INDONESIA • 2019

ISSN 2411-0140
VOL. 45 NO. 4

JOURNAL OF PAEDIATRICS,
OBSTETRICS & GYNAECOLOGY

YOUR PARTNER IN PAEDIATRIC, OBSTETRIC & GYNAECOLOGY PRACTICE

OBSTETRICS
Vaccinations
in Pregnancy

GYNAECOLOGY
Dysmenorrhoea

CME ARTICLE
Prevention
of Pre-eclampsia
 MIMS JPOG 2019 VOL. 45 NO. 4 i

2019 VOL. 45 NO. 4

Editorial Board
CONFERENCE COVERAGE
Board Director, Paediatrics
Annual Meeting of the American Society of
Professor Pik-To Cheung
Associate Professor, Department of Paediatrics and Adolescent Medicine Nephrology Kidney Week 2019 (ASN Kidney Week
The University of Hong Kong, Hong Kong
2019), November 5-10, Washington, DC, US
Board Director, Obstetrics and Gynaecology
Professor Pak-Chung Ho
Director, Centre of Reproductive Medicine 133
The University of Hong Kong - Shenzhen Hospital, China
• Poor sleep, fatigue tied to
cognitive, behavioural problems
in children with CKD
Professor Biran Affandi Professor Seng-Hock Quak
University of Indonesia, Indonesia National University of Singapore, • High androgen levels up risk of
Singapore hypertension in women
Professor Hextan
Yuen-Sheung Ngan Adjunct Associate Professor
The University of Hong Kong, Hong Kong Tan Ah Moy
KK Women’s and Children’s Hospital,
Professor Kenneth Kwek
KK Women’s and Children’s Hospital,
Singapore
134
Singapore Dr. Catherine Lynn Silao

Professor Kok Hian Tan

University of the Philippines Manila, • Combined tests may improve severe AKI detection,
Philippines
KK Women’s and Children’s Hospital, prediction in children
Dwiana Ocviyanti, MD, PhD
Singapore
University of Indonesia, Indonesia
Professor Dato’
Dr. Karen Kar-Loen Chan
Dr. Ravindran Jegasothy The University of Hong Kong,
Dean Faculty of Medicine, Hong Kong
MAHSA University, Malaysia
Associate Professor Daisy Chan
Dr. Kwok-Yin Leung
The University of Hong Kong,
JOURNAL WATCH
Singapore General Hospital, Singapore Hong Kong
Associate Professor Raymond Dr. Mary Anne Chiong
University of the Philippines Manila,
Hang Wun Li
The University of Hong Kong, Hong Kong Philippines 135
Dr. Wing-Cheong Leung
Adjunct Associate Professor
Kwong Wah Hospital, Hong Kong,
• New assay identifies paediatric
Ng Kee Chong
Division of Medicine & Academic Clinical
Hong Kong TB with high sensitivity
Program (Paediatrics), c/o KK Women’s and
Children’s Hospital, Singapore
• Foetal exposure to acetaminophen
tied to increased risk for ADHD,
autism

136
• High trunk fat mass may increase CVD risk in
postmenopausal women regardless of BMI
 MIMS JPOG 2019 VOL. 45 NO. 4 iii

2019 VOL. 45 NO. 4

REVIEW ARTICLE
PAEDIATRICS
CEO Yasunobu Sakai
Managing Editor Elvira Manzano
Medical Editor Elaine Soliven
Designer Sam Shum
137
Production Tetsuya Hamaki, Agnes Chieng
Circulation Christine Chok A Review of Growth Hormone Deficiency
Finance Manager Jessie Seow
Advertising Coordinator Pannica Goh
Growth hormone deficiency (GHD)
is a rare but important cause of short
Published by: stature in children. It is treatable.
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often requires referral to a specialist
paediatric endocrinologist to facilitate
testing and the interpretation of results.
This short article gives an overview of the importance of GHD and
Enquiries and Correspondence offers advice on how to take a history, conduct and examine, and
China Singapore
begin investigation for a child with suspected GHD.
Yang Xuan Josephine Cheong, Bernice Eng, Mehul T Dattani, Neha Malhotra
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OBSTETRICS
Indonesia
Fatmawati, Fransiska Simamora,
Ruth Theresia, Sari Wiyanti 148
Tel: (62 21) 729 2662
Email: enquiry.id@mims.com Vaccinations in Pregnancy
Malaysia
Brenda Yong, Xavier Wee, Vaccinations are a cost-effective means
Kam Zhi Yan, Sugalia Santhira of preventing disease. They may be
Tel: (60 3) 7623 8000
Email: enquiry.my@mims.com recommended primarily for maternal
Philippines benefit or for prevention of intrauterine
Rowena Belgica foetal or early neonatal infection. This
Tel: (63 2) 886 0333
Email: enquiry.ph@mims.com article aims to guide such decisions
by discussing the issues surrounding
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iv MIMS JPOG 2019 VOL. 45 NO. 4

2019 VOL. 45 NO. 4

REVIEW ARTICLE CME Accreditation

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

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

160 review of articles through the SMC website at www.smc.gov.sg.
Dysmenorrhoea
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• 1 non-core CME point per article for self-reading
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between primary and secondary dysmenorrhoea. We present an
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Akshatha Kulkarni, Shilpa Deb

CONTINUING
MEDICAL EDUCATION
169
Prevention of Pre-eclampsia
Pre-eclampsia is a major obstetric complication that can lead
to adverse maternal and foetal outcomes. It is recognized as
a new-onset hypertension (≥140 mm Hg systolic and ≥90 mm
Hg diastolic) with co-occurring proteinuria (≥300 mg/day) that
develops after 20 weeks of gestation.
Pui Wah HUI

The Cover:
A Review of Growth Hormone Deficiency
©2019 MIMS Pte Ltd

Peggy Tio, Designer

CONFERENCE COVERAGE
Annual Meeting of the American Society of Nephrology Kidney Week 2019 (ASN Kidney Week 2019),
November 5-10, Washington, DC, US
Poor sleep, fatigue tied
to cognitive, behavioural
problems in children with CKD
Children with chronic kidney disease
(CKD) who experienced sleep difficulty
and fatigue were more likely than those
without such issues to have a poorer
executive functioning and increased
emotional-behavioural symptoms, ac-
cording to a study presented at ASN
Kidney Week 2019.
“Children with CKD are at risk for
deficits in neurocognitive function. It is
not known how sleep problems/fatigue
within the context of CKD may con-
tribute to these deficits,” according to
Dr Rebecca Johnson from Children’s
Mercy Hospital in Kansas City, Mis-
souri, US.
Using data from the CKiD*
study, the researchers conducted a
study involving 1,030 children with
mild-to-moderate CKD (median dis-
ease duration 6 years, 63 percent
male) to examine the relationship
between sleep problems or fatigue
and emotional-behavioural and neu-
rocognitive outcomes. Fatigue, sleep
disturbance, low energy, and trouble
sleeping measures were assessed.
[ASN Kidney Week 2019, abstract TH-
OR127]
In the overall population, the prev-
alence of having low energy, trouble
sleeping, sleep disturbance, and fa-
tigue were 52 percent, 39 percent, 30
percent, and 26 percent, respectively.
After adjusting for sociodemo-
graphic and disease-related covar-
iates, trouble sleeping (β=1.87, 95
percent confidence interval [CI], 0.87–
2.87; p=0.0003), sleep disturbance
(β=1.28, 95 percent CI, 0.25–2.32;
p=0.02), and low energy (β=1.85, 95
percent CI, 0.79–2.90; p=0.0006) were
significantly associated with worse
parent-reported overall executive func-
tions.
Children who reported having low
energy also had a significantly poorer
working memory (β=-0.37, 95 percent
CI, 0.72 to -0.01; p=0.05 [for digit span
forward] and β=-0.48, 95 percent CI,
-0.87 to -0.09; p=0.02 [for digit span
backward]).
In addition, low energy was signif-
icantly associated with lower inhibition
(β=-0.92, 95 percent CI, 1.57–0.28;
p=0.0006) and worse problem-solving
ability (β=-0.67, 95 percent CI, -1.25 to
-0.09; p=0.02).
“Each of the four sleep meas-
ures was significantly related to more
internalizing symptoms on a measure
of emotional-behavioural functioning,
and sleep disturbance, low energy,
and trouble sleeping were associated
with more externalizing symptoms,”
Johnson and her team noted.
“[Our results showed that] fa-
tigue and sleep problems are prevalent
among children with CKD and may affect
neurocognitive and emotional-behav-
ioural functioning,” said Johnson, who
suggested that “assessment of sleep
problems and fatigue, interventions to
improve sleep, and treating medical co-
morbidities may promote more positive
emotional-behavioural and neurocogni-
tive outcomes for children with CKD.”
*CKiD: Chronic Kidney Disease in Children
– ELAINE SOLIVEN
Dr Rebecca Johnson, et al. Annual Meeting of the Ameri-
can Society of Nephrology, Kidney Week 2019 (ASN Kidney
Week 2019), November 5-10, Washington, DC, US [abstract
TH-OR127].
MIMS JPOG 2019 VOL. 45 NO. 4 133
High androgen levels up risk of
hypertension in women
Excess androgen in women is associ-
ated with increases in blood pressure
(BP), claims an expert who presented
several studies at the recent ASN Kid-
ney Week 2019.
Dr Licy Yanes Cardozo from the
Departments of Cell and Molecular Bi-
ology and Medicine/Endocrinology at
the University of Mississippi Medical
Center shared two cases in which high
levels of androgen correlated with ele-
vated BP.
The first case was of a 30-year-old
woman diagnosed with polycystic ova-
ry syndrome (PCOS). On her physical
exam, she had a BP of 140/90 mm Hg
and a body mass index (BMI) of 38 kg/
m2. Her laboratory test revealed high
levels of free (1.57 ng/dL) and total tes-
tosterone (120 ng/dL).
“PCOS is recognized as the most
common endocrine disorder that af-
fects reproductive age women,” said
Cardozo. “One of the cardinal features
of these women is that they can pres-
ent with elevated levels of androgen”.
Moreover, PCOS is the leading
cause of infertility in young women, but
women with this condition also have a
cluster of cardiovascular risk factors
such as elevated BP, Cardozo added.
Of note, up to 40 percent of those with
PCOS will have increases in BP.
An epidemiological study by
Chen and colleagues showed that
characteristic hyperandrogenaemia in
young women with PCOS was asso-
ciated with an elevated BP, independ-
ent of age, insulin resistance, obesi-
ty, or dyslipidaemia. [Hypertension
2007;49:1442-1447]
134 MIMS JPOG 2019 VOL. 45 NO. 4
Another study in which Cardozo
was a part of highlighted the impor-
tance of early detection and treatment
of hyperandrogenaemia “to prevent
the cardiometabolic derangements
found in patients with PCOS… be-
cause once cardiometabolic dysreg-
ulations have been established, nor-
malization of the androgenic profile
may have little beneficial effect.” [J
Endocr Soc 2018;2:949-964]
“In clinical scenarios charac-
terized by hyperandrogenaemia in
women, prompt normalization of an-
drogen levels may be necessary to
prevent their long-lasting cardiomet-
abolic effects,” Cardozo said.
The second case involved a
41-year-old biological female who
identified himself as a male was seek-
ing gender reassignment therapy with
testosterone. On physical examination,
the transgender patient had a BP of
150/94 mm Hg and a BMI of 41 kg/m2.
Two months after administration
of testosterone cypionate injections,
his free (5.7 ng/dL) and total testos-
terone levels (540 ng/dL) reached
the normal range of those in biolog-
ical men (free: 4.26–16.4 ng/dL; to-
tal: 280–950 ng/dL). However, his BP
(160/94 mm Hg) and BMI (51 kg/m2)
increased even further despite being
counselled about the side effects of
testosterone in women.
This finding was consistent with
that of a 2018 study, in which testos-
terone therapy led to an increase in
systolic and diastolic BP, as well as
an increase in low-density lipopro-
tein cholesterol and a decrease in
high-density lipoprotein cholesterol,
in transgender men. [Rev Endocr Me-
tab Disord 2018;19:243-251]
Of note, there have been “no
clinical trials or long-term prospective
studies in the effect of sex steroids and
cardiovascular diseases in transgen-
ders,” according to Cardozo.
In the management of excess an-
drogen, Cardozo said that the combi-
nation of glucagon-like peptide type 1
receptor agonists and ACE inhibitors
“could be a promising therapeutic tool
to treat hyperandrogenaemia-induced
cardiometabolic complications.” [Endo-
crinology 2019;160:2787-2799]
— STEPHEN PADILLA
Dr Licy Yanes Cardozo, et al. Annual Meeting of the American So-
ciety of Nephrology, Kidney Week 2019 (ASN Kidney Week 2019),
November 5-10, Washington, DC, US.
Combined tests may
improve severe AKI detection,
prediction in children
Combining Renal Angina Index (RAI)
and urinary Neutrophil Gelatinase Asso-
ciated Lipocalin (uNGAL) tests may help
clinicians to detect and predict the de-
velopment of severe acute kidney injury
(AKI) in children admitted to the PICU*,
according to a study presented at ASN
Kidney Week 2019.
“Integration of the RAI and uNGAL
assessments can be used early in the
PICU course to identify patients truly at
risk for AKI and its associated morbid-
ity,” said study lead author Kelli Krall-
man, a research nurse at Cincinnati
Children's Hospital Medical Center in
Cincinnati, Ohio, US.
Researchers conducted a study in-
volving 627 children who underwent an
automated RAI assessment within 12
hours after PICU admission. Of these,
63 children were found to be RAI-posi-
tive (defined as an RAI score of ≥8) and
were referred for an additional uNGAL
assessment (cut-off value of at least 150
CONFERENCE COVERAGE
ng/mL). [ASN Kidney Week 2019, ab-
stract SA-OR017]
On day 2–4 in the PICU, patients
who were RAI-positive children had
a significantly higher rate of severe
AKI compared with those who were
RAI-negative (38.0 percent vs 1.8 per-
cent; p<0.001).
When an additional uNGAL test was
performed, a significantly higher rate of
severe AKI was also observed among
patients positive for both RAI and uNGAL
(55.5 percent vs 17.6 percent; p<0.0001)
compared with patients tested negative
for both RAI and uNGAL.
Of note, the need for renal re-
placement therapy was found to be
higher among the RAI-positive group
compared with the RAI-negative group
(13.0 percent vs 0.4 percent; p<0.001).
RAI-positive patients also experi-
enced a significantly longer stay in the
PICU (4.6 vs 3.1 days; p<0.02) and
hospital (17.8 vs 7.5 days; p<0.001)
than the RAI-negative patients.
However, there was no difference
in the occurrence of fluid overload be-
tween the RAI-positive and RAI-nega-
tive patients (p=0.14 vs p=0.11).
“The RAI alone continues to be
a good rule-out test for severe AKI in
the PICU, and [the] addition of uNGAL
is promising for improved severe AKI
prediction,” said the researchers, rec-
ommending that “additional research
needs to be conducted on a larger
sample size to better assess the clini-
cal relevance of the RAI-[u]NGAL mod-
el in predicting severe AKI and other
relevant outcomes”.
*PICU: Paediatric intensive care unit
— ELAINE SOLIVEN
Kelli Krallman, et al. Annual Meeting of the American Society of
Nephrology, Kidney Week 2019 (ASN Kidney Week 2019), No-
vember 5-10, Washington, DC, US [abstract SA-OR017].
JOURNAL WATCH PEER REVIEWED
P tested positive with Ultra decreased
Paediatrics
New assay identifies paediatric
TB with high sensitivity
A new Mycobacterium tuberculosis (TB)
and rifampin assay, Ultra, demonstrated
high sensitivity in diagnosing paediatric
pulmonary TB vs traditional bacteriologic
testing, new research has shown.
Researchers retrospectively ana-
lysed the accuracy of Ultra using bac-
teriologic results collected at the Beijing
Children’s Hospital in Beijing, China.
Ninety-three children with pulmonary
TB and 128 children with other respira-
tory tract infections were enrolled in the
study.
The Ultra test demonstrated 70
percent sensitivity in pulmonary TB cas-
es and 91 percent in bacteriologically
confirmed cases. It was also able to
detect Mycobacterium TB in 58 percent
of cases that had a negative culture or
negative acid fast-staining results and
the specificity was 98 percent.
There were no significant differ-
ences in Ultra’s sensitivity with different
sample sizes of bronchoalveolar lavage
fluid (≤1 mL, 66 percent; >1 mL,73 per-
cent; p=0.5; odds ratio [OR], 0.71).
The percentage of children who
from 93 percent to 63 percent after 1
month of treatment (p=0.01) and further
decreased after 2 months of treatment
(p=0.03).
“The World Health Organization
has highlighted that existing tests in-
cluded in the diagnostic algorithms of
active TB can be tailored to be highly
specific to each country’s settings and
resources,” said the researchers. “Our
data showed an added value for Ultra
in the diagnosis of paediatric pulmo-
nary TB in China, which has a high bur-
den of TB.”
In a related commentary, Dr
Heather Zar, director of the School of
Child and Adolescent Health at the
University of Cape Town, South Africa,
and Dr Mark Nicol from the Universi-
ty of Western Australia in Australia,
said the number of children who test-
ed positive for TB after 2 months of
treatment raises a concern. They also
noted that no comparisons were made
between yield for repeated induced
sputum samples and bronchoalveolar
lavage.
“As most cases of childhood TB
occur in low- and middle-income coun-
tries, a better, rapid, accurate, and
point-of-care diagnostic for use in these
settings is a priority,” they concluded.
MIMS JPOG 2019 VOL. 45 NO. 4 135
Sun L, et al. A Test for More Accurate Diagnosis of Pulmonary
Tuberculosis. Pediatrics 2019;doi:10.1542/peds.2019-0262; Zar
HJ, Nicol MP. Strengthening Diagnosis of Pulmonary Tubercu-
losis in Children: The Role of Xpert MTB/RIF Ultra. Pediatrics
2019;doi:10.1542/peds.2019-2944.
O
Obstetrics
Foetal exposure
to acetaminophen tied
to increased risk for
ADHD, autism
Foetal acetaminophen exposure may
increase a child’s risk for attention‐defi-
cit/hyperactivity disorder (ADHD) and
autism spectrum disorder (ASD), ac-
cording to a new study.
Researchers analysed data from 996
mother-infant dyads, which were a sub-
set of the Boston Birth Cohort, from Oc-
tober 1998 and June 2018 and measured
three cord acetaminophen metabolites
— unchanged acetaminophen, aceta-
minophen glucuronide, and 3-[N-acetyl-
L-cystein-S-yl]-acetaminophen — in ar-
chived cord plasma samples collected
at birth.
Included in the final sample were
257 children (25.8 percent) with ADHD
only, 66 (6.6 percent) with ASD only,
42 (4.2 percent) with both ADHD and
ASD, 304 (30.5 percent) with other de-
velopmental disabilities, and 327 (32.8
percent) who were neurotypical. Un-
changed acetaminophen levels were
detected in all cord plasma samples.
Being in the second and third tertiles
of cord acetaminophen burden was asso-
ciated with higher odds of ADHD diagnosis
(odds ratio [OR] for second tertile, 2.26, 95
percent confidence interval [CI], 1.4–3.69;
OR for third tertile, 2.86, 95 percent CI,
1.77–4.67), and ASD diagnosis (OR for
136 MIMS JPOG 2019 VOL. 45 NO. 4 JOURNAL WATCH PEER REVIEWED

second tertile, 2.14, 95 percent CI, 0.93–
5.13 and OR for third tertile, 3.62, 95 per-
cent CI, 1.62–8.6).
There were consistent associations
between acetaminophen burden and
ADHD and acetaminophen burden and
ASD which persisted across strata of po-
tential confounders, such as child age
and sex, preterm birth, substance use,
and maternal indication.
“We identified a significant posi-
tive association between cord plasma
acetaminophen metabolites and the
risk for ADHD diagnosis and the risk for
ASD in childhood,” said Yuelong Ji, a
post-doctoral fellow at Johns Hopkins
Bloomberg School of Public Health in
Baltimore, Maryland, US. “The signif-
icant positive associations between
cord acetaminophen and ADHD and
the cord acetaminophen and ASD were
observed across strata of pertinent co-
variates, including maternal fever dur-
ing pregnancy, which is an indicator for
acetaminophen use”.
metabolites of acetaminophen, support
previous studies regarding the associ-
ation between prenatal and perinatal
acetaminophen exposure and child-
hood neurodevelopmental risk,” said the
researchers.
Ji Y, et al. Association of Cord Plasma Biomarkers of In Utero
Acetaminophen Exposure with Risk of Attention-Deficit/Hyper-
activity Disorder and Autism Spectrum Disorder in Childhood.
JAMA Psychiatry 2019;doi:10.1001/jamapsychiatry.2019.3259.
G ceptionally higher risk of CVD (HR, 3.33,
Gynaecology
High trunk fat mass may
increase CVD risk in
postmenopausal women
regardless of BMI
High levels of trunk fat mass (FM) may be
associated with an increased risk of car-
diovascular disease (CVD)-related events
such as coronary death, nonfatal myocar-
dial infarction, or coronary heart disease
in postmenopausal women with normal
with high trunk FM levels compared with
those with low trunk FM levels (41.80
percent vs 22.99 percent; hazard ratio
[HR], 1.91, 95 percent confidence inter-
val [CI], 1.33–2.74; ptrend<0.001).
In contrast, CVD risk was reduced
more frequently in women with high leg
FM levels than those with low leg FM
levels (52.62 percent vs 37.94 percent;
HR, 0.62, 95 percent CI, 0.43–0.89;
ptrend=0.008).
Women with both high trunk and
low leg FM levels demonstrated an ex-
95 percent CI, 1.46–7.62). “[Of note,]
trunk and leg FM [levels] were contrast-
ingly associated with several biomarkers
implicated in the development of CVD,”
the researchers said.
“Among postmenopausal women
with normal BMI, higher trunk fat was
associated with increased risk of CVD,
while higher leg fat was associated with
decreased risk of CVD, independent-
ly of central adiposity measures,” they
concluded.
Kelli Krallman, et al. Annual Meeting of the American Heart As-
sociation (AHA) Scientific Sessions 2019, November 16-18, Phil-
adelphia, Pennsylvania, US [abstract 206].

body mass index (BMI), according to a re-

“Our findings, the first to investigate
associations between neurodevelop-
mental disabilities with adjustments for
potential covariates and cord plasma
cent study presented at AHA 2019.
Using data from the Women’s Health
Initiative database, the researchers con-
ducted a study involving 2,683 postmen-
opausal women with a normal BMI (18.5
to <25.0 kg/m2) and without a history of
CVD at baseline. Dual energy X-ray ab-
sorptiometry was used to measure the
percentage of regional body FM level,
mainly trunk and leg FM. [AHA 2019, ab-
stract 206]
Over a median follow-up of 17.9
years, a total of 291 incident cases of CVD
were reported.
An increased risk of CVD was sig-
nificantly more common among women
PAEDIATRICS PEER REVIEWED MIMS JPOG 2019 VOL. 45 NO. 4 137

A Review of Growth
Hormone Deficiency
Mehul T Dattani MD FRCP FRCPCH; Neha Malhotra MBBS MD

Growth hormone deficiency (GHD) is a rare but important cause of short

stature in children. It is treatable. However, diagnosis is challenging and
often requires referral to a specialist paediatric endocrinologist to facilitate
testing and the interpretation of results. Careful history and examination with
meticulous auxology data are critical components of the initial evaluation in
clinic. Thereafter, further investigations are required to exclude other causes
of short stature, and to establish the diagnosis. It is a highly variable condition
and to an extent the clinical features depend upon the severity of GHD itself. GH
stimulation tests may be indicated in the short child who is growing slowly and
who has low growth factor concentrations. There is, however, no consensus
with respect to a diagnostic gold standard test for GHD, and this is usually
based upon a combination of clinical, biochemical, and neuroradiological data,
although molecular diagnosis may aid in years to come. This short article gives
an overview of the importance of GHD and offers advice on how to take a history,
conduct and examine, and begin investigation for a child with suspected GHD.
It discusses the known benefits and potential risks of treatment and offers
practical advice for the generalist.
138 MIMS JPOG 2019 VOL. 45 NO. 4
Table 1. Causes of Short Stature
Non-endocrine 1. Chronic systemic diseases (eg, coeliac disease,
renal failure, gastrointestinal disease)
2. Chromosomal and genetic disorders (eg, Turner
syndrome, Prader–Willi syndrome)
3. Skeletal dysplasia
4. Familial short stature
5. Constitutional delay in growth
6. Small for gestational age
7. Psychosocial deprivation
Endocrine 1. Hypothyroidism
2. Pseudohypoparathyroidism
3. Growth hormone deficiency (Tables 1 and 2)
4. GH insensitivity (eg, Laron syndrome due to
GH receptor mutations, STAT5B mutations,
IGF-1 deficiency, IGF-1 receptor mutations,
ALS mutations)
INTRODUCTION
One of the commonest referrals made to pae-
diatric endocrine clinics is for short stature,
with a view to excluding GHD. The causes of
GHD include both congenital and acquired
pituitary disorders. The presentation of GHD
is highly variable, including early neonatal hy-
poglycaemia and later growth failure without
an underlying systemic disorder. It remains
an important diagnosis to exclude, as it is
easily treatable with daily recombinant hu-
man growth hormone (rhGH) injections. Care-
ful history and examination with meticulous
auxology data are critical components of the
initial evaluation in clinic. Thereafter, further
investigations are required to exclude other
causes of short stature, and to establish the
diagnosis.
EPIDEMIOLOGY
Normal growth is the result of the interplay
between multiple factors all acting simultane-
ously. Short stature may be due to non-endo-
crine or endocrine causes (Table 1). The latter
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includes GHD which may be isolated (isolated
GHD or IGHD) or combined with other pitui-
tary hormone deficiencies (multiple pituitary
deficiency or MPHD).
Although rare with a prevalence of
approximately 1:4,000 to 1:10,000 (1–4),
GHD is an important condition warranting
evaluation and management by a paediat-
ric endocrinologist. In approximately half
of the children with GHD (50%), the cause
is unknown (idiopathic GHD).
DEFINITION
GHD, defined as suboptimal GH secretion,
includes a group of disorders with different
aetiologies (Table 2). It may be isolated or
combined with other anterior and/or posteri-
or pituitary hormone deficiencies. Combined
pituitary hormone deficiency is defined as a
deficiency in two or more pituitary hormones.
GHD may be congenital or acquired, sporadic,
or familial.
PATHOGENESIS
Growth hormone (GH) is produced maximally
at night during sleep in a pulsatile fashion from
the somatotrope cells within the anterior pitui-
tary. GH secretion is modulated by stimulatory
GH releasing hormone and inhibitory somato-
statin from the hypothalamus.
The complex pattern of release of these
hypothalamic hormones is believed to result
from the interaction of multiple neurotransmit-
ters and neuropeptides including serotonin,
histamine, norepinephrine, dopamine, acetyl-
choline, gamma-aminobutyric acid (GABA),
thyroid hormone – releasing hormone (TRH),
corticotrophin-releasing hormone (CRH), vas-
oactive intestinal peptide (VIP), gastrin, neu-
rotensin, substance P, calcitonin, neuropeptide
Y, vasopressin, and galanin. The alteration of
GH secretion observed in various physiologi-
cal states (eg, stress, sleep, fasting, hypogly-
caemia, and exercise) is believed to be medi-
ated through these factors.
PAEDIATRICS PEER REVIEWED
GH increases growth by both a direct ac-
tion on the growth plates as well as the pro-
duction of insulin-like growth factors (especial-
ly IGF-1), mainly in the liver. Human GH also
has important effects on the metabolism of
proteins, lipids, and carbohydrates, not only
during childhood, but also throughout adult
life. Inadequate production or insufficient se-
cretion of GH from the anterior pituitary gland
results in short stature.
GHD may present with other pituitary hor-
mone deficiencies when it is referred to as hy-
popituitarism, panhypopituitarism, or MPHD.
The anterior portion of the pituitary gland forms
from Rathke’s pouch around the third week of
gestation, and its development is regulated by
the expression of numerous transcription fac-
tors and signalling molecules; some of these
are required for continued normal function of
the pituitary gland.
SHORT STATURE
There are many causes of short stature. Fa-
milial short stature is the commonest cause,
but a child who is unexpectedly small for their
family requires careful evaluation. Some of the
causes are listed in Table 1 (above). GHD is an
important cause of short stature because, if it
is diagnosed it can be treated. It is not a single
condition. Some of the possible known causes
are summarized in Tables 2 and 3.
CLINICAL COURSE
The clinical course of GHD is highly variable and
depends, to an extent upon the severity of GHD.
It may present in the neonatal period with ne-
onatal hypoglycaemia, microphallus with/with-
out cryptorchidism, and prolonged jaundice. In
affected individuals, birth size is typically with-
in the normal range, although there may be a
reduction of approximately 10% which occurs
typically late in pregnancy. Growth velocity is
reduced during the first year of life in children
with severe GHD with growth failure manifest-
ing by 6 months of age, but the phenotype
MIMS JPOG 2019 VOL. 45 NO. 4 139
Table 2. Causes of Growth Hormone Deficiency
Congenital Genetic (See Table 3)
Associated with structural brain defects:
• Agenesis of the corpus callosum
• Septo-optic dysplasia
• Holoprosencephaly
• Encephalocele
• Hydrocephalus
Associated with midline facial defects:
• Cleft lip/palate
• Single central incisor
• Cornelia de Lange syndrome
• CHARGE syndrome
Acquired causes • Tumours in and around pituitary area (eg,
craniopharyngioma, germinoma)
• Metastatic tumours
• Cystic lesions
• Radiotherapy
• Chemotherapy
• Brain trauma
• Inflammation/infection (eg, sarcoidosis,
Langerhans cell histiocytosis, TB)
• Infiltration
• Pituitary infarction
• Psychosocial deprivation
evolves after 1 year of age in those with milder
GHD.
GHD sometimes remain undiagnosed un-
til later in childhood, when parents or health
workers have concerns regarding physical
growth. The earliest manifestations may be a
reduction in height velocity followed by a re-
duction in height standard deviation score
(SDS) adjusted for mean parental height SDS.
The child’s height SDS will ultimately fall below
-2 SD. The time taken depends on the severity
and duration of GHD. There are some “typi-
cal” clinical features. A child with GHD often
has mid-face hypoplasia, hypotonia, a high-
pitched voice, immature appearance, delayed
140 MIMS JPOG 2019 VOL. 45 NO. 4
Box 1. Consensus Guidelines on Diagnosis of Growth Hormone
Deficiency (Growth Hormone Research Society)
When to consider investigation for GHD:
1. Severe short stature, defined as a height more than 3 SD below the
mean.
2. Height more than 1.5 SD below the mid-parental height.
3. Height more than 2 SD below the mean and a height velocity over
1 year more than 1 SD below the mean for age, or a decrease in
height SD of more than 0.5 over 1 year in children more than 2 years
of age.
4. In the absence of short stature, a height velocity more than 2 SD
below the mean over 1 year or more than -1.5 SD sustained over 2
years.
5. Signs indicative of an intracranial lesion.
6. Signs of MPHD.
7. Neonatal symptoms and signs of GHD (unexplained hypoglycaemia,
prolonged jaundice, clinical appearance suggestive of GHD,
microphallus, and cryptorchidism).
dentition, thin sparse hair, slow nail growth,
and truncal adiposity.
RESPONSE TO TREATMENT
The growth response to rhGH treatment is typ-
ically maximal in the first year of treatment and
then gradually decreases over the subsequent
years of treatment. First year growth response
to rhGH is generally 200% of the pre-treatment
velocity, and after several years, averages 150%
of the baseline. Height improvements of 1 SD
are typically achieved in children with GHD after
2 years of treatment, and between 2 and 2.5 SD
after 5 or 7 years. GH doses are often increased
if catch-up growth is inadequate and/or to com-
pensate for the waning effect of rhGH with time.
It has been suggested that a significant
improvement in HV is seen when rhGH dose
is adjusted based on IGF-1 concentrations. It
is critically important to maximize height with
GH therapy before the onset of puberty. The
earlier the GH is commenced, the more likely
is the child likely to achieve a height that is
appropriate for the target height.
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DIAGNOSIS
Presenting features
Height SDS of less than -2 SDS on the growth
chart or a parent concerned about the child’s
linear growth as compared to his peers should
prompt further evaluation. This should include
a detailed history and physical examination
including auxology and pubertal examination.
This will help direct the course of investiga-
tions and management. The clinical features of
GHD are summarized in Box 1.
History
A detailed family history may point towards a
genetic form of short stature (see Table 3). The
height of the patient needs to be plotted on the
growth chart, together with the MPH (mid-pa-
rental height), having corrected for the height
of the parent of the opposite sex. Neonatal
history of hypoglycaemia and other midline or
craniofacial defects would suggest further in-
vestigations for MPHD, of which GHD is a com-
ponent. Another essential aspect of the history
should include clinical features suggestive of
previous CNS infection, trauma, tumours, or
their treatment including radiotherapy. These
would be most likely to result in multiple pitui-
tary hormone deficiencies. Malnutrition in early
childhood, psychological abuse, and anorexia
in adolescents can also impact GH secretion
from the anterior pituitary, and are important
components of the history. Growth data from
birth onwards form a valuable component of
the history and help identify the pattern of
growth failure. Some of the important ques-
tions are summarized in Table 1.
Examination
Physical examination may reveal certain clinical
clues to the underlying condition such as dys-
morphic features and the presence of midline
craniofacial abnormalities (eg, cleft lip/palate).
The presence of a micropenis with undescend-
ed testes may alert the physician to a diagno-
Table 3. Some Known Genetic Defects of Pituitary Development and their Phenotype

Gene Pituitary deficiencies MRI phenotype Inheritance Other phenotypic features

POU1F1 GH, TSH, and prolactin Small or normally sized anterior pituitary (AP) AR and AD
PAEDIATRICS

PROP1 GH, TSH, LH, FSH, prolactin, and ACTH Variable size AP – may evolve over time AR
HESX1 Isolated GHD through to panhypopituitarism Optic nerve hypoplasia, absent septum AR and AD Developmental delay, visual abnormalities, SOD
pellucidum, ectopic posterior pituitary, small AP
LHX3 GH, TSH, LH, FSH, prolactin. Late ACTH Small, normal, or enlarged AP AR Short neck with limited rotation
LHX4 GH, TSH, ACTH, and gonadotrophin Small AP, ectopic posterior pituitary (PP), AD (variable
PEER REVIEWED

cerebellar abnormalities, corpus callosum penetrance)

hypoplasia
SOX3 Most commonly isolated GHD. TSH, LH, AP and infundibular hypoplasia, ectopic PP, X-linked recessive Learning difficulties
FSH, and ACTH can be affected corpus callosum abnormalities, persistent
craniopharyngeal canal
SOX2 LH, FSH variable GH deficiency AP hypoplasia, optic nerve hypoplasia, AD (usually de novo) Micropenis, anophthalmia, microphthalmia,
septo-optic dysplasia, hypothalamic sensorineural deafness, gastro-intestinal tract defects
hamartoma
GLI2 GH, TSH, and ACTH with variable AP hypoplasia AD Holoprosencephaly, cleft lip/palate, laryngeal cleft,
gonadotrophin deficiencies anophthalmia, postaxial polydactyly, imperforate
anus, renal agenesis
GLI3 GH, TSH, LH, FSH, and ACTH AP hypoplasia AD Pallister-Hall syndrome. Postaxial polydactyly,
hamartoma
OTX2 GH, TSH, LH, FSH, and ACTH Normal or small AP, pituitary stalk agenesis, AD (usually de novo) Cleft palate, microcephaly, bilateral anophthalmia,
ectopic PP, Chiari malformation developmental delay
FGFR1 GH, TSH, LH, FSH, and ACTH Normal or small AP, corpus callosum AD ASD, VSD, brachydactyly, brachycephaly,
agenesis preauricular skin tags, eye abnormalities, seizures
FGF8 GH, TSH, ACTH, gonadotrophin, and ADH Holoprosencephaly, absent corpus callosum, AD or AR
optic nerve hypoplasia
PROKR2 GH, TSH, ACTH, and gonadotrophin Hypoplastic corpus callosum, normal or AD
small AP
ARNT2 GH, TSH, ACTH, and ADH deficiencies Absent PP, thin stalk, thin corpus callosum, AR Microcephaly, prominent forehead, deep set
delayed myelination eyes, retrognathia, hip dysplasia, hydronephrosis,
vesicoureteric reflux, neuropathic bladder
TCF7L1 GH Absent PP, AP hypoplasia, optic nerve AD
hypoplasia, partial agenesis of corpus
callosum, thin anterior commissure
IGSF1 GH (transient/partial), TSH, and prolactin Normal in the majority of cases X-linked recessive Macroorchidism, delay in puberty
RNPC3 GHD Small AP with normal stalk and ectopic PP AR
KCNQ1 GH, ACTH, TSH and gonadotrophin Normal/small AP AR Maternally inherited gingival fibromatosis

Data from Murray PG, Clayton PE. Disorders of Growth Hormone in Childhood. [Updated 2016 Nov 16]. In: De Groot LJ, Chrousos G, Dungan K et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com,
Inc.; 2000.
MIMS JPOG 2019 VOL. 45 NO. 4
141
142 MIMS JPOG 2019 VOL. 45 NO. 4
Table 4. Growth Hormone Stimulation Tests
Stimulatory agent used Dose Timing of GH,
glucose sampling
Insulin tolerance test i.v. 0.05–0.01 U/kg 0, 15, 30, 45, 60, and 90
Arginine HCl i.v. 0.5 g/kg (max 40 g) 0, 30, 60, 90, and 120
Clonidine i.v. 0.15 m g/m 2
0, 30, 60, and 90
Glucagon i.m. 0.1 mg/kg (max 1 mg) 0, 30, 60, 90, 120, 150,
and 180
sis of possible associated hypogonadotropic
hypogonadism.
Pubertal rating (Tanner staging) in ado-
lescents will help determine whether puberty
and sexual maturation have been established.
Constitutional delay in puberty among boys is
a well-recognized cause of short stature which
does not require treatment with growth hor-
mone. On the other hand, a young 10-year-old
girl who has already attained menarche will not
benefit from GH treatment as she is likely to
have a mature skeletal age.
Developmentally, most children with GHD
progress well and attain all milestones appro-
priately, although gross motor skills are often
delayed and muscle tone reduced. Visual in-
attention must be looked for, as nystagmus
could indicate an underlying diagnosis of
septo-optic dysplasia (SOD) with optic nerve
hypoplasia. This is a rare condition character-
ized by the classical triad of optic nerve hypo-
plasia, midline forebrain anomalies including
an absent septum pellucidum or hypoplas-
tic/absent corpus callosum, with structural
and functional abnormalities of the pituitary
gland.
Other causes of short stature should be
excluded before proceeding to testing for GHD
(see under Investigations). Thereafter, it is es-
sential to confirm the diagnosis of GHD further
by Growth Hormone provocative testing and
other investigations including magnetic res-
onance imaging (MRI). A missed diagnosis
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would deprive the child of treatment for a con-
dition which is easily treatable. However, an in-
correct diagnosis of GHD would subject a child
to unnecessary and costly daily injections.
INVESTIGATIONS
Investigations can be divided into:
1. Investigations to help determine identifiable
causes of short stature as guided by history
and physical examination (see Table 4).
2. GH stimulation tests.
3. Radiological and genetic testing.
Initial screening tests for short stature
are fairly extensive. They should include a
full blood count, urea and electrolytes, liver
function tests, calcium, magnesium and phos-
phate, coeliac screen, basal pituitary function
tests including FT4, TSH, early morning corti-
sol, IGF-1, and IGFBP-3, prolactin, and gonad-
otrophins (LH and FSH at the age of puberty)
(see below). Genetic studies should be per-
formed in all girls with short stature to exclude
a diagnosis of Turner syndrome.
A skeletal survey should be performed in
children with disproportion, those with a family
history of skeletal disproportion, and those with
short stature that is disproportionate to that of
the family. Pituitary MRI is required in all patients
confirmed to have GHD in addition to those with
known or suspected intracranial tumours, optic
nerve hypoplasia/septo-optic dysplasia, or oth-
er neurodevelopmental anomalies.
Once other causes of short stature in-
cluding hypothyroidism have been excluded,
testing should proceed with a GH stimulation
test and measurement of IGF-I ± IGFBP-3 con-
centrations.
GROWTH HORMONE STIMULATION
TESTS
The first test of GH secretion used was the in-
sulin tolerance test. Subsequently, a number of
other pharmacological stimuli were identified
including arginine, glucagon, clonidine, pyri-
dostigmine, levodopa, GH-releasing hormone

PAEDIATRICS PEER REVIEWED
(GHRH), and GHRH combined with arginine as
summarized in Table 4. In the UK, the gluca-
gon test and arginine stimulation test remain
the most commonly used in clinical practice.
Some of the more important considerations
with respect to biochemical diagnosis of GHD
are summarized in Box 2.
Current UK guidelines recommend the
use of two pharmacological tests for the diag-
nosis of idiopathic isolated GHD (see Further
reading). This strategy is used to improve di-
agnostic accuracy given the large number of
false positive diagnoses from single stimula-
tion tests in normal children. In those with a
history of defined central nervous system pa-
thology, history of irradiation, genetic defect
known to cause GHD or multiple pituitary hor-
mone deficiency, one GH test will suffice.
Perhaps the most challenging aspect is
that there is little evidence to support the clas-
sically suggested peak GH cut-off value of less
than 10 μg/L that has been set rather arbitrar-
ily. This may lead to misdiagnosis of GHD,
because up to 85% of short pre-pubertal chil-
dren (28 of 33) who were diagnosed with GHD
(peak GH less than 10 μ g/L in 2 provocation
tests) had a normal GH response when retest-
ed 1–6 months later. In the UK, most centres
currently use a GH cut-off of 6–7 μ g/L.
RADIOLOGICAL INVESTIGATION OF
CONFIRMED GROWTH HORMONE
DEFICIENCY
Generally, the severity and duration of GHD af-
fects bone maturation. Bone age is usually as-
sessed using the Greulich and Pyle radiological
atlas and/or the Tanner and Whitehouse (the
TW2) method. X-Ray of the left wrist is a simple
and cost-effective method of estimating bone
age. However, this is of limited benefit and not
easily interpretable below the age of 5 years.
MRI is the most frequently used tech-
nique to visualize hypothalamo-pituitary anat-
omy (see Figures 1–3). Neuroimaging in short
children may rule out a tumour, in particular, a
GROWTH HORMONE DEFICIENCY
MIMS JPOG 2019 VOL. 45 NO. 4 143
Box 2. Biochemical Diagnosis of Growth Hormone Deficiency in
Childhood
• The international standard IS 98/574 has been recommended by the
recent international consensus statement on the standardization of
GH assays.
• These recommendations and the use of monoclonal assays make
it imperative to review the accepted GH cut-off for the diagnosis of
GHD in children.
• In neonates, a single GH measurement of less than 7 µg/L measured
by a highly sensitive human GH-ELISA in dry blood spot samples
would have high sensitivity and specificity for the diagnosis of GHD
in this age group.
• In peripubertal children, the biochemical diagnosis of GHD, with or
without sex steroid priming, remains controversial.
• An increasing BMI in children, even within the normal distribution,
has an impact on stimulated peak GH; the type of secretagogue and
strength of the stimulus are also to be taken into account.
• There is a need for BMI and provocation-test-dependent cut-off
values.
craniopharyngioma or optic nerve glioma. The
most common radiological findings in GHD
children are those of an ectopic or undescend-
ed posterior pituitary gland, anterior pituitary
hypoplasia, and a thin or absent pituitary stalk,
which may also be present in a combination
known as pituitary stalk interruption syndrome
(PSIS). Other abnormalities associated with
GHD include features of septo-optic dysplasia,
corpus callosum hypoplasia, and presence of
an empty sella.
However, many children with idiopathic
GHD show no pituitary abnormalities. Addi-
tionally, it has been demonstrated that those
GHD children with MRI abnormalities have
more severe short stature and younger age at
diagnosis compared with those GHD patients
with a normal pituitary.
GENETIC TESTING
Genetic analysis in patients with GHD is
largely performed on a research basis. The
144 MIMS JPOG 2019 VOL. 45 NO. 4
Abbreviations: AP = anterior pituitary; PP = posterior pituitary; CC = corpus callosum; SP = septum
pellucidum; OC = optic chiasm
Figure 1. MRI showing SOD with absence of the septum pellucidum, hypoplasia
of the optic nerves, and a structurally abnormal pituitary gland (PSIS).
Figure 2. MRI showing craniopharyngioma.
identification of a genetic mutation is par-
ticularly useful in supporting the diagno-
sis in cases of isolated GHD with a normal
pituitary MRI. There are many other genes
associated with GHD along with other pi-
tuitary hormone deficiencies (see Table 2),
which are associated with additional clinical
and radiological features. With the increas-
PAEDIATRICS PEER REVIEWED
Figure 3. MRI showing pituitary stalk-interruption
syndrome: the anterior pituitary is hypoplastic
with an absent stalk and an ectopic posterior
pituitary.
ing clinical availability of genetic technol-
ogies such as whole exome and genome
sequencing, screening for mutations to pro-
vide confirmation of the diagnosis of GHD is
likely to increase.
MANAGEMENT
Human pituitary-derived GH was first used in
children with hypopituitarism over 50 years
ago, and abruptly ceased in 1985, after the
first cases of Creutzfeldt-Jakob disease were
recognized. Since 1986, rhGH has been the
exclusive form of GH used to treat GHD in
most of the world. Once the diagnosis of
GHD has been made, an estimation of bone
age, target adult height (based on mid-pa-
rental height), and sexual maturation rating
in each individual case will help predict the
benefit of GH. At the initiation of GH therapy,
there should be a discussion with the family/
carers about expected outcomes and re-eval-
uation of the treatment decision based on
response.
PAEDIATRICS PEER REVIEWED
Timing of administration
Administration of rhGH in the evening is de-
signed to mimic physiologic rhGH secretion.
Treatment is continued until target adult height
is achieved. The usual site of administration
is the lateral aspect of either side of the thigh
and parents/carers are advised to rotate the
sites on a regular basis. It is important to max-
imize height with GH therapy before the onset
of puberty. Several investigators have advo-
cated delaying puberty or the production of
oestrogen by the use of GnRH analogues and
aromatase inhibitors, respectively, in order to
expand the therapeutic window for GH treat-
ment. However, these are largely experimental
studies and currently, the use of these agents
should not be recommended.
Dose
Even within the cohort of subjects with GHD,
there is a wide response to GH therapy, which
is likely to be due to compliance issues, varia-
bility in the degree of GHD, and in the patient’s
tissue responsiveness to GH. The licensed
dose of GH for GHD is 0.7–1.0 mg/m2/day (23–
39 mcg/kg/day).
Treatment should be discontinued if any
of the following applies:
• 
Growth velocity increases less than 50%
from baseline in the first year of treatment
on optimal GH doses.
• Final height is approached and growth ve-
locity is less than 2 cm in 1 year.
• 
There are insurmountable problems with
adherence.
• Final height is attained.
In Prader–Willi syndrome, which may
be associated with GHD, evaluation of re-
sponse to therapy should also consider body
composition.
Treatment should not be discontinued by
default. The decision to stop treatment should
be made in consultation with the patient and/or
carers either by a paediatrician with specialist
expertise in managing growth disorders in chil-
MIMS JPOG 2019 VOL. 45 NO. 4 145
dren, or an adult endocrinologist, if care of the
patient has been transferred from paediatric to
adult services.
Stopping GH at least 1 month prior to re-
testing in the transition period was practiced by
92% of respondents in one audit, which is the
current advice based on the above-referenced
reviews. Insulin, glucagon, GHRH–arginine,
and arginine stimulation tests are suggested
for use in the transition period.However, the
issue is further complicated by different GH
peak “cut-offs” recommended for each test
which can also be dependent on BMI.
Advancements in recent technology have
made it more practicable for parents and
young people to administer growth hormone
easily at home. In the past few years, improve-
ment in the design of GH pen devices has led
to improved compliance in the paediatric and
adolescent cohort with GHD. Careful evalu-
ation of growth together with measurement
of biomarkers such as IGF-1 in the first few
months after commencing treatment is essen-
tial in order to optimize treatment and to make
any necessary dose adjustments. The long-
term outcomes and safety of GH treatment
have been under scrutiny recently. Although
generally considered safe and effective ther-
apy in children and young persons with GHD,
there is no doubt that careful monitoring of the
use of rhGH is indicated in order to promote
optimal management.
PROGNOSIS
The overall prognosis for the treatment of GHD
in childhood is excellent, with the majority of
children having a good height prognosis. GH
is generally safe and well-tolerated, when used
in appropriate doses in children with GHD.
LONG-TERM SAFETY OUTCOME OF
rhGH TREATMENT
The Safety and Appropriateness of Growth
hormone treatments in Europe (SAGhE), a
large study aiming to evaluate the long-term
146 MIMS JPOG 2019 VOL. 45 NO. 4 PAEDIATRICS PEER REVIEWED

Table 5. Summary of Follow-up Evaluation

Parameters Assessment
Born age 12-month interval to assess the predicted height
Thyroid function test 12-month interval, or immediately, if growth velocity decreases
Serum IGF-1 and IGBP-3 12-month interval. Aim is to maintain IGF-1 in the mid-normal range, considered the
“safe” region. Concentrations do not necessarily correlate with growth velocity
Metabolic panel, early am cortisol, FBC, HbA1C 12-month interval
Dose adjustment Weight-adjustment, growth response, pubertal stage, IGF-1 concentration and
comparison to predicted height
Adverse events Every visit

Data from Berrin Ergun-Longmire, MD, FAA and Michael P Wajnrajch, MD, MPA 2018. Growth and Growth Disorders. Endotext.

health of about 30,000 patients treated with
rhGH during childhood in the 1980s and 1990s
in eight European countries, as a means of as-
sessing the long-term safety of childhood GH
treatment.
The French component of the SAGhE
study reported that patients treated in France
showed an increase in the SMR (1.33), with
most deaths occurring in the group of idio-
pathic GHD. Interestingly, the increase in all-
cause mortality was associated with higher
rhGH doses of more than 50 mcg/kg/d, but
not with the duration of total rhGH exposure.
There was an increased mortality from cardi-
ovascular events, cerebrovascular haemor-
rhage, and bone tumours. The release of these
data caused major concerns worldwide (see
Further reading).
However, in contradiction to the French
SAGhE data, the results reported by the SAGhE
cohorts of 2,543 patients from Belgium, the
Netherlands, and Sweden were largely reas-
suring. In a preliminary report, the majority of
deaths (16 of 21; 76%) were caused by acci-
dents or suicide. Of the five patients who died
from an underlying medical disorder, no death
was caused by cancer or cardiovascular dis-
ease, and none of these patients were treated
with a daily GH dose exceeding 0.036 mg/kg.
Overall, these data stress the importance of
studies of long-term outcomes after childhood
treatment and highlight the importance of the
EU SAGhE study and the need for similar on-
going studies.
Albertsson-Wikland, et al, recently ex-
amined mortality in 3,847 patients with IGHD,
ISS, or SGA treated with GH between 1985
and 2010. There was no excess mortali-
ty compared to the wider Swedish popula-
tion once appropriate corrections had been
made for birth characteristics and congenital
anomalies.
METABOLIC EFFECTS OF
RECOMBINANT HUMAN GROWTH
HORMONE
All published studies agree that rhGH does not
affect the risk of developing type 1 diabetes
mellitus (standard incidence ratio [SIR] of 0.9–
1.4). However, the reported overall incidence
of type 2 diabetes mellitus (T2DM) ranges from
14–34.4 per 100,000 patient-years. Although it
is known that reduced insulin sensitivity asso-
ciated with rhGH treatment is reversible when
treatment is discontinued, stopping rhGH
may not always reverse T2DM, indicating that
pre-existing risk factors are important for mod-
ulating the risk of developing T2DM.
PAEDIATRICS PEER REVIEWED
RISK OF CANCER
The rhGH treatment does not increase the risk
of primary malignancy in children and adoles-
cents without preceding risk factors. The re-
sults of a recent study conducted on a cohort
of 23,984 patients treated with rhGH in eight
European countries since this treatment was
first used in 1984 do not generally support a
carcinogenic effect of rhGH. However, the un-
explained trend in cancer mortality risk in rela-
tion to GH dose in patients with previous can-
cer, and the indication of possible effects on
bone cancer, bladder cancer, and Hodgkin’s
lymphoma risks need further investigation.
FOLLOW-UP
Once treatment has commenced, monitoring
by an experienced paediatric endocrinolo-
gist is required at 6–12 monthly intervals (see
Table 5).
FURTHER READING
1. Albertsson-Wikland K, Martensson A, Savendahl L, et al. Mortality
is not increased in recombinant human growth hormone-treated
patients when adjusting for birth characteristics. J Clin Endo-
crinol Metab 2016; 101: 2149–59, https://doi.org/10.1210/jc.2015-
3951.
2. Baumann G. Growth hormone heterogeneity: genes, isohormones,
variants and binding proteins. Endocr Rev 1991; 12: 424–429.
3. Bell J, Parker KL, Swinford RD, Hoffman AR, Maneatis T, Lippe B.
Long-term safety of recombinant human growth hormone in children.
J Clin Endocrinol Metab 2010; 95: 167–177.
4. Carel JC, Ecosse E, Landier F, et al. Long-term mortality after recom-
binant growth hormone treatment for isolated growth hormone de-
ficiency or childhood short stature: preliminary report of the French
SAGhE study. J Clin Endocrinol Metab 2012; 97: 416–425.
5. Chesover AD, Dattani MT. Evaluation of growth hormone stimulation
testing in children. Clin Endocrinol 2016; 84: 708e14. https://doi.
org/10.1111/cen.13035.
6. Cutfield WS, Wilton P, Bennmarker H, et al. Incidence of diabetes
mellitus and impaired glucose tolerance in children and adoles-
cents receiving growth-hormone treatment. Lancet 2000; 355:
610–613.
7. Grote Floor K, Oostdijk Wilma, De Muinck Keizer-Schrama Sabine
MPF, et al. The diagnostic work up of growth failure in secondary
healthcare. BMC Pediatr 2008; 8: 21, https://doi.org/10.1186/1471-
2431-8-21.
8. Growth Hormone Research S. Consensus guidelines for the diagno-
sis and treatment of growth hormone (GH) deficiency in childhood
and adolescence: summary statement. J Clin Endocrinol Metab 2000;
85: 3990–3993.
9. Human growth hormone (somatropin) for the treatment of growth fail-
ure in children. 2010. NICE, http://www.nice.org.uk/guidance/TA188.
10. Kyriaki S, Alatzoglou E, Webb A, Le Tissier P, Dattani MT. Isolated
growth hormone deficiency (GHD) in childhood and adolescence:
recent advances. Endocr Rev 2014; 35: 376–432, https://doi.
org/10.1210/er.2013-1067.
11. Lindsay R, Feldkamp M, Harris D, Robertson J, Rallison M. Utah
Growth Study: growth standards and the prevalence of growth hor-
mone deficiency. J Pediatr 1994; 125: 29e35 [PubMed:8021781].
12. Loche S, Bizzarri C, Maghnie M, et al. Results of early re-evaluation
of growth hormone secretion in short children with apparent growth
hormone deficiency. J Pediatr 2002; 140: 445–449.
MIMS JPOG 2019 VOL. 45 NO. 4 147
Practice Points
• Growth should be monitored during childhood, as this could be the
only clue pointing towards an underlying diagnosis of GHD.
• GH is vital not only for physical growth but also for maintaining
healthy body composition.
• GHD is easily treatable and therefore should not be missed. Early
treatment is warranted to achieve better long-term outcomes in
terms of growth.
• One should investigate the cause of GHD as well as it could hint
towards an intracranial lesion or be associated with the risk of
MPHD.
• Diagnosis is based upon the use of growth hormone stimulation
tests; in the UK, most centres currently use a GH cut-off of 6–7 μg/L.
• Growth hormone is usually administered subcutaneously on a daily
basis by a pen device. Parents should be educated with respect to
the appropriate mode of administration of the rhGH, and counselled
with respect to potential adverse effects before commencing
treatment.
• End of growth evaluation is necessary to decide if the young
adolescent qualifies for adult GHD before discontinuing GH.
Acknowledgement
MTD receives support from Great Ormond Street Hospital Children’s
Charity and the NIHR GOSH BRC.
13. Murray PG, Dattani MT, Clayton PE. Controversies in the diagnosis
and management of growth hormone deficiency in childhood and
adolescence. Arch Dis Child 2016; 101: 96–100.
14. Oostdijk W, Grote FK, de Muinck Keizer-Schrama S, Wit JM. Diag-
nostic approach in children with short stature. Horm Res 2009; 72:
206e17. https://doi.org/10.1159/000236082.
15. Sheppard MC. Growth hormone assay standardization: an important
clinical advance. Clin Endocrinol (Oxf). 2007; 66: 157–161. https://
doi.org/10.1111/j.1365-2265.2007.02703.x.
16. Stanley T. Diagnosis of growth hormone deficiency in childhood. Curr
Opin Endocrinol Diabetes Obes 2012; 19: 47–52.
17. Swerdlow AJ, Cooke R, Beckers D, et al. Cancer risks in patients
treated with growth hormone in childhood: the SAGhE European co-
hort study. J Clin Endocrinol Metab 2017; 102: 1661–1672.
© 2019 Elsevier Ltd. All rights reserved. Initially published in Paediatrics
and Child Health 2018;29(5):197–204.
About the authors
Mehul T Dattani is a Professor of Paediatric Endocrinology, Genetics and
Genomic Medicine Programme at UCL Great Ormond Street Institute of
Child Health, London, UK. Conflicts of interest: none declared.
Neha Malhotra is a Clinical Fellow in Pediatric Endocrinology at Great Or-
mond Street Hospital for Children, London, UK. Conflicts of interest: none
declared.
148 MIMS JPOG 2019 VOL. 45 NO. 4 OBSTETRICS PEER REVIEWED

Vaccinations in Pregnancy
Jennifer Hogan MD MRCOG MRCPI PDip Clin Ed; Sarah French BM BCh MA MRCP DTM&H; Lucy Mackillop BM BCh MA FRCP

Vaccinations are a cost-effective means of preventing disease. They may be

recommended primarily for maternal benefit or for prevention of intrauterine
foetal or early neonatal infection. Increasingly, they are a recognized
technique of providing protection through passive immunity to the newborn
infant. The MBRRACE-UK 2014 report, covering 2009–2012 during the H1N1
epidemic, demonstrated that one in 11 maternal mortalities were directly from
influenza virus. More than half of these could have been prevented by the flu
vaccine in pregnancy. Research is ongoing for the development of additional
vaccines for infections that can cause detrimental effects to pregnant women
and their infants. Theoretical concerns regarding adverse effects to the
foetus and lack of efficacy have, in general, not been confirmed by clinical
evidence. Nevertheless, live attenuated vaccines remain contraindicated due
to risk of foetal infection. As with any clinical decision, advice on antenatal
vaccination should be based on the balance of risks and benefits to the
mother and foetus. This article aims to guide such decisions by discussing the
issues surrounding commonly used vaccines and presenting current UK
guidelines.
OBSTETRICS PEER REVIEWED
INTRODUCTION
Vaccination is one of the most cost-effective tech-
niques available in preventative medicine and
has the potential to reduce neonatal and ma-
ternal morbidity and mortality. As with any other
intervention during pregnancy, vaccination pro-
grammes may be complicated by safety, social,
and organizational concerns. For many medical
conditions, pregnant women are consistently un-
der treated or under investigated, largely due to
both physician's and patient's concerns of the po-
tential harm to the foetus. As vaccines are used
for prevention of diseases, there is often the mis-
conception that vaccines should be deferred until
after pregnancy. However, women and their ba-
bies can come to harm during pregnancy or in the
post-partum period if they develop diseases that
could have been prevented by safe vaccination.
Despite widespread educational campaigns to
encourage certain vaccinations in pregnancy, up-
take still remains suboptimal. This article aims to
provide up-to-date guidance for practitioners ad-
vising women on vaccination during pregnancy.
GENERAL PRINCIPLES
Purpose of immunization
The rationale for vaccinations in pregnancy may
be either protection of the mother or the foetus/
neonate or both. Access to healthcare provides
an opportunity to identify and treat women with
inadequate immunization status for vaccinations
unrelated to pregnancy. Vaccination may also be
indicated to protect against pathogens which are
particularly severe during pregnancy. By prevent-
ing maternal infection, vaccinations may protect
the foetus from intrauterine infections and their po-
tentially teratogenic consequences. Early neona-
tal vaccination promotes a variable response and
so maternal vaccination is an accepted technique
of passively immunizing the newborn at an age
when vaccination may be unsuccessful. By delay-
ing neonatal vaccination until it will be more effec-
tive and simultaneously immunizing the mother,
there may also be cost savings.
MIMS JPOG 2019 VOL. 45 NO. 4 149
Safety
There is growing safety data on vaccination in preg-
nancy with vaccines such as those for influenza
and pertussis vaccine in widespread use in recent
years. Traditionally, manufacturers were reluctant
to include pregnant women in clinical trials for
fear that the trial would implicate their vaccine in
the normal foetal loss rate. Most older data used
to guide women and clinicians are the product of
vaccine registries which collated information from
women receiving the vaccine inadvertently during
pregnancy. Whilst providing reassurance, these
lacked the rigorous control of a clinical trial. With re-
cent recommendations of vaccinating all pregnant
women with the influenza and pertussis vaccines,
there is a growing body of reassuring safety data.
Live attenuated vaccines are contraindicated
in pregnancy due to theoretical risk of transmission
across the placenta. Administration of vaccines,
live or otherwise, however has not been associ-
ated with adverse clinical outcomes, except in one
Brazilian study of inadvertent maternal rubella vac-
cination. This found a greater rate of prematurity
and low birth weight in neonates where there was
proven transplacental transfer of the attenuated vi-
rus. As the risk of adverse outcomes appears to
be low, live vaccines may occasionally be recom-
mended for an individual if the disease risk is high.
Women who receive live vaccines should be
counselled to avoid pregnancy from 4–12 weeks
following inoculation, but should a vaccine be re-
ceived inadvertently, this is not an indication for
termination. Clinicians are not advised to routine-
ly test for pregnancy prior to vaccine administra-
tion, provided the woman is confident that she is
not pregnant.
Yellow fever and smallpox are the only
vaccines contraindicated post-partum or when
breastfeeding. Smallpox, however, is no longer
recommended for the general public and is only
for researchers who work with smallpox.
Efficacy
Pregnancy is a time of immunomodulation and
concerns exist about the ability to mount an
150 MIMS JPOG 2019 VOL. 45 NO. 4 OBSTETRICS PEER REVIEWED

Table 1. UK Routine Vaccination Schedule IgG2 and so vaccines that promote the former
response will result in better protection of the
neonate. IgG1 antibodies tend to be induced
Age Vaccine
by protein antigens, whereas polysaccharide
2 months DTaP/IPV/Hib/HepB (6 in 1)
antigens promote an IgG2 response. Conju-
Pneumococcal
Rotavirus gate vaccines may therefore favour an IgG1 re-
Men B sponse and provide better neonatal protection.
3 months DTaP/IPV/Hib/HepB (6 in 1) Maternal factors that may influence placental
Rotavirus transfer of IgG include placental abnormalities,
4 months DTaP/IPV/Hib/HepB (6 in 1) such as those caused by malaria or HIV, which
Pneumococcal reduce antibody transfer.
Men B
Some pregnant women may be taking im-
12–13 months Hib/Men C
MMR munomodulatory medication for medical condi-
Pneumococcal booster tions such as inflammatory bowel disease. They
Men B may have reduced seroconversion rates and im-
2–8 years (annual) Influenza mune responses to vaccines because of these
Pre-school (3 yrs and 4 MMR medications. They should still receive the same
months) DTaP/IPV or DTaP/IPV (4 in 1) vaccines as other pregnant women (live vaccines
12–14 years (girls only) HPV (2 doses within 12 months) contraindicated). The vaccine may have reduced
14 years Td/IPV (3 in 1) efficacy which the clinician should be mindful of.
MenACWY Neonates that are exposed in utero to biologics
65 and over Influenza (annual) should not receive live attenuated vaccines for
Pneumococcal
the first 6 months of life. They can receive other
70 years Shingles vaccines safely. Therefore, with regards to rou-
Boosters Tetanus: Every 10 years or upon tine vaccinations, this means the avoidance of
sustaining a soil contaminated
bacillus Calmette-Guerin (BCG) and rotavirus
wound. Five doses should provide
lifetime protection. vaccinations.

IPV: Every 10 years. Five doses

should provide lifetime protection.
Abbreviations: DTaP = diphtheria, tetanus, and acellular pertussis; IPV = inactivated polio
vaccine; Hib = haemophilus influenzae type B; HepB = hepatitis B; Men B = meningitis B;
Men C = meningitis C; MMR = measles, mumps, and rubella; HPV = human papilloma virus;
Td = tetanus and diphtheria; MenACWY = meningitis A, C, W, and Y. BCG vaccine from birth
for high risk groups.
adequate vaccine response during pregnancy.
So far, the evidence does not support this hy-
pothesis. It has been shown that IgG is active-
ly transported across the placenta primarily in
the third trimester, providing the neonate with
protective levels of antibody, whereas T cell im-
munity does not appear to be transferred. The
efficacy of antibody transfer is affected by many
variables. In terms of the vaccine itself, pla-
cental transport favours IgG1 antibodies over
Timing (Table 1)
Preconception vaccination is optimal, providing
the benefits of vaccination without any theoret-
ical risk to the foetus. Unfortunately, as at least
40% of UK pregnancies are unplanned, this is
often not feasible and the first clinical interaction
is usually once conception has occurred. A de-
cision then needs to be made whether to vacci-
nate during pregnancy or wait until post-partum.
The key deciding factor in this situation should
be whether the woman or offspring is at high risk
of the infectious agent during the pregnancy or
puerperium. If not, the full maternal benefit of
vaccination can be gained by post-partum ad-
ministration without any potential risk posed by
pregnancy. Loss to follow-up may, however, be
high (Table 1).
OBSTETRICS PEER REVIEWED
Should the balance of risks favour antenatal
vaccination, then there is the question of optimal
timing. The first trimester is the time of organogen-
esis and has the highest teratogenic risk, so should
be avoided if possible. It is also the time of great-
est foetal loss, so interventions in this period risk
implication in unrelated adverse outcomes. If the
primary purpose is prevention of maternal disease,
administration should occur as soon as possible
after the commencement of the second trimester.
In situations where the main driver is foetal protec-
tion, the dynamics of placental immunoglobulin
transfer must be considered. As pregnancy pro-
gresses, active transport of maternal antibod-
ies increases such that at 33 weeks’ gestation,
foetal levels match those of the mother and by
term they exceed them. About 30–32 weeks is
considered optimal for vaccination, marrying the
maximal immune response at 2 weeks post-inoc-
ulation with a time of efficient placental transfer,
whilst allowing leeway for premature delivery.
VACCINATIONS WITH SPECIFIC
RELEVANCE TO PREGNANCY
(Table 2)
Influenza
Influenza in pregnancy and post-partum has a
higher morbidity and mortality than in the gener-
al population, especially during the third trimes-
ter. MBRRACE-UK, the confidential enquiry into
maternal mortality, reported that one in 11 mater-
nal deaths from 2009–2012 were directly caused
by influenza infection in pregnancy. At least half
of these could have been prevented by influenza
vaccination in pregnancy.(Table 2)
Influenza vaccination has been recom-
mended in the UK for all pregnant women since
2010, for both maternal and foetal benefit. It may
be given in any trimester and should be admin-
istered post-partum to those who did not receive
it antenatally. Current influenza vaccine uptake
rates during pregnancy in the UK are still subop-
timal but are improving (increased from 44.9% in
2016–2017 to 47.2% in 2017–2018).
MIMS JPOG 2019 VOL. 45 NO. 4 151
Two types of influenza vaccines are avail-
able: inactivated intramuscular vaccine (trivalent
or quadrivalent), which is recommended, and a
live attenuated intranasal vaccine that is contrain-
dicated. The inactivated vaccine has been used
in pregnancy for many years, with extensive in-
vestigation not revealing any link to foetal or ma-
ternal complications. In women who received the
intranasal vaccine inadvertently, there have been
no reported adverse events. Neither vaccine is
contraindicated in breastfeeding or in household
contacts of pregnant women, although clinicians
often avoid the live vaccine post-partum due to
theoretical risks of viral shedding.
Vaccination is also important for neonatal
protection. Infants under 6 months have the high-
est rate of hospitalization and death from influen-
za. No vaccine is licensed for this group, leav-
ing them reliant on passive protection from their
mothers. Maternal immunization is recommended
to reduce the incidence of neonatal influenza with
protection lasting up to 6 months. The majority of
infantile influenza originates from household con-
tacts, so vaccinating the mother will have a dual
effect by reducing maternal disease and hence in-
fant pathogen exposure. Some argue for vaccina-
tion of all close contacts of infants for this reason:
a technique known as cocooning; but this is not
currently common practice in the UK.
The influenza vaccine is recommended in
each pregnancy as a slightly different vaccine is
manufactured every year to reflect the predicted
strains of influenza for the coming flu season.
Most years, the influenza vaccine is thought to
be about 50% effective due to varying strains of
influenza causing the illness. Some years, the flu
vaccine is not an effective match to the actual
influenza virus causing the flu illness (due to an-
tigenic drift of the virus), so healthcare workers
still need to be vigilant for signs of influenza in
vaccinated women.
Pertussis
In the 1950s, routine childhood vaccination was
introduced and there was a dramatic reduction
152 MIMS JPOG 2019 VOL. 45 NO. 4 OBSTETRICS PEER REVIEWED

Table 2. Summary of Vaccinations in Pregnancy

Vaccine Type Safety Comments

Vaccines with specific relevance to pregnancy
Influenza Inactivated (intramuscular) No evidence of adverse outcomes Recommended for all pregnant
Live attenuated (intranasal) Contraindicated women in any trimester.
Pertussis Given as Boostrix-IPV® (Diphtheria and No evidence of adverse outcomes Recommended for all
tetanus toxoids, acellular pertussis, and pregnant women between 16
inactivated poliomyelitis) and 32 weeks during vaccine
programme.
Tetanus and Toxoids No evidence of adverse outcomes Give as per non-pregnant
diphtheria women.
Exchange one dose in later
pregnancy for Boostrix-IPV®.
MMR Live attenuated Contraindicated Give pre-conceptually if
possible.
All pregnant women should
have rubella IgG measured
and be vaccinated post-
partum if nonimmune.
Varicella Live attenuated Contraindicated
HPV Inactivated No evidence of adverse outcomes Not recommended
Vaccines where indications are unchanged in pregnancy
Pneumococcal Polysaccharide No evidence of adverse outcomes
Hib Conjugate No evidence of adverse outcomes
Meningococcal C Conjugate No evidence of adverse outcomes
Polysaccharide Insufficient data but low theoretical risk
Meningococcal B Recombinant Insufficient data but low theoretical risk
Hepatitis A Inactivated Insufficient data but low theoretical risk
Hepatitis B Recombinant No evidence of adverse outcomes Consider accelerated course
in high-risk groups.
BCG Live attenuated Contraindicated
Anthrax Live attenuated Contraindicated
Inactivated Contraindicated for prevention
Advised post-exposure
Travel vaccines
Polio Inactivated Some theoretical safety concerns but Exchange one dose in later
UK guidelines recommend pregnancy for Boostrix-IPV®.
Live attenuated Contraindicated
Rabies Inactivated No evidence of adverse outcomes
Typhoid Inactivated Insufficient data but low theoretical risk
Live attenuated Contraindicated
Japanese Inactivated Insufficient data but low theoretical risk
encephalitis
Plague Inactivated Insufficient data but low theoretical risk
Cholera Inactivated Insufficient data but low theoretical risk
Yellow fever Live attenuated Low rate foetal infection from Risk of disease usually
vaccination but no evidence of major outweighs risk of vaccine so
adverse outcomes recommended on travel to
endemic area.
Not recommended if
breastfeeding.
OBSTETRICS PEER REVIEWED
in cases of pertussis to a nadir in the late 1970s.
Since then, case numbers have steadily increased
and, in 2012, there was a pertussis outbreak. In
the UK, there were nearly 10,000 cases (which is
more than 10 times than previous years) with in-
fants under 3 months most at risk. In 2013 and
2014, case numbers continued to be high and it
was recommended that the temporary vaccina-
tion programme in pregnancy be extended for
at least another 5 years. Infants under 3 months
are too young to be protected by their routine
vaccinations, which are given at 2 months when
their immune system is mature enough to mount
a sufficient response. The vast majority of deaths
during the 2012 pertussis outbreak were in infants
younger than 3 months. A large observational
study of pregnant women vaccinated since the
start of the outbreak showed no increase in preg-
nancy adverse outcomes. In the first year of the
pertussis vaccine programme in the UK, the risk of
pertussis in infants less than 3 months born to vac-
cinated mothers was reduced by more than 90%.
Women should receive a single pertussis
vaccination during pregnancy. Antipertussis
antibodies have been shown to decline after 1
year so the vaccine is recommended in each
pregnancy. The Department of Health advise
vaccination between 16 and 32 weeks’ gesta-
tion. Women may be vaccinated after 32 weeks
but this may not offer as a high level of passive
protection to the baby. Pertussis vaccination
may safely be given with the influenza vaccine,
regardless of previous immunization status and
women should be warned that cumulative doses
increase the likelihood of injection site reactions
and fever. Should vaccination during the preg-
nancy not be possible, it should be performed
post-partum. As there is no exclusive pertussis
vaccination, the vaccine used in UK adults since
2014 is Boostrix-IPV which also protects against
®
diphtheria, tetanus, and polio (dTAp/IPV). With
maternal pertussis vaccination, the infant gains
passive immunity from immunoglobulin transfer
across the placenta. Protection by cocooning
also occurs with maternal vaccination as infant
MIMS JPOG 2019 VOL. 45 NO. 4 153
pathogen exposure is reduced through close
contact immunization. The USA currently rec-
ommends immunization of all close contacts in
addition to the maternal vaccination programme,
but this advice has not been adopted in the UK.
Several studies have shown blunted pertussis
antibody production at 2, 3, and 4 months following
active immunization to infants of mothers vaccinat-
ed in pregnancy. It is not clear, however, how close-
ly antibody levels correlate with clinical protection
and ongoing studies are not sufficiently powered
to assess clinical outcomes. Current evidence sug-
gests a short blunting of the infant response, but
the benefit of protection in neonates outweighs
possible increased risk later in infancy, when the
burden of mortality is lower. A mathematical mod-
el with a conservative estimate of 20% efficacy of
maternal antibodies and a generous estimate of
60% risk increase later in infancy due to blunting
still found vaccination during pregnancy to be more
cost-effective than post-partum vaccination.
Tetanus
Neonatal tetanus accounts for a large, though
happily diminishing, global health burden and
has an untreated mortality approaching 100%.
In response to neonatal tetanus deaths reaching
6.7 per 1,000 live births, the World Health Assem-
bly prioritized elimination of this disease in 1989,
and in 1999, the WHO launched the Maternal
and Neonatal Tetanus Elimination Initiative. Since
then, there has been a 96% reduction in neonatal
cases as per WHO 2015 estimates. Eradication is
impossible due to environmental spores, so the
target is for elimination of the disease; defined as
less than one case per 1,000 live births. Fourteen
countries still had this to achieve in March 2018;
predominantly in Sub-Saharan Africa and Asia.
Neonatal and maternal tetanus is most
commonly contracted through unhygienic birth
practices or poor umbilical cord care and so the
WHO has focused on these areas, as well as ro-
bust vaccination programmes. Maternal tetanus
antibodies are placentally transferred, providing
protection to the neonate until their active immu-
154 MIMS JPOG 2019 VOL. 45 NO. 4
nization at 2 months. Protection is sufficient even
with vaccination prior to conception. Millions of
doses have been administered worldwide with no
evidence of increased risk to the mother or foetus.
In the UK, if a woman is up to date with teta-
nus immunizations, no action is required during
pregnancy. Currently, however, all pregnant wom-
en should receive tetanus vaccination as a by-
product of the pertussis vaccination programme,
which uses Boostrix-IPV®: a pertussis, polio, teta-
nus, and diphtheria combination vaccine. Should
a woman be due to her tetanus booster or require
one for wound-management purposes, this should
be given in the same way as for any adult. During
the temporary pertussis vaccination programme,
however, the Boostrix-IPV vaccine should be used
®
in preference to the usual combination vaccine of
tetanus, diphtheria, and polio, ensuring protection
against pertussis and convenience for the woman
by minimizing the number of injections required.
For the reasons described above, Boostrix-IPV®
should ideally be given between 16 and 38 weeks
and may be delayed until this time if safe to do
so. Insufficiently, vaccinated women with high-risk
wounds should receive Boostrix-IPV®, with or with-
out immunoglobulin, immediately regardless of
gestation. Women with unknown or no tetanus im-
munization, should receive the routine three-dose
course of vaccinations and those with incomplete
vaccination should complete the course but do not
need to restart it. Again, one of the doses should
be replaced with Boostrix-IPV®, preferably between
16 and 38 weeks, to provide pertussis protection.
In the developing world, guidelines differ
with the WHO recommending two doses given
one month apart in the first pregnancy, the third
dose given at least 6 months later and then one
dose in each subsequent pregnancy (or intervals
of at least 1 year) to a total of five doses. The first
two vaccinations provide over 80% protection
against neonatal tetanus.
Measles, mumps, and rubella
Women in the UK should have been fully im-
munized against measles, mumps, and rubella
OBSTETRICS PEER REVIEWED
(MMR) in childhood, with the two doses of vac-
cine providing lifelong immunity. Whilst vaccina-
tion had reduced the incidence of these condi-
tions in the UK, unfounded publications linking
the vaccine to autism decreased vaccine uptake
and has led to resurgence of these diseases.
There was a sharp rise in the number of measles
cases in the UK from 2001–2013 with a decrease
in numbers after this. However, the case num-
bers were high again in 2018 (with 913 labora-
tory confirmed cases).
All three diseases are associated with ad-
verse foetal outcomes; measles increases the
risk of prematurity, miscarriage, and possibly
stillbirth. First trimester mumps can lead to intra-
uterine death. In addition to miscarriage and foe-
tal death, the foetuses of women infected with ru-
bella before 20 weeks’ gestation have a 20–85%
risk of congenital rubella syndrome: a devastat-
ing constellation of auditory, visual, cardiac, and
neurological abnormalities. There is no known
effective preventative treatment for congenital
rubella syndrome in women infected with rubella
during pregnancy. In the mother, measles may
also be more severe in pregnancy and could de-
velop into a potentially fatal pneumonitis.
For these reasons, it is imperative that,
whenever possible, pregnant women have immu-
nity to these diseases. Unfortunately, MMR vac-
cine is contraindicated in pregnancy as it is a live
attenuated vaccine. It is therefore highly recom-
mended that women planning a pregnancy have
IgG antibody titres measured and are vaccinated
prior to conception if non-immune. Women who
receive vaccination should be advised to wait for
28 days before trying to conceive. Women are
routinely tested for immunity to rubella in early
pregnancy and those with inadequate immunity
are advised to avoid contact with those with ru-
bella and to receive post-partum vaccination.
Although the vaccine is contraindicated in
pregnancy and there is evidence of placental
transfer of the attenuated virus, a large number of
women have been monitored following inadvert-
ent vaccination with no evidence of congenital
OBSTETRICS PEER REVIEWED
rubella syndrome. Pregnant women who receive
the vaccine should therefore be reassured that
termination of pregnancy is not necessary. The
attenuated virus may be transmitted in breast-
milk, but this does not cause significant clinical
disease and is routinely recommended post-par-
tum for women with insufficient immunity. The
virus is not shed after vaccination and so close
contacts of pregnant women may be immunized
as normal.
Varicella zoster
Chickenpox infection in pregnancy carries both
maternal and foetal risks. For the mother, the
risk of pneumonitis and other complications are
increased, and for the foetus, there is a risk of
congenital varicella syndrome if infection oc-
curs before 28 weeks. Compared with rubella,
this congenital syndrome is much rarer and con-
sists of segmental areas of skin deformity, limb
hypoplasia, neurological, and ophthalmological
abnormalities. Should maternal varicella occur
in the perinatal period, there is a risk of severe
neonatal varicella with a high mortality rate.
Varicella vaccination does not form part of
the routine UK immunization programme, but the
vast majority of adults have natural immunity from
childhood infection. The vaccine is live attenuat-
ed and hence is contraindicated in pregnancy.
Preconception consideration of vaccination is
therefore recommended by the Royal College of
Obstetricians and Gynaecologists. Immunity can
be assessed by a history of chickenpox which
is 97–99% predictive of protective antibodies. In
women without a definite history of the disease,
IgG can be measured and, if seronegative, pre-
conception vaccination considered, with two
doses 1 month apart. UK guidelines suggest de-
laying pregnancy for 3 months post-vaccination,
whereas in the USA, 1 month is recommended.
If the vaccine be administered during preg-
nancy or in the preceding 3 months, no interven-
tion is needed. Despite theoretical concerns, the
vaccine registry has not demonstrated any link
with adverse outcomes, although the data set is
MIMS JPOG 2019 VOL. 45 NO. 4 155
small. Recently vaccinated individuals rarely trans-
mit the virus to close contacts, and the theoreti-
cal risk of doing so is outweighed by the reduced
chance of wild type transmission. Contacts of
pregnant women may therefore be vaccinated as
normal, but should be warned to avoid high risk
groups (non-immune pregnant women, infants,
immunocompromised people) should they devel-
op a varicella-like rash, when the risk of transmis-
sion is higher.
Nonvaccinated women exposed to varicella
during pregnancy should be tested for IgG and
should receive varicella immunoglobulin if non-
immune. This is safe in pregnancy and reduces
maternal morbidity, but has not been shown to
have any direct foetal benefit when given ante-
natally. The RCOG recommends that neonates
born to mothers who develop chickenpox within
the period of 7 days before to 7 days after deliv-
ery should receive prophylaxis with immunoglob-
ulin with or without acyclovir. These neonates are
at high risk of developing varicella infection of the
newborn despite high titres of passively acquired
maternal antibody.
Human papilloma virus
Human papilloma virus (HPV) is an inactivated vi-
ral vaccine, which theoretically should be safe in
pregnancy. Vaccination during pregnancy is not
recommended, however, as the vaccine provides
no benefit to the foetus, and the maternal risk dur-
ing pregnancy is not sufficient to warrant potential
foetal risk. HPV vaccination should be deferred
until post-partum, including any outstanding
vaccinations in a partially completed course. In
view of the demographic targeted and because
formal pregnancy testing is not required prior to
administration, it is likely that many women will re-
ceive the vaccine inadvertently during pregnancy.
When this occurs, women should be reassured
that there is no evidence of teratogenicity and
that no intervention is necessary. Phase III clinical
trials analysing over 2,500 exposed pregnancies
did not find any significant increase in adverse
outcomes and pregnancy registries also sup-
156 MIMS JPOG 2019 VOL. 45 NO. 4
port this conclusion. Vaccinating women who are
breastfeeding is considered safe.
VACCINATIONS WHERE
INDICATIONS ARE UNCHANGED IN
PREGNANCY (see Table 2)
Pneumococcal
In the UK, pneumococcal vaccination is only re-
ceived by infants, those over 65 and those in a
risk group due to long-term health conditions, for
example, sickle cell disease. Pregnancy is not an
indication for vaccination. Therefore, women due
for pneumococcal vaccine should receive it in the
second or third trimester of pregnancy (there is not
enough information about safety in the first trimes-
ter) unless preconception vaccination is possible,
which would be preferable. Controlled studies have
demonstrated safety and efficacy in pregnancy
and, as a polysaccharide vaccine, theoretical con-
cerns are minimal. Research is ongoing into the role
of placental antibody transfer in potential neonatal
protection. However, a Cochrane database sys-
tematic review has stated that there is insufficient
evidence at present to determine if the vaccine in
pregnancy could reduce infant infections.
Haemophilus influenzae type B
This conjugate vaccine is safe and efficacious in
pregnancy and should be used if there are any
specific indications for it, such as those unimmu-
nized diagnosed with Haemophilus influenzae type
B (Hib) infection (as disease can recur), functional
or anatomical asplenia, immunodeficiency, or com-
plement deficiency. Other than in these situations,
most adults do not require vaccination, even during
pregnancy. Herd immunity provides some neonatal
protection prior to active immunization, so there is
no indication for maternal vaccination for neonatal
benefit. It may be relevant in the developing world
however, which carries most of the disease burden.
Meningococcal C and B
Meningococcal C vaccine should be administered
using the same guidelines as for non-pregnant
OBSTETRICS PEER REVIEWED
women. Meningococcal C vaccine is available
in conjugate and polysaccharide vaccine forms,
both of which are immunogenic in pregnancy.
The polysaccharide vaccine has been adminis-
tered extensively in pregnancy with no adverse
effects. There is limited data for the conjugate
vaccine to date, but it is reassuring so far. Menin-
gococcal B vaccine was introduced to the UK im-
munization schedule in 2015. This vaccine is a re-
combinant DNA vaccine. There is insufficient data
on this vaccine in pregnancy, but there have been
no reports of any safety concerns and the vaccine
should not be withheld when there is a clear risk
of meningococcal infection.
Hepatitis B
There is no requirement for routine hepatitis B
vaccination in pregnancy, but high-risk groups
such as intravenous drug users or healthcare
workers should be vaccinated, as they would be
outside of pregnancy. Hepatitis B vaccine is a re-
combinant vaccine and is safe and efficacious in
pregnancy. For women at especially high risk, an
accelerated vaccination course of three vaccines
over 1 month is suggested.
Bacillus Calmette-Guerin
This is a live attenuated vaccine and is contrain-
dicated in pregnancy, although limited research
has not revealed adverse outcomes. As its
efficacy in adults is poor, however, the protection
it provides to the mother would rarely outweigh
the theoretical risk to the foetus. The BCG vac-
cine is now recommended only for neonates in
at-risk groups in the UK (infants living in areas
where the annual incidence of TB is 40/100,000
or greater or infants who have a parent or grand-
parent who was born in a country where the an-
nual incidence of TB is 40/100,000 or greater).
Anthrax
Anthrax vaccination is compulsory for some
US military personnel and data has been col-
lected from inadvertent pregnancy exposures.
The vaccine exists in live attenuated and inac-
OBSTETRICS PEER REVIEWED
tivated forms. The live form is contraindicated
in pregnancy. The inactive form has previously
been linked with a possible increase in birth
defects, however more recent evidence failed
to detect an association. However, the vac-
cine is not recommended as a preventative
measure due to theoretical concerns. Women
known to be exposed to anthrax should re-
ceive the inactivated vaccine and antibiotics,
as the risk of disease is greater than the risk
from the vaccine.
TRAVEL VACCINES
Travel to areas endemic for tropical disease is not
advised in pregnancy, but is sometimes unavoid-
able. In this situation, the balance of risks and
benefits for each vaccine should be assessed
and it may be helpful to seek advice from a travel
medicine specialist. Women should receive gen-
eral advice on sun exposure and adequate hy-
dration, venous thromboembolism risk on long
flights, travel insurance requirements, and, of
course, bite avoidance and malaria prophylaxis
if relevant. Mefloquine and chloroquine and pro-
guanil are safe in pregnancy.
Diphtheria
Diphtheria is not particularly associated with
pregnancy or the neonatal period, and hence
recommendations for pregnancy are the same
as for any adult. Diphtheria and tetanus vaccines
are always given in combination, and therefore
if advice for tetanus vaccination is followed,
patients will automatically receive adequate
diphtheria protection. Situations which require
specific diphtheria vaccination should be man-
aged as per any other adult. As with tetanus,
however, one dose should be exchanged for
Boostrix-IPV® to protect against pertussis during
the current outbreak.
Polio
Similar to diphtheria, new cases of polio no long-
er represent a significant disease burden in the
UK and there are no additional requirements for
MIMS JPOG 2019 VOL. 45 NO. 4 157
pregnancy over any other adult. There are two
forms of polio vaccines; inactivated vaccines
and oral live attenuated vaccines. The latter are
contraindicated in pregnancy, although data
from population studies failed to show adverse
pregnancy or neonatal effects. The former may
be combined with tetanus and diphtheria alone
or tetanus, diphtheria, and pertussis together
in the Boostrix-IPV® vaccine. Pregnant women
should receive polio boosters as per clinical in-
dication for any adult.
Hepatitis A
The safety of this vaccine is unknown but, as an
inactivated vaccine, the theoretical risk is low.
Pregnant women in risk groups are therefore
advised to be vaccinated, and exposed wom-
en should receive both the vaccine and immu-
noglobulin regardless of pregnancy.
Rabies
This inactivated vaccine has not been implicated
in any adverse outcomes and therefore preg-
nant women should receive vaccination as per
any other adult. Pregnant women should also
receive pre- or post-exposure prophylaxis with
the vaccine and immunoglobulin if the risk of
exposure is high as the potential consequences
of inadequately managed rabies exposure are
severe.
Yellow fever
Although this is a live attenuated vaccine, the
risk of the vaccine is usually outweighed by its
benefits due to the severity of this disease. This
vaccine is thought to be less effective in preg-
nancy with lower seroconversion rates compared
with non-pregnant women. A study showed a
slight increased risk for minor skin malforma-
tions in infants but not major malformations in
women vaccinated during pregnancy. There
have been two serious adverse events in breast-
fed babies following vaccination and, therefore,
breastfeeding is discouraged. Pregnant women
who decide against vaccination should receive a
158 MIMS JPOG 2019 VOL. 45 NO. 4
medical waiver if traveling to a country where it is
an entry requirement, although this waiver may
not be accepted.
Typhoid, Japanese encephalitis,
plague, and cholera
Women may receive these inactivated vaccines
if indicated, although there is inadequate data
to comment on safety. It is assumed that the
risk is low as with other inactivated vaccines.
There is a live attenuated oral typhoid vaccine
(Ty21a), which is contraindicated. The Vi capsu-
lar polysaccharide (inactivated typhoid) vaccine
can be given. IXIARO® is the Japanese encepha-
litis vaccine that is licensed and is inactivated.
There is no safe and efficient vaccine for plague
currently, although research is ongoing into sub-
unit vaccines. Current vaccines require multiple
doses to achieve protection. Officially, cholera
vaccine requirements no longer exist for any
country. It is only now considered for those at
high risk of cholera exposure without adequate
access to clean sanitation, such as aid workers
working in disaster relief or backpackers travel-
ling to remote areas.
RELEVANT POTENTIAL FUTURE
VACCINES
Respiratory syncytial virus
Respiratory syncytial virus (RSV) causes signifi-
cant morbidity and mortality in infants less than
6 months, with hospitalizations peaking in the
second month of life. No vaccines are current-
ly sufficiently immunogenic for clinical use, but
these are in development. Previous potential
vaccines have not offered protection to infants
less than 6 months. It has been shown, how-
ever, that infants with high RSV antibody levels
are conferred clinical protection. This may be
achieved by administration of human monoclo-
nal antibody to high-risk neonates. There are
currently phase II and III clinical trials underway
testing maternal immunization in the third trimes-
ter for neonatal benefit (recombinant subunit
OBSTETRICS PEER REVIEWED
preF antigen protein and post-F nanoparticles).
In a similar way to pertussis, once an appropriate
vaccine is available, maternal immunization for
neonatal benefit could reduce disease burden.
Group B streptococcus
Group B streptococcus is carried asymptomati-
cally by many women and has the potential to
cause devastating neonatal sepsis as well as
maternal disease around the time of labour, de-
livery, and early neonatal period. It is the most
frequent cause of severe, early-onset neonatal
infection in the UK, but the RCOG does not ad-
vocate universal prenatal screening, as there is
no convincing evidence of benefit of preventa-
tive antenatal treatment. Currently, no vaccine
is available, but some are in preclinical trials.
These could potentially be used in a similar way
to tetanus vaccines to protect both the mother
and neonate; a recent model estimated that a
vaccine could prevent 61–67% of early-onset
and 70–72% of late-onset neonatal disease.
Herpes simplex
Herpes simplex virus can cause orofacial and
genital infection in adults. The primary infection
tends to be the most symptomatic episode. Her-
pes simplex virus lies dormant in neurons, can
reactivate and cause recurrent, mostly asympto-
matic, infections. It is an important cause of neo-
natal infection. About 85% of neonatal transmis-
sion occurs intrapartum and 5–10% from early
post-partum transmission. Neonatal herpes in-
fection can have devastating sequelae such as
severe neurological morbidity, multiorgan dys-
function, or death. Multiple vaccine candidates
have been in phase I and II clinical trials but, to
date, vaccines developed for herpes simplex vi-
rus have proven ineffective. More recently, vac-
cine targets have been focused on preventing
the recurrent infections.
Ebola
Ebola virus causes serious disease and there
have been a number of much publicized out-
OBSTETRICS PEER REVIEWED
breaks in recent years (most recently in Demo-
cratic Republic of Congo 2018). People can be-
come infected through contact with blood, body
fluids, or organs of an infected person. There is
currently no effective treatment for this disease,
although new therapies and vaccines are being
tested (rVSV-ZEBOV) and are in phase II and III
clinical trials. The rVSV-ZEBOV is a recombinant
vesicular stomatitis virus-based vaccine express-
ing a Zaire Ebolavirus glycoprotein. As this is a
live attenuated vaccine, it would normally not be
recommended in pregnancy. Pregnant women
continue to be excluded from vaccination strat-
egies at present. However, in Ebola outbreaks,
up to 90% of pregnant women infected die and
almost all of the pregnancies of Ebola infected
women end in miscarriage or neonatal death.
Therefore, if the risk of exposure to Ebola virus
disease is high, the benefit of the vaccine would
likely outweigh the risk.
CONCLUSION
Maternal vaccination can prevent and reduce ma-
ternal, foetal, and neonatal infection and decrease
disease burden. Vaccination is a cost-effective in-
tervention and theoretical safety concerns have
not been supported by clinical experience. As
knowledge of safety and efficacy is coupled with
increasing vaccine development and availability,
maternal vaccination is becoming a more wide-
ly used technique. Healthcare providers should
encourage routine maternal influenza and pertus-
sis vaccination to continue to save lives.
FURTHER READING
1. E nglund JA. The influence of maternal immunization on infant immune
responses. J Comp Pathol 2007 Jul; 137: S16–9.
2. Lindsey B, Kampmann B, Jones C. Maternal immunization as a strate-
gy to decrease susceptibility to infection in newborn infants. Curr Opin
Infect Dis 2013; 26: 248–53.
3. Brent RL. Immunization of pregnant women: reproductive, medical
and societal risks. Vaccine 2003 Jul 28; 21: 3413–21.
4. Sukumaran L, McCarthy NL, Kharbanda EO, et al. Infant hospitaliza-
tions and mortality after maternal vaccination. Pediatrics 2018; 141:
e20173310.
5. Hubka TA, Wisner KP. Advisory committee on immunization practices
(ACIP) of the centers for disease control and prevention. Vaccinations
recommended during pregnancy and breastfeeding. J Am Osteopath
Assoc 2011 Oct; 111: S23–30.
6. Churchill D, Rodger A, Clift J, Tuffnell D. on behalf of the MBRRACEUK
sepsis chapter writing group. Think sepsis. In: Knight M, Kenyon S,
Brocklehurst P, et al., eds. on behalf of MBRRACE-UK saving lives, im-
proving mothers’ care- Lessons learned to inform future maternity care
MIMS JPOG 2019 VOL. 45 NO. 4 159
Practice Points
• 
If possible, preconception vaccination is ideal, avoiding foetal
exposure to potential teratogenicity.
• Antenatal vaccination may be for maternal, foetal, or neonatal
benefit or a combination of the three.
• Vaccination for maternal benefit should occur early in pregnancy to
maximize duration of protection. The first trimester is often avoided
to prevent implication in unrelated miscarriage.
• Vaccination for neonatal protection should ideally occur between
30 and 32 weeks to maximize placental antibody transfer.
• Vaccination appears to be as effective in pregnancy as in other
women, with the exception of the yellow fever vaccine.
• Live vaccines have a theoretical risk of transplacental transmission
and foetal infection, although there is minimal evidence of clinical
effects. They are therefore contraindicated in pregnancy but may
occasionally be used where there is high risk of disease.
• Women should never be advised to terminate a pregnancy solely
because of inadvertent vaccine administration.
• 
Vaccinations missed during pregnancy should be received
post-partum. Only yellow fever and smallpox vaccines are not
recommended in breastfeeding.
• 
All pregnant women in the UK should be offered influenza
vaccination for maternal and foetal benefit.
• There was a pertussis outbreak in 2012 and a temporary recommend-
ation is that all pregnant women should be offered vaccination for
neonatal protection. This temporary recommendation was extended
in 2014 for a further 5 years.
• All healthcare providers should use every encounter with pregnant
women as a health promotion opportunity and should encourage
maternal vaccination.
from the UK and Ireland confidential enquiries into maternal deaths
and morbidity 2009-2012. Oxford: National Perinatal Epidemiology
Unit, University of Oxford, 2014; p47–64.
7. Getahun D, Fassett MJ, Peltier M, et al. Association between seasonal
influenza with pre- and postnatal outcomes. Vaccine 2019; 37(13):
1785–91.
8. Donegan K, King B, Bryan P. Safety of pertussis vaccination in preg-
nant women in UK: observational study. BMJ 2014; 349: g4219.
9. Griffin JB, Yu L, Watson D, et al. Pertussis immunisation in pregnancy
(PIPS) study: a retrospective cohort study of safety outcomes in preg-
nant women vaccinated with Tdap vaccine. Vaccine 2018; 36: 5173–9.
© 2019 Elsevier Ltd. All rights reserved. Initially published in Obstetrics,
Gynaecology and Reproductive Medicine 2019;29(7):181–188.
About the authors
Jennifer Hogan is an Obstetrics and Gynaecology Specialist Registrar
at Coombe Women and Infants University Hospital, Dublin, Ireland.
Conflicts of interest: none declared.
Sarah French is a Palliative Medicine Registrar at North Bristol NHS
Trust, Bristol, UK. Conflicts of interest: none declared.
Lucy Mackillop is a Consultant Obstetric Physician at Oxford University
Hospitals NHS Trust, Oxford, UK. Conflicts of interest: none declared.
160 MIMS JPOG 2019 VOL. 45 NO. 4 GYNAECOLOGY PEER REVIEWED

Dysmenorrhoea
Akshatha Kulkarni MBBS MS DNB MRCOG; Shilpa Deb MBBS DGO PhD MRCOG

Dysmenorrhoea is a medical condition characterized by severe uterine pain dur-

ing menstruation manifesting as cyclical lower abdominal pain. It is commonly
classified into primary dysmenorrhoea in the absence of coexistent pathology
and secondary dysmenorrhoea when there is an identifiable pathological condi-
tion. About 40–70% of women of reproductive age suffer with dysmenorrhoea
along with its associated psychological, physical, behavioural, and social dis-
tress. The exact pathophysiological processes are not fully understood but it
probably reflects increased myometrial activity induced by an excessive produc-
tion of prostaglandin causing ischaemia (uterine “angina”). History is critical in
establishing the diagnosis of dysmenorrhoea and also in differentiating between
primary and secondary dysmenorrhoea. Mainstay treatment is generally sup-
portive providing symptomatic relief and more directive surgical treatment is re-
served for specific secondary causes of dysmenorrhoea or for refractory cases.
Therefore, patients with primary dysmenorrhoea may simply need reassurance
and simple analgesics, while those with secondary dysmenorrhoea require in-
vestigation and treatment of the underlying organic problem. We present an over-
view of managing this condition.
GYNAECOLOGY PEER REVIEWED
BACKGROUND
Dysmenorrhoea is a very common gynaecologi-
cal condition affecting anywhere from 45–95% of
women with one in five cases being severe. Dys-
menorrhoea is a medical condition characterized
by severe uterine pain during menstruation mani-
festing as cyclical lower abdominal or pelvic pain,
which may also radiate to the back and thighs. The
term dysmenorrhoea is derived from the Greek
words “dys” meaning difficult, painful, or abnormal,
“meno” meaning month, and “rrhea” meaning flow.
It is commonly divided into primary dysmen-
orrhoea, where there is no coexistent pathology,
and secondary dysmenorrhoea where there is an
identifiable pathological condition known to con-
tribute to painful menstruation. Symptoms of pri-
mary dysmenorrhoea begin a few hours before
the start of menstruation and are often relieved
during the first few days of bleeding. The initial
onset of primary dysmenorrhoea is usually short-
ly after menarche (6–12 months), when ovulatory
cycles are established. Secondary dysmenor-
rhoea can also occur at any time after menarche
but is most commonly observed in women in
their third and fourth decade of life in association
with an existing condition.
RISK FACTORS
Risk factors for primary dysmenorrhoea include
earlier age at menarche, heavy menstrual flow,
nulliparity, family history of dysmenorrhoea, and
stress.
According to NICE Clinical Knowledge
Summary on Dysmenorrhoea (November 2018):
• 
Primary dysmenorrhoea improves with
increased age, parity, and use of oral
contraceptives.
• There is inconsistent and conflicting evidence
on the association between primary dysmenor-
rhoea and modifiable factors, such as cigarette
smoking, diet, obesity, depression, and abuse.
PATHOPHYSIOLOGY
The most important physiological event reported with
dysmenorrhoea is increased myometrial activity with
MIMS JPOG 2019 VOL. 45 NO. 4 161
accompanying uterine ischemia (uterine “angina”),
which stimulates the type C afferent pain neurones.
In a normal menstrual cycle, at the end of the
luteal phase as the corpus luteum regresses after
non-fertilization of an ovum, there is a decline in pro-
gesterone levels. It is this withdrawal of progester-
one that leads to the shedding of endometrium and,
during its destruction, an increase in inflammatory
cytokines, vascular endothelial growth factors, and
matrix metalloproteinases (MMPs). This also leads
to a degradation and loss of integrity of blood ves-
sels and destruction of endometrial interstitial matrix
and hence the bleeding of menstruation. Uterine
contraction and vasoconstriction is caused by the
disintegrating endometrial cells releasing PGF2á
which is a myometrial stimulant and vasoconstrictor.
The uterine contractions and ischaemia that results
from decreased blood flow results in uterine pain.
Primary dysmenorrhoea
In women with primary dysmenorrhoea, there are
increased levels of inflammatory markers such as
vasopressin, prostaglandins PGE2 and PGF2á, and
leukotrienes in endometrial fluid. PGF2á is a potent
myometrial stimulant and vasoconstrictor. Leukot-
rienes increased myometrial stimulation and vaso-
constriction as well as increasing the sensitivity of
pain fibres. Vasopressin stimulates uterine activity,
decreased uterine blood flow, and in vitro, con-
stricts uterine arteries. The primary stimulus for
these increased levels is unknown but it is thought
that this myometrial activity is modulated and aug-
mented by prostaglandin synthesis. In addition to
stimulating uterine contractions, PGF2, and PGE2
can cause contraction of bronchial, bowel, and
vascular smooth muscle resulting in bronchoc-
onstriction, nausea, vomiting, diarrhoea and hy-
pertension. Diarrhoea and nausea are commonly
associated with primary dysmenorrhoea. Com-
pared with controls, women with primary dysmen-
orrhoea have increased uterine pressures from
increased uterine muscle activity and frequency
of contractions (frequently >150 mm Hg). Dop-
pler flow studies have supported this by showing
higher uterine and arcuate artery resistance on the
162 MIMS JPOG 2019 VOL. 45 NO. 4
Table 1. Differential Characteristics of Primary and Secondary Dysmenorrhoea
Primary
Age (years) 16–25
Onset of pain Just prior to menstruation (spasmodic)
Pathophysiology Excess prostaglandins and leukotrienes
Symptoms Usually self-limiting, lasts for first 1–3 days
menstruation
Responds to COCP and NSAIDs
Periods normal or light
Signs Unremarkable
first day of menses in women with primary dys-
menorrhoea than in controls. Pain fibres are also
stimulated from ischaemia caused by vasocon-
striction and anaerobic metabolites produced by
an ischaemic endometrium which stimulate type
C pain neurons.
Added to this is the possible effect of psy-
chological and behavioural factors, which can
act centrally and contribute to pain perception.
There is an increased prevalence of dysmenor-
rhoea in women with a history of sexual abuse
but there is little research into this compared with
other chronic pelvic pain syndromes.
Secondary dysmenorrhoea
Secondary dysmenorrhoea is caused by an un-
derlying pelvic pathology. Endometriosis is the
most common cause. However, there is no cor-
relation between the severity of the disease and
extent of pain. Pelvic inflammatory disease (PID)
causes both increased inflammatory mediators
and scar tissue. Adenomyosis causes tonic con-
tractions through endometrial gland infiltration
and polyps, submucous fibroids and IUDs cause
increased uterine contractions in order to expel
them. All of the less common causes of dysmen-
orrhoea are due to abnormal uterine contractions.
See Table 1 for a comparison of primary and sec-
ondary dysmenorrhoea.
GYNAECOLOGY PEER REVIEWED
Secondary
30–45
Pain often progresses through late luteal (congestive)
Underlying disorder
Associated with other features related to underlying
disease
Resistant to COCP and NSAIDs
Periods often heavy
Dependent on cause but may include a tender,
enlarged, fixed, retroverted uterus with adnexal
tenderness and a mass
Evaluation of dysmenorrhoea
Secondary dysmenorrhoea must be exclud-
ed before considering a diagnosis of primary
dysmenorrhoea.
š History and clinical assessment:
 Relation of pain to menarche.
 Characteristics of the pain, including type of
pain, timing and duration, severity, and exac-
erbating and alleviating factors.
 Any associated symptoms, including other
gynaecological symptoms and non-gynae-
cological symptoms.
 Menstrual history, including length of men-
strual cycle, regularity, and duration, and the
volume of menstrual flow.
Risk factors for primary dysmenorrhoea,
 
such as family history of dysmenorrhoea.
 Medical history. Several conditions (eg, irrita-
ble bowel syndrome and lactose intolerance)
can mimic pain similar to dysmenorrhoea.
Obstetric history, including plans for pregnancy.

 Drug history, including prior treatment and
effect.
š Examination:
P
erform an abdominal examination in all

women – to assess for large fibroids and
other masses.
GYNAECOLOGY PEER REVIEWED MIMS JPOG 2019 VOL. 45 NO. 4 163

P
erform a pelvic examination (including a
 Table 2. Major Causes of Secondary Dysmenorrhoea
speculum examination of the cervix), except
in young women who are not sexually active
Gynaecologic disorders:
if the symptoms are suggestive of primary
• Endometriosis
dysmenorrhoea.
• Adenomyosis
š Consider the following investigations: • Pelvic inflammatory disease
A
n ultrasound scan — to rule out fibroids,
 • Fibroids
adnexal pathology, and endometriosis. • Endometrial polyps
H
igh vaginal and endocervical swabs — if
 • Ovarian cysts
the woman is at risk of a sexually transmit-
• Intrauterine contraceptive device
ted infection, especially if pain is associated
• Intrauterine adhesions (Asherman’s syndrome)
with vaginal discharge and abnormal vaginal
bleeding. • Congenital obstructive Mullerian malformations
Pregnancy test — to exclude an ectopic
 • Pelvic congestion syndrome
pregnancy. • Cervical stenosis
Non-gynaecologic disorders:
•
Primary dysmenorrhoea is the most • Inflammatory bowel disease
likely diagnosis when:
• Irritable bowel syndrome
š Menstrual pain starts 6–12 months after
• Urogenital disease
the menarche, once cycles are regular.
• Psychogenic disorders
š 
Pain, usually cramping in nature, oc-
curs in the lower abdomen but may ra-
diate to the back and inner thigh.
š 
Pain starts shortly before the onset but is exacerbated by menstruation.
of menstruation and lasts for up to š Other symptoms are present, including:
72 hours, improving as the menses Other gynaecological symptoms, such
 
progresses. as dyspareunia, vaginal discharge, men-
š Non-gynaecological symptoms, such orrhagia, intermenstrual bleeding, and
as nausea, vomiting, diarrhoea, fatigue, post-coital bleeding.
irritability, dizziness, bloating, head- Non-gynaecological symptoms, such as
 
ache, lower back pain, and emotional rectal pain and bleeding (which may be
symptoms, are present. associated with endometriosis).
š 
Other gynaecological symptoms are š 
Pelvic examination is abnormal, al-
not present. though the absence of abnormal
š Pelvic examination is normal. findings does not exclude secondary
dysmenorrhoea.
•
Secondary dysmenorrhoea is the most
 For primary dysmenorrhoea, history and ex-
likely diagnosis when: amination should suffice and further investigation
š  Pain starts after several years of pain- is rarely necessary. If there are atypical symp-
less periods. toms or a trial of non-steroidal anti-inflammatory
š Pain is not consistently related to men- medication or combined oral contraceptive is un-
struation alone and may persist af- successful, then pelvic ultrasound scan should
ter menstruation finishes or may be be considered. For secondary dysmenorrhoea
present throughout the menstrual cycle pelvic USS should be considered. Hysteroscopy
164 MIMS JPOG 2019 VOL. 45 NO. 4 GYNAECOLOGY PEER REVIEWED

Table 3. Clinical Features and Evaluation of Some Common Causes of Secondary Dysmenorrhoea

Condition Clinical features Evaluation

Endometriosis (most
common cause of secondary
dysmenorrhoea)
Adenomyosis
Fibroids
Pelvic inflammatory disease
Endometrial polyps
Pelvic congestion syndrome
Cyclical or chronic pelvic pain frequently
occurring prior to menstruation and
accompanied by heavy menstrual bleeding
and deep dyspareunia.
Usually associated with menorrhagia and
intermenstrual bleeding.
Enlarged, tender, boggy uterus on
examination.
Lower abdominal pain, frequently
accompanied by menorrhagia; a pelvic
mass may be identified on examination.
Lower abdominal pain and tenderness
that may be accompanied by dyspareunia,
abnormal vaginal bleeding, and abnormal
vaginal discharge. In acute infection, fever
may be present.
Menorrhagia, congestive, and spasmodic
dysmenorrhoea and intermenstrual
bleeding.
Chronic pelvic pain that increases
premenstrually with prolonged standing,
postural changes, walking, or activities that
increase intra-abdominal pressure, and
after intercourse (post-coital ache).
Transvaginal pelvic ultrasound is highly
accurate for ovarian endometrioma.
MRI may be indicated for deep infiltrating
endometriomas.
Laparoscopy allows confirmation of diagnosis
and treatment.
Transvaginal ultrasound or MRI.
Transvaginal/transabdominal ultrasound.
Cervical infection with Chlamydia trachomatis
or Neisseria gonorrhoeae is confirmatory. May
have elevated C-reactive protein. Transvaginal
ultrasound useful in detecting tubo-ovarian
masses.
Transvaginal USG, saline infusion sonography,
or hysteroscopy.
Radiological imaging is frequently used to
confirm the clinical suspicion of this condition.
Gold standard is selective venography.

and laparoscopy have a role in confirming a sus-
pected diagnosis and treating the underlying pa-
thology (See Tables 2 and 3).
MANAGEMENT
For primary dysmenorrhoea, treatment is based
on tackling the aetiology with cyclo-oxygenase
inhibitors and inhibiting ovulation. Treatment of
secondary dysmenorrhoea targets the cause.
One must treat women individually taking ac-
count of their age, desire for fertility, and concur-
rent symptoms.
Many studies have employed patient
self-reporting using a visual analogue or other
pain scale, quality of life scales, or other simi-
lar measures, such as the Menstrual Distress or
Menstrual Symptom Questionnaires. Additional
measures include analysis of the proportion of
women requiring analgesics in addition to their
assigned treatment and recording the percent-
age of women reporting restriction of social ac-
tivities or absence from work or school. Which-
ever system is used, grading dysmenorrhoea
according to severity of pain and limitation of
daily activity will help guide the treatment strat-
egy and catalogue the response to treatment.
According to NICE Clinical Knowledge Sum-
mary for Managing Dysmenorrhoea (Nov 2018):
1. 
First-line treatment for women with pri-
mary dysmenorrhoea should be a non-
steroidal anti-inflammatory drug (NSAID),
unless contraindicated (Figures 1 and 2).
Women with dysmenorrhoea have high
levels of prostaglandins (hormones known to
cause cramping abdominal pain). NSAIDs act by
blocking prostaglandin production by inhibiting
GYNAECOLOGY PEER REVIEWED MIMS JPOG 2019 VOL. 45 NO. 4 165

the action of cyclo-oxygenase (COX, an enzyme

responsible for the formation of prostaglandins). Cell membrane phospholipids
The COX enzyme exists in two forms: ‡ Phospholipase A2
COX-1 and COX-2. Standard NSAIDs (such as
ibuprofen, naproxen, and mefenamic acid) are Arachidonic acid
considered “non-selective” because they inhibit ‡ COX1 and 2

‡
– NSAIDs
both COX-1 and COX-2 enzymes. Coxibs (such
Prostaglandin G2
as celecoxib and etoricoxib) are highly selective
for COX-2 but can interact with COX-1 in certain ‡ Peroxidase
circumstances.
Prostaglandin H2
A Cochrane systematic review compared 20
‡ ‡

‡
different NSAIDs (18 nonselective and two COX-
PG12 TXA2
2-specific) with placebo, paracetamol, or each
PGF2alpha PGE2
other in 5,820 women with dysmenorrhoea and
found that:
NSAIDs were more effective for pain relief
 
Figure 1. Action of NSAIDS.
than placebo but were associated with more
adverse effects.
 NSAIDs appeared to be more effective for
pain relief than paracetamol. There was no Dysmenorrhoea
evidence of a difference with regard to ad-
verse effects, although data was very scanty. History, examination,
and investigation
Choice of NSAIDs
Options include ibuprofen, naproxen, mefenamic
acid, flurbiprofen, or tiaprofenic acid. Primary Secondary
dysmenorrhoea dysmenorrhoea
The Cochrane systematic review found lit-
tle evidence of the superiority of any individu-
al NSAID for either pain relief or safety, but the
available evidence had little power to detect Contraception Contraception Treat the cause
not needed needed
such differences as most individual comparisons
were based on very few small trials. There was Consider
laparoscopy
no evidence that COX-2-specific inhibitors were NSAIDs COC
if not done
more effective or tolerable for the treatment of previously
to exclude
dysmenorrhoea than standard NSAIDs, although NSAIDs COC secondary
data was very scanty. + paracetamol + NSAIDs causes of
dysmenorrhoea
Licensed indications
š  Ibuprofen, naproxen, and flurbiprofen are li-
censed for the treatment of dysmenorrhoea. Figure 2. Treatment of dysmenorrhoea.
š  Mefenamic acid is also licensed for the treat-
ment of dysmenorrhoea. However, there are es the risk of accidental overdose. The Na-
concerns that it is more likely to cause sei- tional Poisons Information Service considers
zures in overdose than other NSAIDs. It has an ingestion of 40 mg/kg or more to be po-
a narrow therapeutic window, which increas- tentially toxic. This means that a woman who
166 MIMS JPOG 2019 VOL. 45 NO. 4
About 40–70% of women of reproductive age suffer with dysmenorrhoea along with its associated psychological, physical, behavioural,
and social distress.
weighs 50 kg would only need to ingest one
extra dose of 500 mg of mefenamic acid in
24 hours (total of 2,000 mg) to be consid-
ered to be at risk of toxicity.
2. Offer paracetamol if NSAIDs are contrain-
dicated or not tolerated, or in addition to
an NSAID, if the response is insufficient.
Evidence from the Cochrane systematic re-
view showed that NSAIDs appeared to be more
effective than paracetamol in the treatment of
primary dysmenorrhoea. However, paraceta-
mol is a well-tolerated analgesic and is a widely
used alternative to NSAIDs for musculoskeletal
pain.
If the woman does not wish to conceive,
consider prescribing a 3- to 6-month trial of a
hormonal contraceptive as an alternative first-line
treatment.
Combined hormonal contraceptives, in-
cluding combined oral contraceptives, the con-
traceptive ring, and the transdermal patch, all
GYNAECOLOGY PEER REVIEWED
work to decrease the endometrial lining, which
produces prostaglandins and leukotrienes that
contribute to the menstrual pain. In addition,
their role in inhibiting ovulation and subsequent
progesterone production also decreases the
formation of prostaglandins and leukotrienes.
Thus, these products have been prescribed for
primary dysmenorrhoea, as well as some caus-
es of secondary dysmenorrhoea, particularly
endometriosis.
a. 
Monophasic combined oral contracep-
tive (COC) preparations containing 30–35
μg of ethinyloestradiol and norethister-
one, norgestimate, or levonorgestrel are
usually first choice.
i. A Cochrane systematic review found
limited evidence that COCs are ef-
fective for relieving pain associated
with primary dysmenorrhoea. Howev-
er, the overall quality of the trials was
poor, some trials were over 25 years
old, and some used COCs with higher
GYNAECOLOGY PEER REVIEWED
doses of oestrogen than is present in
currently available products.
ii. 
Despite the limited trial evidence,
COCs are widely recommended by ex-
perts for this indication, and the added
contraceptive advantages make them
a suitable first-line option for some
women.
COCs containing 20 μg of ethiny-
iii. 
loestradiol are less preferred be-
cause they are more likely to cause
un-scheduled bleeding.
Oral (desogestrel 75 μg), parenteral
b. 
(Depo-Provera or Sayana Press, and
Nexplanon), and intrauterine progesto-
gen-only (Mirena) contraceptives may
also be considered after a full discussion
of the advantages and disadvantages.
Oral progestogen-only contraceptives
iv. An observational study assessed the
effects of desogestrel 75 μg (Cera-
zette) in women with dysmenorrhoea
and found that dysmenorrhoea re-
solved or considerably improved in
93% of the study population.
Parenteral progestogens
v. 
A review of open-label, noncompar-
ative, and comparative studies as-
sessed the effects of etonogestrel sub-
dermal implant (Implanon, which is
bioequivalent to Nexplanon) on men-
strual bleeding patterns and found
that it reduced both the incidence
and severity of dysmenorrhoea. Most
women (77%) who had baseline dys-
menorrhoea experienced complete
resolution of symptoms.
vi. Some experts recommend that par-
enteral progestogens (such as de-
pot medroxyprogesterone acetate)
may be considered in the treatment
of dysmenorrhoea. Depot medroxy-
progesterone acetate works primar-
MIMS JPOG 2019 VOL. 45 NO. 4 167
ily by suppressing ovulation, and it
can also induce endometrial atrophy.
One of its benefits is amenorrhoea
with a resultant reduction in the inci-
dence of dysmenorrhea.
Intrauterine contraception
vii. A longitudinal population study as-
sessed the prevalence and sever-
ity of dysmenorrhoea in women
using an intrauterine contraception
and found that the levonorgestrel-
releasing intrauterine system (LNG-
IUS, Mirena) was associated with
reduced dysmenorrhoea sever-
ity compared with other methods
of contraception (barrier methods,
natural family planning, coitus in-
terruptus, and sterilization) or no
method of contraception. The cop-
per intrauterine device did not re-
duce the severity of dysmenorrhoea
when compared with other methods
of contraception.
viii. The RCOG guideline states that non-
endometriosis-related cyclical pain
also appears to be well controlled by
the LNG-IUS. It is also an option for
those who do not require contracep-
tion, particularly older women who
have had children and women with
heavy menstrual bleeding.
3. If the response to individual treatments
is insufficient, a combination of an NSAID
(or paracetamol) and hormonal contracep-
tion may be considered.
4. 
Consider recommending the following
non-drug measures (in addition to drug
treatments) to help reduce pain:
c. Local application of heat (eg, a hot wa-
ter bottle or heat patch).
d. Transcutaneous electrical nerve stimu-
lation (TENS) – set to a high frequency.
168 MIMS JPOG 2019 VOL. 45 NO. 4
Practice Points
• Around 45–95% of menstruating women suffer with dysmenorrhoea.
• Increased myometrial activity induced by an excessive production
of prostaglandin causing uterine ischaemia is the most accepted
pathophysiological mechanism.
• Primary dysmenorrhoea is seen in young women with ovulatory
cycles and is characterized by spasmodic menstrual pain
starting just before menstruation lasting for 24–48 hours. There is
no coexisting pathology.
• 
Secondary dysmenorrhoea is always associated with an
underlying pathology and is characterized by congestive
menstrual pain, which increases progressively through the late
luteal phase, peaking with onset of menstruation.
• History is critical in establishing the diagnosis of dysmenorrhoea.
• 
Treatment is aimed at symptomatic relief with analgesics–
especially NSAIDs – and at treating the underlying pathology.
Heat therapy and transcutaneous electrical
nerve stimulation
A systematic review assessed the effectiveness of
heat therapy and TENS interventions for pain relief
and quality of life improvement in women with pri-
mary dysmenorrhoea:
i. Evidence from trials on heat therapy
showed individual improvement in
pain levels.
ii. Evidence from trials on TENS showed
relatively positive effects in pain reduc-
tion. Overall, the evidence suggested
that conventional TENS is better op-
tion in dysmenorrhoeal pain relief
than other forms of TENS (such as ac-
upuncture-like TENS and OVA TENS)
and that high-frequency TENS is more
effective for pain relief, although there
was insufficient to determine the ef-
fectiveness of low frequency TENS in
reducing dysmenorrhoea.
5. Other non-drug measures
e. There is a lack of good-quality evidence
to support the use of herbal remedies,
dietary supplements, acupuncture,
acupressure, spinal manipulation, be-
havioural therapy, and exercise to treat
GYNAECOLOGY PEER REVIEWED
dysmenorrhoea. In addition, herbal
remedies have the potential to cause
adverse effects and may interact with
other medicines.
Prognosis
There are very few longitudinal studies examining
the progression and eventual outcome of primary
or secondary dysmenorrhoea. Primary dysmen-
orrhoea often improves in the third decade of a
woman’s reproductive life and appears to be re-
duced after childbirth. The prognosis of second-
ary dysmenorrhoea is not known as its severity,
progression, and eventual outcome depend on
the underlying pathology.
CONCLUSIONS
Dysmenorrhoea has a significant physical, behav-
ioural, psychological, and social impact, affecting
a large proportion of women of reproductive age.
The exact pathophysiological processes are not
fully understood but it probably reflects increased
myometrial activity induced by an excessive pro-
duction of prostaglandin causing ischaemia.
Mainstay of treatment is generally supportive pro-
viding symptomatic relief with NSAIDs or COCP
and more directive surgical treatment should be
reserved for specific secondary causes of dys-
menorrhoea or for refractory cases.
FURTHER READING
1. Best Practice BMJ. Assessment of dysmenorrhoea. BMJ 2018. COG.
The initial management of chronic pelvic pain. Royal College of Obste-
tricians and Gynaecologists, 2012.
2. Lacovides S, Avidon I, Baker FC. What we know about primary dys-
menorrhea today: a critical review. Hum Reprod Update 2015; 21:
762–78.
3. Proctor M, Farquhar C. Diagnosis and management of dysmenor-
rhoea. Br Med J 2006; 332: 1134–8.
4. Wallace S, Keightley A, Gie C. Dysmenorrhoea. The Obstetrician &
Gynaecologist 2010; 12: 149–54.
© 2019 Elsevier Ltd. All rights reserved. Initially published in Obstetrics,
Gynaecology and Reproductive Medicine 2019;29(10):286–291.
About the authors
Akshatha Kulkarni is a Senior Registrar in Obstetrics and Gynaecol-
ogy at Queen’s Medical Centre, Nottingham, UK. Conflicts of interest:
none declared.
Shilpa Deb is a Consultant in Obstetrics and Gynaecology at Notting-
ham University Hospitals NHS Trust at Queen’s Medical Centre Cam-
pus, Nottingham, UK. Conflicts of interest: none declared.
CONTINUING MEDICAL EDUCATION MIMS JPOG 2019 VOL. 45 NO. 4 169

Prevention of Pre-eclampsia
Pui Wah HUI, MBBS, MMedSc (HK), MD (HK), FRCOG, FHKCOG, FHKAM (O&G), Cert RCOG (Maternal & Fetal Med)

INTRODUCTION
Pre-eclampsia is a major obstetric com-
plication that can lead to adverse mater-
nal and foetal outcomes. It is recognized
as a new-onset hypertension (≥140 mm
Hg systolic and ≥90 mm Hg diastolic)
with co-occurring proteinuria (≥300 mg/
day) that develops after 20 weeks of
gestation. Multiorgan system involve-
ment such as renal failure, haemolysis,
elevated liver enzymes, and low plate-
lets (HELLP), cerebral oedema, and
eclamptic seizures are possible asso-
ciations. In recognition of the syndro-
mic nature of pre-eclampsia, revised
diagnostic criteria was proposed by the
American College of Obstetricians and
Gynecologists (ACOG) in 2013 (Table 1)
and International Society for the Study
of Hypertension in Pregnancy (ISSHP)
in 2014 (Table 2). In the absence of
proteinuria, diagnosis of pre-eclampsia
can be made based on hypertension Aspirin should be recommended for women at risk of pre-eclampsia before 16 weeks
with thrombocytopenia impaired liver of gestation.
function, renal insufficiency, pulmonary
oedema, and cerebral or visual distur- was thought to be the central patho- Various studies have been conduct-
bances. 1-2
genic mechanism of pre-eclampsia. ed in the past decades to examine how
According to occurrence, pre-ec- The severity and timing of anti-angio- pre-eclampsia can be prevented. Apart
lampsia can be classified as preterm genic state and maternal susceptibili- from aspirin and calcium supplementa-
(before 37 weeks) or term (after 37 ty may determine the ultimate clinical tion, antioxidants (vitamins C and E), fish
weeks). According to the gestational presentation. In general, preterm or oil, nitric oxide supplements, nitric oxide
age at diagnosis or delivery, pre-ec- early onset pre-eclampsia is believed donors, folic acid, weight loss, and bed
lampsia can be classified as early to be more related to villous and vas- rest have not been shown effective. More
onset (before 34 weeks) and late on- cular lesions of placenta and foetal recent data suggested that statin may be
set (after 34 weeks).3 The underlying growth restriction, and term or late on- beneficial for term pre-eclampsia.
pathophysiology is not yet fully under- set pre-eclampsia is more likely a con-
stood but the placenta plays an essen- sequence of metabolic disorders of the ROLE OF ASPIRIN
tial role. Defective deep placentation mother and the pre-existing cardiovas- Aspirin is a cyclooxygenase inhibitor with
with an imbalance of angiogenesis cular risk factors.4 anti-inflammatory and antiplatelet prop-
170 MIMS JPOG 2019 VOL. 45 NO. 4 CONTINUING MEDICAL EDUCATION

Table 1. Diagnostic Criteria of Pre-eclampsia by ACOG1

Blood pressure • Systolic blood pressure of 140 mm Hg or higher, or diastolic blood pressure of 90 mm Hg or
higher on two occasions at least 4 hours apart after 20 weeks of gestation in a woman with
a previously normal blood pressure
• Systolic blood pressure of 160 mm Hg or higher, or diastolic blood pressure of 110 mm Hg or higher

and
Proteinuria • Greater than or equal to 300 mg per 24-hour urine collection
• Protein/creatinine ratio greater than or equal to 0.3 mg/dL
• Dipstick reading of 1+

or in the absence of proteinuria, new-onset hypertension with new onset of any of the following:

Thrombocytopenia • Thrombocytopenia (platelet count <100,000/mL)

Impaired liver • Elevated blood concentrations of liver enzymes (to twice normal concentration), severe
function persistent right upper quadrant or epigastric pain unresponsive to medication and not
accounted for by alternative diagnoses, or both
Renal insufficiency • Serum creatinine concentration >1.1 mg/dL or a doubling of the serum creatinine
concentration in the absence of other renal disease
Pulmonary oedema
Cerebral of visual
symptoms

Table 2. The Revised ISSHP Definition of Pre-eclampsia2

Hypertension developing after 20 weeks of gestation and the coexistence of one or more of the following new onset
conditions:
1. Proteinuria
2. Other maternal organ dysfunction
• Renal insufficiency (creatinine >90 µmol/L)
• Liver involvement (elevated transaminases and/or severe right upper quadrant or epigastric pain)
• Neurological complications (eg, eclampsia, altered mental status, blindness, stroke, or more commonly
hyperreflexia when accompanied by clonus, severe headaches when accompanied by hyperreflexia,
persistent visual scotomata)
• Haematological complications (thrombocytopenia, disseminated intravascular coagulopathy, haemolysis)
3. Uteroplacental dysfunction
• Foetal growth restriction

Abbreviation: ISSHP = International Society for the Study of Hypertension in Pregnancy

erties. The beneficial effect of aspirin
in the prevention of pre-eclampsia was
first reported in 1985, where 102 wom-
en at high risk of pre-eclampsia and/or
foetal growth restriction were given as-
pirin 150 mg aspirin and dipyridamole
300 mg daily. There were no cases of
5
pre-eclampsia, foetal growth restriction,
and stillbirth in the group receiving as-
pirin compared with the group without
aspirin. A series of multicentre trials with
conflicting results on the role of aspirin
CONTINUING MEDICAL EDUCATION MIMS JPOG 2019 VOL. 45 NO. 4 171

Table 3. Risk Factors for Pre-eclampsia

NICE in 2010 ACOG Committee Opinion in 2018

Major risk factors: High-risk factors:
• Hypertensive disease in previous pregnancy • History of pre-eclampsia
• Autoimmune disease • Multifoetal gestation
• Diabetes mellitus • Autoimmune disease
• Chronic hypertension • Type 1 or 2 diabetes
• Chronic kidney disease • Chronic hypertension
Moderate risk factors: • Renal disease
• First pregnancy Moderate risk factors:
• Maternal age of 40 years or older • First pregnancy
• BMI = >35 kg/m2 • Maternal age of 35 years or older
• Family history of pre-eclampsia • BMI = ≥30 kg/m2
• Inter-pregnancy interval >10 years • Family history of pre-eclampsia
• Multiple pregnancy • Sociodemographic characteristics (African-American
race, low socioeconomic status)
• Personal history factors (low birthweight or small
for gestational age, previous adverse pregnancy
outcome, more than 10-year pregnancy interval)

in prevention of pre-eclampsia were
published. 6-10
A meta-analysis in 2007
concluded that aspirin could reduce the
risk of pre-eclampsia and preterm birth
of <34 weeks by 10%. However, trials
11
using various aspirin dosages of 50–150
mg and different starting points of aspi-
rin from first to third trimester in women
with a diverse risk background were in-
cluded in the meta-analysis.
Given the heterogeneity of pub-
lished data, questions were then raised
on the optimal dosage, administration
time, and gestational age at initiation of
aspirin, and particularly, who should be
given aspirin.
To address the dosage of aspi-
rin, a systematic review by Roberge,
et al, including 45 randomized con-
trolled trials with a total of 20,909 preg-
nant women was published in 2017. A
dose-response effect was observed.
While a daily dosage of 60 mg had no
impact on pre-eclampsia, a daily dos-
age of 150 mg demonstrated a greater
reduction of severe pre-eclampsia.
This finding could be echoed by the
lack of platelet functional response at
a dosage of 81 mg observed in almost
30% of pregnant women, which in most
cases could be overcome by a higher
dosage. 13
In addition, aspirin was also
found to be more effective when taken
at night rather than during the day. 14
In
the same review, aspirin initiated before
16 weeks of gestation was associated
with a significant reduction in the risk
of severe pre-eclampsia (relative risk,
0.47). Those who started aspirin af-
ter 16 weeks had a smaller reduction
of pre-eclampsia (relative risk, 0.87),
but no significant reduction in severe
pre-eclampsia. The dose effect relation-
ship was also not observed for aspirin
started after 16 weeks of gestation.12
Another meta-analysis focusing on
12
the optimum time of commencement
suggested that the beneficial effect of
aspirin was consistent and women at
increased risk of pre-eclampsia should
be offered aspirin regardless of whether
treatment was started before or after 16
weeks of gestation.15
The most recent largest study was
the Aspirin for Evidence-Based Pre-ec-
lampsia Prevention (ASPRE) trial pub-
lished in 2017, and 1,776 women were
screened as high risk using a combined
model of maternal factor, mean arterial
pressure (MAP), uterine artery pulsatili-
ty index (UtA-PI), pregnancy-associated
plasma protein A (PAPP-A), and placental
growth factor (PlGF). Women were rand-
172 MIMS JPOG 2019 VOL. 45 NO. 4
Screening of high-risk group using a combination of maternal, ultrasound, and biochemical markers is superior than screening by
demographic factors and medical history.
omized to receive aspirin 150 mg/day or
placebo from 11–14 weeks to 36 weeks of
gestation. Preterm pre-eclampsia with de-
livery before 37 weeks occurred in 1.6% in
the aspirin group compared with 4.3% in
the placebo group. The trial demonstrat-
ed a major reduction in the rate of preterm
pre-eclampsia by 62%, pre-eclampsia be-
fore 34 weeks of gestation by 82% and
before 32 weeks of gestation by 89%. 16
Who should be given aspirin?
In 2010, NICE guideline identified histo-
ry of hypertensive disease in previous
pregnancy, chronic kidney disease, au-
toimmune disease, diabetes mellitus, or
chronic hypertension as major factors
for pre-eclampsia. For moderate risk
factors, they include first pregnancy,
age ≥40 years, inter-pregnancy inter-
val >10 years, body mass index (BMI)
at first visit of ≥35 kg/m2, family history
of pre-eclampsia or multiple pregnancy
(Table 3). Women with one major risk
CONTINUING MEDICAL EDUCATION
factor or any two or more moderate
factors should be given aspirin 75 mg
daily. 17
The 2011 World Health Organ-
ization (WHO) guideline also recom-
mended low-dose aspirin for women at
high risk of developing pre-eclampsia.
In 2013, ACOG considered nullipar-
ity, age >40 years, BMI ≥30 kg/m , con-
2
ception by in vitro fertilization, history of
previous pregnancy with pre-eclampsia,
chronic hypertension, chronic renal dis-
ease, diabetes mellitus, systemic lupus
erythematosus, or thrombophilia as risk
factors for pre-eclampsia. Low-dose as-
pirin (81 mg/day) should be reserved for
women with pre-eclampsia in more than
one prior pregnancy or those affected
by early onset pre-eclampsia requiring
delivery before 34 weeks. In the latest
1
update of the ACOG Committee Opin-
ion published in July 2018, an expanded
spectrum of aspirin use was adopted.19
Women at risk of pre-eclampsia are de-
fined based on the presence of one or
more high-risk factors or more than one
of several moderate-risk factors (Table 3).
Aspirin should be recommended if the
woman has one or more high-risk factors,
and it can be considered if the woman
18
has more than one moderate risk factor.
It should be initiated between 12 and 28
weeks of gestation (optimally before 16
weeks) and continued daily until delivery.
These international guidelines use
maternal demographic characteristics
and medical history to identify women at
risk of pre-eclampsia. Different maternal,
ultrasound, and biochemical parame-
ters have been investigated to develop a
prediction model for pre-eclampsia. The
measurement of MAP, Doppler measure-
ment of the UtA-PI, and biochemical mark-
ers of PAPP-A and PlGF were proposed as
useful markers to screen for pre-eclamp-
sia in the first trimester at around 11–13
weeks. An algorithm combining maternal
characteristics with these ultrasound and
biochemical factors was generated in
CONTINUING MEDICAL EDUCATION MIMS JPOG 2019 VOL. 45 NO. 4 173

2013.20 A detection rate of 96% for pre-ec-

lampsia requiring delivery before 34
weeks, 76.6% for preterm pre-eclampsia
before 37 weeks, and 54% for all cases
of pre-eclampsia at a false-positive rate
of 10% were suggested. The results of
ASPRE trial were comparable to the per-
formance of this prediction model. Using
a risk cut-off of 1 in 100, the detection
was 76.7% for preterm pre-eclampsia and
43.1% for term pre-eclampsia at a screen-
ing positive rate of 10.5% and false-posi-
tive rate of 9.2%.21
The prediction model was subse-
quently validated as accurate in a Eu-
ropean cohort by a prospective study
published in 2017.22 Further studies in
the UK and US also demonstrated a
better performance of screening for pre-
term pre-eclampsia by using a combi-
nation of maternal blood pressure and
biochemical markers with or without
Doppler study of uterine artery in the
first trimester compared with NICE or
ACOG guidelines. From the study on
screening programme for pre-eclamp- Chronic hypertension was the strongest risk factor for pre-eclampsia.

sia (SPREE) in UK, Tan, et al, reported

that in a cohort of 16,747 pregnan-
cies with preterm pre-eclampsia rate
of 0.8%, the screen-positive rate using
NICE guideline was 10.5% and the de-
tection rate for preterm pre-eclampsia
was 40.8%. 23
The screening perfor-
mance based on NICE risk factor iden-
tification was inferior to screening com-
bining MAP, PAPP-A, and PlGF in the
first trimester (detection rate of 69% at a
false-positive rate of 10%). When UtA-PI
was included, a higher detection rate of
82.4% could be achieved.
Comparison of the screening
method has been made with ACOG
guidelines. ACOG recommendations in
2013 could detect 90% preterm pre-ec-
lampsia and 89% term pre-eclampsia
at a false-positive rate of 64.2%. Using
ACOG screening guidelines for the use
of aspirin detected 5% preterm pre-ec-
lampsia and 2% term pre-eclampsia
at a false-positive rate of 0.2%.24 A re-
cent studies on US population provid-
ed further support on the superiority of
combined maternal, ultrasound, and
biochemical screening model for early
onset pre-eclampsia with higher detec-
tion rate, and lower false-positive rate
compared with risk factor screening. 25
Does aspirin work for all
women at risk of pre-eclampsia?
While the evidence was highlighting its
role to preterm pre-eclampsia, aspirin
did not seem to have a significant effect
on term pre-eclampsia.16,26 The screen-
ing using maternal characteristics and
biomarkers yielded a much poorer per-
formance for term pre-eclampsia.25,27
Chronic hypertension was the strong-
est risk factor for pre-eclampsia.28
However, the beneficial effect of aspirin
in the prevention of preterm pre-ec-
lampsia among women with chronic
hypertension was not apparent in the
subgroup analysis of ASPRE trial.29
Furthermore, it remains to be proven if
the screening strategy and preventive
regimen are applicable to the Asian
population.30-31
In normal placentation, the first
wave of trophoblast invasion is com-
pleted around 10 weeks. This is fol-
174 MIMS JPOG 2019 VOL. 45 NO. 4
The current evidence suggested that aspirin works mainly in the prevention of preterm pre-eclampsia but not term pre-eclampsia.
lowed by the second wave occurring at
around 14–16 weeks leading to a trans-
formation of the uterine spiral arteries.
Aspirin was postulated to work by im-
proving placentation and reducing en-
dothelial dysfunction, which could be
the underlying pathophysiology pre-
term pre-eclampsia. For women with
chronic hypertension, pre-eclampsia
might develop in the absence or less
severe degree of impaired placenta-
tion in a background of pre-existing
endothelial dysfunction and inflam-
mation which was exacerbated during
pregnancy.
Safety issues of aspirin
Aspirin is generally considered safe
in pregnancy and not associated with
congenital foetal abnormality, but data
on long-term effects are insufficient.
No increase in haemorrhagic compli-
CONTINUING MEDICAL EDUCATION
cations, post-partum haemorrhage, or
mean blood loss was found. It has been
shown that taking aspirin at a dose of
more than 100 mg before 16 weeks, in
fact, decreases the risk of antepartum
haemorrhage or placental abruption. 33
There are few contraindications to as-
pirin use, namely aspirin allergy or
hypersensitivity to other salicylates or
non-steroidal anti-inflammatory drugs
and known history of aspirin-induced
acute bronchospasm. Gastrointestinal
or genitourinary bleeding, active peptic
ulcer disease, severe hepatic dysfunc-
tion, and Reye’s syndrome are relative
contraindications.19
CALCIUM SUPPLEMENTATION
Early epidemiologic study demon-
strated a reverse relationship of blood
1,32
pressure and calcium intake. Several
34
trials have examined the role of calci-
um in the prevention of pre-eclampsia.
The randomized trial by WHO in 2006
suggested that calcium supplemen-
tation of 1.5 g/day among pregnant
women with low calcium intake could
reduce the severity of pre-eclampsia.35
Based on the recommendation from
WHO in 2011 and Cochrane review
in 2014, calcium supplementation
of at least 1 g/day reduced the risk
of pre-eclampsia especially among
women of high risk and low calcium
intake. 36
A recent meta-analysis gave a
concurring finding that calcium might
prevent pre-eclampsia when initiated at
about 20 weeks or later.37 Until stronger
evidence is available, calcium supple-
mentation for the prevention of pre-ec-
lampsia should be reserved for popula-
tions with low baseline calcium intake
(<600 mg daily).1,38
CONTINUING MEDICAL EDUCATION MIMS JPOG 2019 VOL. 45 NO. 4 175

TERM PRE-ECLAMPSIA achieved by a combination of maternal best prophylactic outcome. Screening

The current evidence suggested that
aspirin works mainly in the prevention
of preterm pre-eclampsia but not term
pre-eclampsia. Research has been car-
ried out to develop a prediction and
prevention strategy for term pre-ec-
lampsia which represents a major pro-
portion of all pre-eclampsia. An ele-
vated anti-angiogenic soluble fms-like
tyrosine kinase-1 (sFlt-1) was found to
be associated with term pre-eclampsia.
Screening for term eclampsia could be
factors, MAP, UtA-PI, PlGF, and sFlt-1 at
30–34 weeks.39-40 Further studies are on-
going to examine the emerging role of
pravastatin for the prevention and treat-
ment of term pre-eclampsia.
CONCLUSION
The current evidence suggests that as-
pirin is an effective drug for the preven-
tion of pre-eclampsia. Data favours a
higher dosage started before 16 weeks
of gestation and taken at night for the
of high-risk group using a combination
of maternal, ultrasound, and biochemi-
cal factors at 11–14 weeks of gestation
is superior to screening by maternal
41
demographic risk factors. The overall
performance of screening and aspi-
rin appeared much better for preterm
pre-eclampsia than term pre-eclampsia.
About the author
Dr Pui Wah HUI is a Consultant in the Department of Obstet-
rics & Gynaecology, Queen Mary Hospital, Hong Kong SAR.
Conflict of interest: None.

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176 MIMS JPOG 2019 VOL. 45 NO. 4 CME QUESTIONS

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CME ARTICLE

Prevention of Pre-eclampsia
Answer True or False to the questions below.

True False
1. Proteinuria may not be present in all cases of pre-eclampsia.
2. The pathophysiology of preterm pre-eclampsia is related to impaired implantation.
3. Aspirin is effective in preventing both preterm and term pre-eclampsia.
4. Aspirin works well for the prevention of pre-term pre-eclampsia in women with
chronic hypertension.
5. Low-dose aspirin should be given as it is associated with a lower risk of placental
abruption.
6. Aspirin should be taken at night time instead of daytime.
7. Screening performance for women at risk of pre-eclampsia by demographic risk
factors is comparable to the screening performance by MAP, Doppler artery study,
and biochemical parameters.
8. Folate supplementation is essential for the prevention of pre-eclampsia.
9. The daily calcium supplementation of 1 gram should be considered for all
pregnant women to prevent pre-eclampsia.
10. The sFlt-1 is elevated in the third trimester for women at risk of developing
pre-eclampsia.

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