preterm labour. However, the predictive
ability of these biomarkers for spontane-
ous PTB in asymptomatic women is poor
CONTINUING MEDICAL EDUCATION
Table 1. Summary of Methods of Prevention for Women with a History of PTB and/or Short Cervix
Method of prevention
History of PTB
Cervical cerclage Useful for women
with ≥3 previous
second trimester
miscarriage/PTB
Oral progesterone Useful
17-OHPC Useful
Vaginal progesterone Useful
Cervical pessary
to moderate. Thus, the search for predic-
tive CVF biomarker continues. 14
Methods of prevention
For women with history of PTB and/or
a short cervical length, there are essen-
tially three preventive measures – cervi-
cal cerclage, progesterone therapy, and
cervical pessary (Table 1).
Cervical cerclage
In the general obstetric population, ap-
proximately 0.5–1% of pregnant women
have been found to have an incompetent
cervix. Such women may report a history
of early or mid-trimester pregnancy loss,
which is often associated with painless
cervical dilatation. Cerclage is a circum-
7
ferential suture carefully placed in the
cervix, with the aim to provide mechan-
ical support to the cervix and thereby re-
duce the risk of PTB.
A landmark randomized controlled
trial (RCT) conducted by the Royal Col-
lege of Obstetricians and Gynaecolo-
gists evaluated 1,292 women whose
obstetricians were uncertain whether to
recommend cervical cerclage. Majority
of the participants had a history of PTB
or cervical surgery. The findings showed
Singleton
Short cervix Both
Not useful Useful
Not useful
Useful Useful
Not useful
that the application of cervical cerclage
decreased the rate of delivery at <33
weeks’ gestation from 17% to 13%
(odds ratio [OR], 0.72, 95% confidence
interval [CI], 0.53–0.97). This risk reduc-
tion is mainly attributed to the effect of
cervical cerclage on women with prior
history of ≥3 second trimester miscar-
riage or PTB compared with <37 weeks’
gestation (15% vs 32%; OR, 0.37, 95%
CI, 0.14–0.95). These findings led to the
recommendation that cervical cerclage
should be offered to women at high risk
of PTB, such as those with a history of
≥3 pregnancies ending before 37 weeks’
gestation. The Cervical Incompetence
15
Prevention Randomized Cerclage Trial
(CIPRACT) evaluated 67 women with a
history of PTB at <34 weeks’ gestation,
demonstrated no significant difference
in the rate of PTB at <34 weeks’ gesta-
tion between the cerclage and expectant
management groups (13.0% vs 13.6%;
OR, 0.95, 95% CI, 0.21–4.21). However,
in the subgroup of women with a short
cervix of <25 mm, the rate of PTB at
<34 weeks’ gestation was significant-
ly reduced in the cerclage group vs the
expectant management group (10.0% vs
62.5%; OR, 0.07, 95% CI, 0.01–0.82).16
MIMS JPOG 2020 VOL. 46 NO. 3 127
Twin
Unselected Short cervix
Maybe
Not useful Not useful
Not useful Maybe/Useful
Not useful Useful
In relation to isolated short cervi-
cal length of <25 mm, in the absence
of history of PTB, a recent individual
patient-level data (IPD) meta-analysis of
five RCTs involving 419 asymptomatic
singletons reported no significant differ-
ence in the rate of PTB at <35 weeks’
gestation between women with and
without cerclage (21.9% vs 27.7%; RR,
0.88, 95% CI, 0.63–1.23).17 With regard
to women with previous history of PTB
with concurrent short cervix (<25 mm),
a meta-analysis of five trials including
504 women with singleton pregnancy
demonstrated that cerclage was associ-
ated with reduced rates of preterm birth
at <35 weeks’ gestation (30% reduction;
RR, 0.70, 95% CI, 0.55–0.89) and perina-
tal mortality and morbidity (36% reduc-
tion; RR, 0.64, 95% CI, 0.45–0.91).18
A recent Cochrane review and
meta-analysis reported on the effect
of cervical cerclage in singleton preg-
nancy at high risk of pregnancy loss
based on woman’s history and/or ultra-
sound finding of a short cervix. Results
showed that pregnant women with
cerclage are less likely to have PTB at
<34 weeks (average RR, 0.77, 95% CI,
0.66–0.89) and <37 weeks (average
128 MIMS JPOG 2020 VOL. 46 NO. 3
RR, 0.80, 95% CI, 0.69–0.95; 9 studies;
n=2,415). 19
Cervical cerclage was also evalu-
ated in twin gestations. However, exist-
ing evidence is rather controversial. An
IPD meta-analysis comprising three tri-
als with 49 twin gestations with a short
cervix of <25 mm identified before 24
weeks’ gestation showed that women
who received cervical cerclage (n=24)
had a similar rate of PTB at <34 weeks’
gestation compared with those who did
not receive (n=25; 62.5% vs 24.0%; ad-
justed odds ratio [adjOR], 1.17, 95% CI,
0.23–3.79). Based on the results of this
20
meta-analysis, cervical cerclage is not
recommended for clinical use in twin
gestations where the mother has a short
cervical length in the second trimes-
ter. However, results from a recent me-
ta-analysis of 16 studies (RCT and cohort
studies) on 1,211 twin pregnancies with
a cervical length of <15 mm have refut-
ed this recommendation. The meta-anal-
ysis showed that cervical cerclage was
significantly associated with prolonga-
tion of pregnancy (mean difference, 3.8
weeks, 95% CI, 2.2–5.6) and reduction in
the rates of PTB at <34 (RR, 0.57, 95%
CI, 0.43–0.75) and <37 weeks’ gestation
(RR, 0.86, 95% CI, 0.74–0.99) compared
with the no cerclage group,21 suggesting
that cervical cerclage might be beneficial
for women with twin pregnancy with a
short cervix of <15 mm.
Progesterone therapy
Labour begins when there is a decrease
in progesterone and an upsurge in oes-
trogen concentration or when progester-
one activity is halted, resulting in ripen-
ing of the cervix and uterine contractility.
Progesterone functions by preventing
cervical ripening, reducing myometrial
contractility through the suppression
CONTINUING MEDICAL EDUCATION
of oxytocin receptor synthesis and reg-
ulation of inflammation. Several RCTs
have assessed the possible effect of
exogenous progesterone intake, includ-
ing oral intake, weekly intramuscular
injections of 17α-hydroxyprogesterone
caproate (17-OHPC), and daily vaginal
progesterone, in asymptomatic women
at risk of spontaneous PTB. 22-25
A recent meta-analysis of three
RCTs comprising a total of 386 single-
ton pregnancies with history of spon-
taneous PTB showed that those who
received oral progesterone compared
with placebo had a significant decrease
in the risk of preterm delivery at <37
(42% vs 63%; RR, 0.68, 95% CI, 0.55-
0.84; p=0.0005) and <34 weeks’ ges-
tation (29% vs 53%; RR, 0.55, 95% CI,
0.43-0.71; p=0.00001). Conversely, an
increase in gestational age at delivery
was observed in women taking oral pro-
gesterone vs placebo (mean difference,
1.71 weeks, 95% CI, 1.11–2.30).25
With regards to the use of 17-
OHPC in women with a history of mis-
carriage/PTB, a meta-analysis of seven
RCTs including 630 singleton pregnan-
cies with a history of ≥2 miscarriages
and/or PTBs concluded that 17-OHPC
was effective as a prophylactic agent for
PTB, with a pooled OR of 0.50 (95% CI,
0.30–0.85). In an RCT of 659 pregnant
26
women with singleton pregnancy with a
history of spontaneous PTB, the authors
reported no significant difference in the
rate of PTB at <32 weeks’ gestation
between the vaginal progesterone (100
mg/day) and placebo groups (RR, 0.9,
95% CI, 0.52–1.56). On the contrary, a
27
similar trial that included 142 high-risk
singleton pregnancies with a history of
PTB, prophylactic vaginal progesterone
(100 mg/day) reportedly reduced the
rate of preterm delivery at <34 (2.8% vs
18.6%; p=0.002) and <37 weeks’ ges-
tation (13.8% vs 28.5%; p=0.03) com-
pared with placebo.28
The efficacy of weekly 17-OHPC
and daily vaginal progesterone from 16
weeks’ gestation in the prevention of
spontaneous PTB was compared in a
meta-analysis of three RCTs with a total
of 680 singleton pregnancies with prior
spontaneous PTB. The study reported
that vaginal progesterone was associat-
ed with lower rates of spontaneous PTB
at <34 (RR, 0.71, 95% CI, 0.53–0.95) and
<32 weeks’ gestation (RR, 0.62, 95% CI,
0.40–0.94) compared with 17-OHPC,
leading to the conclusion that daily vag-
inal progesterone administered from 16
weeks’ gestation is a better alternative
than weekly 17-OHPC in preventing
spontaneous PTB in women with history
of spontaneous PTB.24
Evidence on the use of 17-OHPC in
preventing PTB in women identified with
a short cervix but no history of PTB is
less convincing. A multicentre RCT com-
pared weekly intramuscular 250 mg 17-
OHPC with placebo in 657 nulliparous
women with singleton pregnancy with
a short cervix of <30 mm (correspond-
ing to 10th percentile) identified at 16–22
weeks’ gestation. This study demonstrat-
ed no difference between 17-OHPC and
placebo in the rates of PTB at <32 (8.6%
vs 9.7%; RR, 0.88, 95% CI, 0.54–1.43),
<35 (13.5% vs 16.1%; RR, 0.84, 95%
CI, 0.58–1.21), and <37 weeks of gesta-
tion (25.1% vs 24.2%; RR, 1.03, 95% CI,
0.79–1.35).29 Similarly, in an open-label,
multicentre RCT of 105 singleton preg-
nancies with a cervical length of <25
mm and a history of PTB, cervical sur-
gery, uterine malformation, or prenatal
DES exposure, there was no significant
difference between the weekly intramus-
cular 500 mg 17-OHPC and control arms
CONTINUING MEDICAL EDUCATION
in terms of enrolment-to-delivery interval
(77 vs 74 days, mean difference 4 days,
95% CI, -9 to -17) and the rate of delivery
at <37 weeks (45% vs 44%; RR, 1.01,
95% CI, 0.66–1.55).30
In relation to the use of vaginal
progesterone in preventing PTB among
women identified with a short cervix,
two major RCTs have provided convinc-
ing evidence. A multicentre RCT of 413
women with a short cervix of ≤15 mm
at 22 weeks’ gestation demonstrated a
significantly lower rate of spontaneous
PTB at <34 weeks’ gestation in the vag-
inal progesterone group vs the placebo
group (19.2% vs. 34.4%; RR, 0.56, 95%
CI, 0.36–0.86). Moreover, the authors
found that vaginal progesterone might
be more beneficial for the subgroup with
a cervical length of ≥12 mm. 22
A similar
trial of 458 women with singleton preg-
nancy and a short cervical length of
10–20 mm at 19–23 weeks’ gestation
demonstrated a lower rate of PTB at <33
weeks’ gestation in women who received
vaginal progesterone than those on pla-
cebo (8.9% vs.16.1%; RR, 0.55, 95% CI,
0.33–0.92).23
Despite promising results on the
efficacy of vaginal progesterone in pre-
venting spontaneous PTB, a large RCT
of 1,228 women (the OPPTIMUM study)
showed no significant effect in the preven-
tion of foetal death or PTB at <34 weeks’
gestation (OR, 0.86, 95% CI, 0.61–0.22)
or neonatal outcome (OR, 0.72, 95% CI,
0.44–1.17). The inclusion criteria for this
trial were previous spontaneous PTB at
<34 weeks’ gestation, a short cervix of
≤25 mm, or a positive foetal fibronectin
test at 22–24 weeks with other clinical
risk factors for PTB. The negative results
may be attributed to several reasons: the
randomized women represented a heter-
ogeneous group with different underly-
ing causes for PTB, the moderate over-
all compliance of 69%, and the lack of
power to detect any significant differenc-
es in preventing PTB between vaginal
progesterone and placebo arms in the
subgroup of women with short cervix.31
A recent IPD meta-analysis that included
data from the OPPTIMUM study and four
other double-blind, placebo-controlled
trials evaluated 974 asymptomatic wom-
en with singleton pregnancies and a
short cervix of ≤25 mm (vaginal proges-
terone [n=498] and placebo [n=476]).
The authors reported that vaginal pro-
gesterone significantly reduced the risk
of spontaneous PTB at <33 (12% vs
17%; RR, 0.70, 95% CI, 0.51–0.95) and
<34 weeks’ gestation (15% vs 20% RR,
0.72, 95% CI, 0.55–0.95), and compos-
ite neonatal morbidity and mortality (RR,
0.59; 95% CI, 0.38–0.91).32
Progesterone was also compared
with cervical cerclage in the prevention
of PTB. A recent meta-analysis including
10 trials (n=769; five trials, vaginal pro-
gesterone vs placebo [n=265] and five
trials, cerclage vs no cerclage [n=504])
indirectly compared the use of vaginal
progesterone and cervical cerclage in
women with singleton pregnancies with
a history of spontaneous PTB and a short
cervix of <25 mm at 16–24 weeks’ ges-
tation. Compared with placebo, vaginal
progesterone decreased the risk of PTB
at <32 (RR, 0.60, 95% CI, 0.39–0.92) and
<35 weeks’ gestation (RR, 0.68, 95% CI,
0.50–0.93), as well as composite peri-
natal morbidity and mortality (RR, 0.43,
95% CI, 0.20–0.94). Cervical cerclage
was also shown to reduce the risk of PTB
at <32 (RR, 0.66, 95% CI, 0.48–0.91) and
<35 weeks’ gestation (RR, 0.70, 95% CI,
0.55–0.89), as well as composite peri-
natal morbidity and mortality (RR, 0.64,
95% CI 0.45-0.91) compared with no cer-
MIMS JPOG 2020 VOL. 46 NO. 3 129
clage. The authors concluded that both
vaginal progesterone and cervical cer-
clage are effective in preventing PTB.33
Some trials have evaluated the
use of progesterone in preventing PTB
in unselected twin pregnancies or twin
pregnancies with a short cervix. Indi-
vidual trials have demonstrated nega-
tive results. An IPD meta-analysis of six
RCTs including 303 women with twin
pregnancies identified with a sono-
graphic short cervix of ≤25 mm (n=159
and 144 assigned to vaginal progester-
one and placebo/no treatment, respec-
tively), reported significant reduction in
the risk of PTB at <33 weeks’ gestation
(31.4% vs 43.1%; RR, 0.69, 95% CI,
0.51–0.93) and in composite neonatal
morbidity and mortality (RR, 0.61, 95%
CI, 0.34–0.81).34 While the results sug-
gest that vaginal progesterone reduces
the risk of PTB and neonatal morbidity
and mortality in women with twin preg-
nancies and a sonographic short cervix,
further research is required before con-
clusive advice can be provided.
Cervical pessary
Emerging evidence suggests that Arabin
cervical pessary could potentially prevent
spontaneous PTB in women identified
with a short cervix. The Arabin cervical
pessary is a silicone ring, which comes
in different sizes with the outer ring di-
ameter varying between 64 and 70 mm,
inner ring diameter between 32 and 35
mm, and height of the curvature between
21 and 25 mm. The inner ring notches
against the cervix and the outer ring fix-
es the cervix against the pelvic floor. The
pessary is designed with the aim to ad-
just the angle of the cervix towards the
posterior wall of the vagina. The device is
considered noninvasive and user-friend-
ly. It can be administered in an outpatient
130 MIMS JPOG 2020 VOL. 46 NO. 3
setting without anaesthesia and can eas-
ily be removed when required.
In a trial that evaluated the treatment
effect of the Arabin pessary (n=192) vs
expectant management (n=193) in wom-
en with singleton pregnancy and a short
cervical length of ≤25 mm, a significant
reduction in the rate of spontaneous PTB
at <34 weeks’ gestation was observed
in the treatment group compared with
the expected management group (6%
vs 27%; OR, 0.18, 95% CI, 0.08–0.37).35
However, subsequent trials failed to rep-
licate the results.36-37 A meta-analysis of
three RCTs including 1,612 singleton
pregnancies with a cervical length of ≤25
mm at 18–24 weeks’ gestation reported
no significant difference between pessa-
ry and expectant management in terms
of spontaneous PTB rate at <34 weeks’
gestation (RR, 0.51, 95% CI, 0.19–1.38).
However, the rate of spontaneous PTB
at <37 weeks’ gestation was reduced
in the pessary group (RR, 0.46, 95% CI,
0.28–0.77).38
In a global, open-label, multicen-
tre trial including 1,180 unselected twin
pregnancies, compared with expectant
management, cervical pessary given at
20–24 weeks’ gestation was not asso-
ciated with a significant reduction in the
rate of spontaneous PTB at <34 weeks’
gestation (RR, 1.05, 95% CI, 0.79–1.41). 39
In another open-label, multicentre, rand-
omized trial in a similar population, there
was no significant difference between
the pessary (n=401) and expectant
management groups (n=407) in terms
of the rate of a composite of poor perina-
tal outcome (13% vs 14%; RR, 0.98, 95%
CI, 0.69–1.39). In a post hoc analysis of
women with cervical length of <25 per-
th
centile (<38 mm), use of the pessary led
to a significant reduction in the rate of
poor perinatal outcomes (12% vs 16%;
CONTINUING MEDICAL EDUCATION
RR, 0.40, 95% CI, 0.19–0.83), but not
spontaneous PTB at <28 (4% vs 2%;
RR, 2.02, 95% CI, 0.64–6.41) and <32
weeks’ gestation (10% vs 8%; RR, 1.20,
95% CI, 0.67–6.41).40 Interestingly, a tri-
al involving 137 women with twin preg-
nancies identified with short cervix ≤25
mm at 18–22 weeks’ gestation reported
that spontaneous PTB at <34 weeks’
gestation was significantly reduced in
the pessary group than in the expectant
management group (5.9% vs 9.1%; RR,
0.41, 95% CI, 0.22–0.76). 41
Antibiotics and infection
treatment
Although infection plays a critical role in
spontaneous PTB, there is no evidence
to suggest that antibiotic is effective in
preventing this adverse outcome. Bac-
terial vaginosis occurs when the Lac-
tobacillus species, which is part of the
normal vaginal flora, is substituted with
anaerobic bacteria such as Gardnerella
vaginalis and Mycoplasma hominis. To
ascertain whether women diagnosed
with bacterial vaginosis and treated with
oral metronidazole and vaginal clinda-
mycin before 28 weeks’ gestation re-
duces the incidence of preterm labour,
a recent systematic review comprising
nine studies and a meta-analysis of eight
RCTs including 10,513 pregnant women
reported that there was no reduction in
the incidence of preterm labour with the
use of oral metronidazole (OR, 0.94, 95%
CI, 0.71–1.25) or vaginal clindamycin
(OR, 1.01, 95% CI, 0.75–1.36). 42
Tocolytic therapy
Spontaneous preterm labour necessi-
tates the use of tocolytics, they act by
reducing uterine contractility and aims
at delaying delivery at least, until the ad-
ministration of antenatal corticosteroids
for foetal lung maturation and to recom-
mend for a referral to a tertiary facility
with appropriate neonatal intensive care
unit.43 Different classes of drugs have
been used for tocolysis. Since a stand-
ard first-line drug has not been iden-
tified, most drugs are currently in use
including beta mimetics (eg, ritodrine,
terbutaline), magnesium sulphate, pros-
taglandin inhibitors (mostly indometh-
acin), calcium channel blockers (eg,
nifedipine), nitrates (eg, nitroglycerine),
and oxytocin receptor blockers (main-
ly atosiban). Each tocolytic agent has
its own mechanism of action, adverse
effects, and administration.44
A large systemic review and net-
work meta-analysis sought to deter-
mine the most effective tocolytic agent
for delaying preterm delivery. A total
of 95 RCTs were included with a mean
participant population of 111.9 (range
20-708). The probability of a 48-hour
delay was highest with prostaglandin
inhibitors (OR, 5.39, 95% credible inter-
val [CRI], 2.14–12.34) followed by mag-
nesium sulphate (OR, 2.76, 95% CRI,
1.58–4.94), calcium channel blockers
(OR, 2.71, 95% CRI, 1.17–5.91), beta mi-
metics (OR, 2.41, 95% CRI, 1.27–4.55),
and oxytocin receptor blockers (OR,
2.02, 95% CRI, 1.10–3.80) compared
with placebo.44
PROFESSIONAL GUIDELINES
Clinical practice guidelines offer a prag-
matic approach to guide clinicians in
the prevention of preterm labour and
delivery. We refer to three key profes-
sional guidelines for consideration. The
American College of Obstetricians and
Gynaecologists (ACOG) recommends
that women with singleton pregnancy
and prior spontaneous PTB should be
offered progesterone supplementation
CONTINUING MEDICAL EDUCATION MIMS JPOG 2020 VOL. 46 NO. 3 131

at 16–24 weeks’ gestation regardless
of transvaginal cervical length. Further-
more, vaginal progesterone is recom-
mended as a treatment option in asymp-
tomatic women with a single pregnancy
without prior PTB and an incidental find-
ing of short cervix of <20 mm before or
at 24 weeks’ gestation. Although uni-
versal cervical length screening is not
mandated for women without history
of spontaneous PTB, it may however
be considered. Vaginal progesterone is
not recommended for multiple pregnan-
cies.45 The ACOG further recommends
that women with singleton pregnancy
with prior spontaneous PTB and short
cervix of <25 mm before 24 weeks’ ges-
tation who do not meet the criteria for
cervical insufficiency, may benefit from
cervical cerclage placement.
In the UK, the National Institute
for Health and Care Excellence recom-
mends a choice of either prophylactic
vaginal progesterone or cervical cer-
clage for women with prior spontaneous
PTB or mid-trimester pregnancy loss
between 16 and 34 weeks’ gestation
and those with short cervix of <25 mm
identified between 16 and 24 weeks’
gestation. For women with short cervi-
cal length of <25 mm, in the absence of
offer prophylactic vaginal progesterone
but not cervical cerclage. Furthermore,
for women with short cervix of <25 mm
between 16 and 24 weeks’ gestation
with either a history of PPROM or cer-
vical surgery, prophylactic cervical cer-
clage is recommended. 46
The Society of Obstetricians and
Gynaecologists of Canada (SOGC) rec-
ommends that asymptomatic women
with a history of PTB who are diagnosed
with short cervix of <25 mm at <24
weeks’ gestation should be offered cer-
vical cerclage.46 With regard to proges-
terone, SOGC recommends that women
with a history of PTB be offered intramus-
cular 17-OHPC 250 mg weekly or vaginal
progesterone 100 mg daily. While wom-
en with a short cervix of <15 mm at 22–
7
26 weeks’ gestation should be offered
vaginal progesterone 200 mg daily.47
CONCLUSION
Prevention of PTB is currently one of the
major goals in obstetrics. Though exten-
sive research has been undertaken to
understand the underlying pathophysi-
ology of the syndrome with the aim to
identify preventative measures, the rate
of PTB is not declining. Currently, the
use of cervical cerclage and progester-
bodies. However, these preventative
measures are not without shortcomings
and the target population for preven-
tion is mainly women with a history of
PTB with or without short cervix, which
constitutes a small number of women
that could benefit from interventions.
Therefore, the impact of the proposed
prevention strategy on the overall rate
of spontaneous PTB is limited. For op-
timal prevention of spontaneous PTB,
risk stratification should aim at combin-
ing risk factors with different screening
tools, such as transvaginal ultrasono-
graphic assessment of cervical length
and biomarkers, to identify women at
risk of this complication in order to in-
stigate timely prophylactic measures.
More research is required to discover
potential biomarkers to improve the pre-
dictive power of existing risk stratifica-
tion strategies. The development of an
effective method for screening will stim-
ulate further research for the discovery
of targeted preventative measures.
About the authors
Dr Kubi Appiah is a PhD student in the Department of Ob-
stetrics and Gynaecology at the Chinese University of Hong
Kong, Hong Kong. Conflict of interest: none.
Dr Piya Chaemsaithong is a clinical lecturer in the Depart-
ment of Obstetrics and Gynaecology at the Chinese Universi-
ty of Hong Kong, Hong Kong. Conflict of interest: none.

history of spontaneous PTB or mid-tri- one for the prevention of spontaneous Prof Liona Chiu Yee Poon is a clinical professor in the De-
partment of Obstetrics and Gynaecology at the Chinese Uni-
mester pregnancy loss, clinicians may PTB is recommended by professional versity of Hong Kong, Hong Kong. Conflict of interest: none.

REFERENCES
1. Liu L, Oza S, Hogan D, Chu Y, Perin J, Zhu
J, et al. Global, regional, and national causes
of under-5 mortality in 2000-15: an updated
systematic analysis with implications for the
Sustainable Development Goals. Lancet
(London, England). 2016;388:3027–3035.
2. Manuck TA, Rice MM, Bailit JL, Grobman
WA, Reddy UM, Wapner RJ, et al. Preterm ne-
onatal morbidity and mortality by gestational
age: a contemporary cohort. Am J Obstet Gy-
necol 2016;215:103.e1-103.e14.
3. Saigal S, Doyle LW. An overview of mor-
tality and sequelae of preterm birth from infan-
cy to adulthood. Lancet (London, England).
2008;371:261–269.
4. https://www.marchofdimes.org/complica-
tions/premature-babies.aspx. 2019.
5. Vogel JP, Chawanpaiboon S, Moller A-B,
Watananirun K, Bonet M, Lumbiganon P. The
global epidemiology of preterm birth. Best
Pract Res Clin Obstet Gynaecol 2018;52:3–12.
6. Laughon SK, Albert PS, Leishear K, Men-
dola P. The NICHD Consecutive Pregnancies
Study: recurrent preterm delivery by subtype.
Am J Obstet Gynecol 2014;210:131.e1-e8.
7. ACOG Practice Bulletin No.142: Cerclage
for the management of cervical insufficiency.
Obstet Gynecol 2014;123:372–379.
8. Beta J, Akolekar R, Ventura W, Syngelaki
A, Nicolaides KH. Prediction of spontaneous
preterm delivery from maternal factors, obstet-
ric history and placental perfusion and function
at 11-13 weeks. Prenat Diagn 2011;31:75–83.
9. Heath VC, Southall TR, Souka AP, Elis-
seou A, Nicolaides KH. Cervical length at 23
weeks of gestation: prediction of spontane-
ous preterm delivery. Ultrasound Obstet Gy-
necol 1998;12:312–317.
10. To MS, Skentou C, Liao AW, Cacho A,
Nicolaides KH. Cervical length and funneling
at 23 weeks of gestation in the prediction of
spontaneous early preterm delivery. Ultra-
sound Obstet Gynecol 2001 ;18:200–203.
11. Celik E, To M, Gajewska K, Smith GCS,
Nicolaides KH. Cervical length and obstetric
history predict spontaneous preterm birth:
development and validation of a model to
provide individualized risk assessment. Ultra-
sound Obstet Gynecol 2008;31:549–554.
12. Souka AP, Heath V, Flint S, Sevastopoulou
I, Nicolaides KH. Cervical length at 23 weeks in
twins in predicting spontaneous preterm deliv-
ery. Obstet Gynecolw1999;94:450–454.
13. Guzman ER, Walters C, O’reilly-Green C,
Meirowitz NB, Gipson K, Nigam J, et al. Use of
cervical ultrasonography in prediction of spon-
taneous preterm birth in triplet gestations. Am
J Obstet Gynecol 2000;183:1108–1113.
14. Heng YJ, Liong S, Permezel M, Rice GE,
Di Quinzio MKW, Georgiou HM. Human cervi-
covaginal fluid biomarkers to predict term and
preterm labor. Front Physiol 2015;6:151.
15. Final report of the Medical Research
Council/Royal College of Obstetricians and
Gynaecologists multicentre randomised trial
of cervical cerclage. MRC/RCOG Working
Party on Cervical Cerclage. Br J Obstet Gy-
naecol 1993;100:516–523.
For a complete list of References material,
please write to the editor.
132 MIMS JPOG 2020 VOL. 46 NO. 3 CME QUESTIONS

This continuing medical education service is brought to you by MIMS. Read the article
‘Prevention of Spontaneous Preterm Birth’ and answer the following questions.
Answers are shown at the bottom of this page. We hope you enjoy learning with MIMS JPOG.

CME ARTICLE

Prevention of Spontaneous
Preterm Birth
Answer True or False to the questions below. True False
1. Any birth that occurs before 37 weeks of gestation can be termed spontaneous PTB.
2. PTB can be classified as spontaneous or iatrogenic and further delineated into
extreme, early, and late PTB.
3. PTB is a syndrome that is associated with multiple risk factors.
4. Prior history of PTB is said to be the most important risk factor and possesses the
highest predictability for spontaneous PTB.
5. Mid-trimester transvaginal ultrasonographic assessment of cervical length is a
useful predictor of spontaneous PTB.
6. In singletons with short cervix, cervical cerclage has proven to be effective in the
prevention of spontaneous PTB.
7. 17-OHPC does not prevent spontaneous PTB in twins.
8. In women with singleton pregnancy with history of PTB and short cervix, vaginal
progesterone is recommended for the prevention of spontaneous PTB.
9. In women with twin pregnancy, cervical pessary has been shown to be useful in
the prevention of spontaneous PTB.
10. Early detection and effective treatment of infection have the potential to prevent
spontaneous PTB.

10.F 9.F 8.T 7.T 6.F 5.T 4.F 3.T 2.T 1.T
Answers