INDONESIA • 2019

ISSN 2411-0140
VOL. 45 NO. 3

JOURNAL OF PAEDIATRICS,
OBSTETRICS & GYNAECOLOGY

YOUR PARTNER IN PAEDIATRIC, OBSTETRIC & GYNAECOLOGY PRACTICE

OBSTETRICS
Early Pregnancy
Complications

PAEDIATRICS
Management
of Meningococcal
Disease

CME ARTICLE
Moving Towards
Evidence-based
Gestational Diabetes
Mellitus Screening
 MIMS JPOG 2019 VOL. 45 NO. 3 i

2019 VOL. 45 NO. 3

Editorial Board
CONFERENCE COVERAGE
Board Director, Paediatrics
Annual Meeting of the European Society of Human
Professor Pik-To Cheung
Associate Professor, Department of Paediatrics and Adolescent Medicine Reproduction and Embryology (ESHRE) 2019, June
The University of Hong Kong, Hong Kong
23-26, Vienna, Austria
Board Director, Obstetrics and Gynaecology
Professor Pak-Chung Ho
Director, Centre of Reproductive Medicine 89
The University of Hong Kong - Shenzhen Hospital, China
• Immediate frozen embryo
transfer improves pregnancy, live
birth rates
Professor Biran Affandi Professor Seng-Hock Quak
University of Indonesia, Indonesia National University of Singapore, • Myo-inositol improves quality of
Singapore oocyte, embryo in ART-treated
Professor Hextan
Yuen-Sheung Ngan Adjunct Associate Professor women with PCOS
The University of Hong Kong, Hong Kong Tan Ah Moy
KK Women’s and Children’s Hospital,
Professor Kenneth Kwek Singapore
KK Women’s and Children’s Hospital,
Singapore Dr. Catherine Lynn Silao
University of the Philippines Manila,
Professor Kok Hian Tan
KK Women’s and Children’s Hospital,
Philippines 90
Dwiana Ocviyanti, MD, PhD
Singapore
University of Indonesia, Indonesia • Long-term sperm cryopreservation does not affect
Professor Dato’
Dr. Ravindran Jegasothy
Dr. Karen Kar-Loen Chan pregnancy success
The University of Hong Kong,
Dean Faculty of Medicine, Hong Kong
MAHSA University, Malaysia
Dr. Kwok-Yin Leung
Associate Professor Daisy Chan The University of Hong Kong,
Singapore General Hospital, Singapore Hong Kong
Associate Professor Raymond
Hang Wun Li
Dr. Mary Anne Chiong
University of the Philippines Manila,
JOURNAL WATCH
The University of Hong Kong, Hong Kong Philippines

Adjunct Associate Professor Dr. Wing-Cheong Leung

Ng Kee Chong
Kwong Wah Hospital, Hong Kong,
Hong Kong
91
Division of Medicine & Academic Clinical
Program (Paediatrics), c/o KK Women’s and • USPSTF recommends screening
Children’s Hospital, Singapore
pregnant women for hepatitis B
• Uptick in foreign body ingestions
among kids ‘alarming’

92
• Women with POI receiving HT experience worse fatigue,
poor sleep quality
 MIMS JPOG 2019 VOL. 45 NO. 3 iii

2019 VOL. 45 NO. 3

REVIEW ARTICLE
OBSTETRICS
CEO Yasunobu Sakai
Managing Editor Elvira Manzano
Medical Editor Elaine Soliven
Designer Sam Shum
93
Production Tetsuya Hamaki, Agnes Chieng
Circulation Christine Chok Early Pregnancy Complications
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The early pregnancy period can be
complicated by a range of symptoms
Published by: varying from nausea, vomiting,
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to more severe conditions such
as hyperemesis gravidarum (HG),
early embryonic demise, mental
health problems, and either molar or ectopic pregnancies. This
Enquiries and Correspondence review summarizes the key presentations, investigations, and
China Singapore
management of the most common complications that can arise
Yang Xuan Josephine Cheong, Bernice Eng, in early pregnancy.
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104
Ruth Theresia, Sari Wiyanti
Tel: (62 21) 729 2662 Prevention and Treatment of Osteoporosis
Email: enquiry.id@mims.com
in Women
Malaysia
Brenda Yong, Xavier Wee, Osteoporosis is a disease with a
Kam Zhi Yan, Sugalia Santhira significant disease burden worldwide,
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Email: enquiry.my@mims.com affecting more than 75 million people
Philippines in the US, Europe, and Japan. With an
Rowena Belgica
Tel: (63 2) 886 0333
ageing population, the incidence of
Email: enquiry.ph@mims.com osteoporosis is growing. Osteoporotic
fractures have significant individual
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iv MIMS JPOG 2019 VOL. 45 NO. 3

2019 VOL. 45 NO. 3

REVIEW ARTICLE CME Accreditation

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PAEDIATRICS accredited for CME points by the Singapore Medical Council (SMC).

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Management of Meningococcal Disease
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CONTINUING
MEDICAL EDUCATION
125
Moving Towards Evidence-based
Gestational Diabetes Mellitus Screening
Recent surveys showed that the Oral Glucose Tolerance Test
(OGTT), using the International Association of the Diabetes and
Pregnancy Study Group (IADPSG) criteria, is now a common
screening practice for gestational diabetes mellitus (GDM).1
The surveys found that hospitals in the Asia-Pacific region
followed recommendation from international studies calling for
a universal method for screening GDM and using evidence from
the international HAPO (Hyperglycemia and Adverse Pregnancy
Outcome) study. This change and standardization in practice
enhance evidence-based practices into GDM screening, allowing
optimal screening and encourages follow-up management for
better outcomes. The Cover:
Prevention and Treatment of Osteoporosis in Women
Kok Hian TAN
©2019 MIMS Pte Ltd

Peggy Tio, Designer

EMPOWERING
HEALTHCARE
COMMUNITIES
CONFERENCE COVERAGE
Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE) 2019,
June 23-26, Vienna, Austria
Immediate frozen embryo
transfer improves pregnancy,
live birth rates
Women who underwent immediate fro-
zen-thawed embryo transfer (FET) following
a stimulated in vitro fertilization (IVF) cycle
were more likely to have ongoing pregnan-
cy and live birth compared with those who
underwent delayed FET, according to a
study presented at ESHRE 2019.
“Immediate FET following a stimu-
lated IVF cycle had a significantly higher
ongoing pregnancy rate than delayed FET.
The findings of the study support immedi-
ate FET after a failed fresh ET cycle or a
freeze all cycle,” said study author Dr He Li
from Shanghai Ji Ai Genetics and IVF Insti-
tute, Obstetrics and Gynecology Hospital,
Fudan University in Shanghai, China.
The researchers conducted a study
involving 724 women (aged ≤43 years)
from Shanghai and Hong Kong who were
randomized to undergo either immediate
FET (n=362; FET performed in the first
cycle) or delayed FET (n=362; FET per-
formed in the second cycle) after a failed
stimulated IVF cycle between August 2017
and December 2018. All FETs were per-
formed in hormonal replacement cycles.
[ESHRE 2019, abstract O-068]
In the intention-to-treat (ITT) analysis,
women who underwent immediate FET
had a significantly higher rate of ongoing
pregnancy than those who had delayed
FET (47.2 percent vs 39.2 percent, relative
risk [RR], 0.72, 95 percent confidence in-
terval [CI], 0.54–0.97; p=0.030), which ex-
ceeded the predefined equivalence mar-
gin of 10 percent.
A similar result was seen in the
per-protocol analysis with a significantly
higher rate of ongoing pregnancy among
women in the immediate FET group com-
pared with the delayed FET group (49.6
percent vs 41.5 percent, RR, 0.72, 95 per-
cent CI, 0.53–0.98; p=0.034).
In addition, women in the immediate
FET group had an increased live birth rate
than those in the delayed FET group (39.5
percent vs 31.5 percent, odds ratio, 0.70,
95 percent CI, 0.52–0.96). However, the
number of live births among 56 women
are still pending, said Li.
Significantly fewer miscarriages oc-
curred among women who had immediate
FET compared with delayed FET (11.2 per-
cent vs 19.7 percent, RR, 1.95, 95 percent
CI, 1.09–3.47; p=0.022 for both ITT and
per-protocol analyses).
“FET has become an increasingly
important part of IVF, but there is still no
good evidence to support when to per-
form FET following a stimulated IVF cycle.
Since all published studies are retrospec-
tive and the findings are contradictory, a
randomized study [was] needed to pro-
vide level one evidence to guide the clini-
cal practice,” said Li.
– ELAINE SOLIVEN
Dr He Li, et al. Annual Meeting of the European Society of
Human Reproduction and Embryology (ESHRE 2019), June
23-26, Vienna, Austria [abstract O-068].
Myo-inositol improves quality of
oocyte, embryo in ART-treated
women with PCOS
Women with polycystic ovarian syndrome
(PCOS) undergoing assisted reproductive
technology (ART) cycles may benefit from
the administration of myo-inositol (MI) which
improves oocyte and embryo quality due to
alterations in gene expression in granulo-
sa cells, according to a study presented at
ESHRE 2019.
MIMS JPOG 2019 VOL. 45 NO. 3 89
“Despite the higher number of oo-
cytes retrieved from PCOS patients during
IVF*, the quality and maturity of oocytes
and embryo are lower than [that of] non-
PCOS infertile women … [thus leading to]
repeated ART attempts,” explained the re-
searchers. “[Our findings showed that] MI
supplementation in ART cycles among pa-
tients with PCOS increases the percentage
of metaphase II oocytes to total oocytes,
as well as the fertilization rate and the ratio
of good quality embryos.”
Fifty IVF candidates aged 20–35
years were randomized 1:1 to receive
daily doses of 400 mg folic acid either
alone (placebo) or in combination with
MI 4 g from a month prior to the IVF cy-
cle until the day of ovum pick-up. [ESHRE
2019, abstract P-690; Arch Gynecol Obstet
2019;299:1701-1707]
Despite the lack of significant be-
tween-group difference in the number of
retrieved oocytes (p<0.6), there was a sig-
nificant increase in the percentage of met-
aphase II oocytes (78.7 percent vs 58.3
percent; p=0.003) and fertilization rate
(65.2 percent vs 46.8 percent; p=0.03)
with MI vs placebo.
MI also improved the percentage of
grade 1 embryos (p=0.006) and reduced
the fraction of grade 3 (bad) embryos
(p=0.029). However, this requires further
elucidation considering the contradicting
results in other studies, [Eur Rev Med
Pharmacol Sci 2011;15:509-514; Gynecol
Endocrinol 2016;32:69-73] which could
be attributed to differences in the type of
ovarian stimulation protocols or the du-
ration of the intervention used, noted the
researchers.
Gene expression of PGK1**,
RGS2***, and CDC42#, which influence
oocyte quality in granulosa cells, was
significantly higher with MI vs placebo
90 MIMS JPOG 2019 VOL. 45 NO. 3
(p=0.013, p=0.021, and p<0.001, re-
spectively).
PGK1 plays an important role in
glycolysis, which is crucial for oocyte
maturation and competence.
Steril 2013;99:979-997; Cell Mol Life Sci
2015;72:251-271] “In the final stages
of folliculogenesis, oocytes are unable
to oxidize glucose during glycolysis …
and are highly dependent on glycolytic
products provided by granulosa cells
for energy supplementation,” noted the
researchers. Therefore, increasing PGK1
expression can improve glycogenesis in
the granulosa cells, consequently influ-
encing oocyte maturation and compe-
tence, they added.
However, despite its molecular ef-
fect, MI did not improve cumulative preg-
nancy rate (40 percent vs 35 percent;
p=0.74). The researchers attributed this
to the small study sample and called for
larger trials to further elucidate the find-
ings. “If the clinical efficacy of our find-
ings on pregnancy rate is approved by
further [randomized controlled trials], the
use of MI as an adjuvant in ART cycles
can be suggested for PCOS patients.”
*IVF: In vitro fertilization
**PGK1: Phosphoglycerate kinase 1
***RGS2: Regulator of G-protein signalling 2
#CDC42: Cell division cycle 42
– AUDREY ABELLA
Dr Akbari Sene, et al. Annual Meeting of the European Soci-
ety of Human Reproduction and Embryology (ESHRE 2019),
June 23-26, Vienna, Austria [abstract P-690].
Long-term sperm
cryopreservation does not
affect pregnancy success
Likelihood of pregnancy following arti-
ficial insemination by donor (AID) or in
vitro fertilization (IVF) was not negatively
affected by using sperm that had been
CONFERENCE COVERAGE
cryopreserved for up to 15 years, according
to a study from China.
[T]he long-term storage of sperm
does not appear to affect live birth rates,”
[Fertil said study author Dr Chuan Huang from
the Reproductive & Genetic Hospital of
CITIC-Xiangya, Human Sperm Bank,
Changsha- Hunan, China, who presented
the findings at ESHRE 2019.
In this study, sperm stored for up to 15
years was still effective in leading to preg-
nancy, said co-author Dr HL Wu, also from
the Reproductive & Genetic Hospital of CIT-
IC-Xiangya.
Huang and co-authors assessed the
sperm quality of 119,558 specimens at the
Hunan Province Human Sperm Bank of Chi-
na. The duration of cryostorage was divid-
ed into three-time frames: 0.5–5, 6–10, and
11–15 years.
There was a significant reduction in the
frozen-thaw survival rate of the sperm over
the 15-year cryopreservation period, from
85.72 to 73.98 percent (p<0.01). [ESHRE
2019, abstract O-018]
The clinical pregnancy rate among
women who underwent AID was numeri-
cally reduced when using sperm cryopre-
served for 11–15 compared with 0.5–5 years
(22.32 percent vs 23.09 percent), as was the
pregnancy rate following IVF (53.48 percent
vs 64.29 percent). Similarly, the live birth rate
was also reduced with longer duration of
sperm cryopreservation, be it following AID
(80.00 vs 82.17 for 11–15 vs 0.5–5 years) or
IVF (73.91 percent vs 81.63 percent).
In contrast, clinical abortion rates
increased with longer duration of sperm
cryopreservation, in pregnancies following
AID (12.00 percent vs 10.06 percent for
11–15 vs 0.5–5 years) or IVF (17.39 per-
cent vs 12.26 percent).
However, the decreases in clinical
pregnancy and live birth rates and increase
in clinical abortion rates did not significantly
differ between sperm that had been cryo-
PEER REVIEWED
preserved for 6–10 or 11–15 years with
that cryopreserved for 0.5–5 years.
Previously published research has
reported on successful live births following
intrauterine insemination using sperm that
had been preserved in liquid nitrogen for
21 and 28 years [Fertil Steril 2005;84:1017]
as well as following intracytoplasmic
sperm injection/IVF using sperm pre-
served for about 40 years. [J Assist Reprod
Genet 2013;30:743-744]
Unlike some countries that maintain
a legal limit as to how long sperm can be
cryopreserved to be used for assisted re-
production, according to Wu, China does
not impose this limit.
Despite the lack of impact on preg-
nancy, Huang and co-authors recommend-
ed that “sperm banks provide sperm in their
order of cryopreservation” based on the
significant reduction in the frozen-thaw sur-
vival rate with time. Furthermore, the num-
ber of men whose sperm was preserved for
up to 15 years in this study was small. This
precludes any firm conclusions from being
made on the safety of using sperm that has
been preserved for that period or longer.
Huang and colleagues cautioned
that these results should also not be gen-
eralized to the general population, seeing
as how the men included in this study
were more likely to have better sperm
quality than other men.
“Donors at our sperm bank must be
in good health according to physical ex-
amination and psychological evaluation,
and have no familial history of a genetic
disease,” said Huang. She also acknowl-
edged that congenital abnormalities fol-
lowing AID or IVF procedures were not
accounted for in this study.
– ROSHINI CLAIRE ANTHONY
Dr Chuan Huang, et al. Annual Meeting of the European
Society of Human Reproduction and Embryology (ESHRE
2019), June 23-26, Vienna, Austria [abstract O-018].
JOURNAL WATCH PEER REVIEWED
O series by the time an infant reaches
Obstetrics
USPSTF recommends
screening pregnant women
for hepatitis B
The US Preventive Services Task Force
(USPSTF) has given an ‘A’ level rec-
ommendation to screening women for
hepatitis B at their first prenatal visit in a
recent report.
“Although there are guidelines for
universal infant HBV vaccination, rates
of maternal HBV infection have in-
creased annually by 5.5 percent since
1998,” wrote the task force. “Children
infected with HBV during infancy or
childhood are more likely to develop
chronic infection which increases long-
term morbidity and mortality.”
Data show there were 85.8 cas-
es of maternal HBV infection for each
100,000 deliveries from 1998 to 2011,
according to the task force.
Aside from screening pregnant
women for hepatitis B, other effec-
tive interventions to prevent perinatal
transmission of HBV include vacci-
nating infants born to HBV-negative
mothers within 24 hours of their birth
and completing the HBV vaccination
18 months old, added the USPSTF.
Enrolling mothers and their children
in case management has also been
shown to provide substantial health
benefits.
The USPSTF recommendation to
screen pregnant women for HBV was
in line with the CDC Advisory Commit-
tee on Immunization Practices, Amer-
ican College of Obstetricians and Gy-
necologists, and American Academy
of Family Physicians recommendations
regarding this field.
In a related editorial, Dr Neil S.
Silverman from the department of ob-
stetrics and gynaecology, David Geffen
School of Medicine at the University of
California, in California, Los Angeles,
US said adherence to the recommen-
dations also allows for discussions and
implementation of treatment modal-
ities, including maternal HBV-target-
ed antiviral therapy during pregnancy
as an adjunct to neonatal immuno-
prophylaxis to address the risk of foetal
infection.
USPSTF. Screening for Hepatitis B Virus Infection in Pregnant
Women – US Preventive Services Task Force Reaffirmation Rec-
ommendation Statement; JAMA 2019;322:349-354; Silverman,
NS. Hepatitis B Screening in Pregnant Women A Perspective on
the New USPSTF Recommendations; JAMA 2019;322:312-314.
MIMS JPOG 2019 VOL. 45 NO. 3 91
P
Paediatrics
Uptick in foreign body
ingestions among kids
‘alarming’
Ingestion of foreign objects among
young children has dramatically in-
creased in the US, with the number of
emergency department (ED) visits dou-
bling between 1995 and 2015, according
to a retrospective analysis of a national
database.
“Kids explore the world with their
mouths, so anything that is in their realm
of reach is something that they could po-
tentially ingest,” said lead study author
Dr Danielle Orsagh-Yentis, a paediat-
ric gastrointestinal motility fellow at the
Nationwide Children’s Hospital in Co-
lumbus, Ohio, US. “This alarming trend
among children is something we should
take note of.”
This spike in foreign body inges-
tions among children has put a strain on
the EDs. Although about 80–90 percent
of foreign bodies pass through the gas-
trointestinal tract spontaneously with-
out difficulties, some may cause serious
complications and require endoscopic or
surgical removal.
A child who presents to the ED on
suspicion of having swallowed a for-
eign body – often a coin, small toy, or
button battery – will undergo evaluation
for symptoms, imaging, and removal of
the object endoscopically or surgically if
necessary, said Orsagh-Yentis. “We, phy-
sicians, should talk about the dangers
of ingesting these types of objects and
educate the families we see on a regular
basis … discuss what may happen when
a child ingests an object.”
92 MIMS JPOG 2019 VOL. 45 NO. 3
The American Academy of Paedi-
atrics recommends that paediatricians
discuss preventive medicine tactics with
parents, such as choking hazards and
safe storage. Orsagh-Yentis explained
that safe storage includes keeping po-
tentially ingestible and hazardous ob-
jects locked in a cabinet at an unreacha-
ble height that is out of children’s sight.
Orsagh-Yentis D, et al. Foreign-Body Ingestions of Young Chil-
dren Treated in US Emergency Departments: 1995–2015. Pedi-
atrics 2019;doi:10.1542/peds.2018-1988.
Gynaecology
Women with POI receiving HT
experience worse fatigue, poor
sleep quality
Women with primary ovarian insuffi-
ciency (POI) who are receiving hor-
mone therapy (HT) experience worse
fatigue and poor sleep quality than
women of similar age with preserved
ovarian function, according to a new
study.
Primary ovarian insufficiency caus-
es physical and psychological effects
resulting from hypoestrogenism, such
as fertility loss, bone loss, an increased
cardiovascular risk, psychological dis-
turbances, altered sexuality, and even
the risk of earlier mortality, said Dr Cris-
tina Laguna Benetti-Pinto, professor at
the Department of Gynaecology and
Obstetrics at the University of Campinas
School of Medical Sciences in Campi-
nas, São Paulo, Brazil. “Treatment
should minimize such repercussions.”
The study involved 61 women with
POI who were receiving hormone ther-
apy (mean HT duration, 7.84 years, 75
percent nulliparous) and 61 women with
preserved ovarian function who served
as controls. They were matched by age
and asked to complete the Pittsburgh
Sleep Quality Index (PSQI) and Chalder
Fatigue Scale, both self-administered
JOURNAL WATCH PEER REVIEWED
questionnaires that assess sleep quality
and severity of fatigue.
PSQI scores were comparable be-
tween the two groups (mean scores, 7.69
for women with POI and 8.03 for controls;
p=0.79). However, women with POI had
higher or worse scores for the sleep laten-
cy component (mean scores, 1.74 vs 1.18;
p<0.001) and use of sleep medication
(mean scores, 1.28 vs 0.85; p=0.008).
In terms of fatigue, women with POI
had higher fatigue indices vs controls
(mean scores, 5.25 vs 3.49; p<0.001), with
fatigue occurring in 59 percent of women
with POI and in 18 percent of controls.
(p=0.001).
“Variables directly related to ovar-
ian insufficiency, such as the diagnosis
time or treatment time, were not related
to sleep. Nevertheless, the greater the
number of children, the worse the quality
of sleep [p=0.001],” said the researchers.
Benetti-Pinto CL, et al. Sleep quality and fatigue in women
with premature ovarian insufficiency receiving hormone ther-
apy: a comparative study. Menopause 2019;doi:10.1097/
GME.0000000000001379.
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OBSTETRICS PEER REVIEWED MIMS JPOG 2019 VOL. 45 NO. 3 93

Early Pregnancy
Complications
Sai Gnanasambanthan MBBS BSc (Hons) MRCOG; Shree Datta MBBS LLM BSc (Hons) MRCOG

The early pregnancy period can be complicated by a range of symptoms varying

from nausea, vomiting, vaginal spotting, and pelvic pain to more severe conditions
such as hyperemesis gravidarum (HG), early embryonic demise, mental health
problems, and either molar or ectopic pregnancies. Some of these conditions require
hospital admission and multidisciplinary team management, whilst others can be
managed in an outpatient setting after the appropriate investigations. Complications
early on in the pregnancy can be distressing, therefore women who experience such
symptoms require close monitoring, reassurance, and information on how to access
help. Early pregnancy units have been specifically designed to serve patients with
complications in early pregnancy and the health professionals are trained to support
women during their treatment, whilst helping these patients make informed decisions
about their care. This review summarizes the key presentations, investigations, and
management of the most common complications that can arise in early pregnancy.

INTRODUCTION period and lasts until the end of the 12th

Early pregnancy, or the first trimester, be- week. Most women are aware of preg-
gins on the first day of the woman’s last nancy-associated symptoms during this
94 MIMS JPOG 2019 VOL. 45 NO. 3
Table 1. Motherisk PUQE-24 Scoring System
In the last 24 hours, for how Not at all (1) 1 hour or less (2)
long have you felt nauseated
or sick to your stomach?
In the last 24 hours, have 7 or more times (5) 5–6 times (4)
you vomited or thrown up?
In the last 24 hours, how No time (1) 1–2 times (2)
many times have you had
retching or dry heaves
without bringing anything up?
PUQE-24 score: Mild = ≤6; Moderate = 7–12; Severe = 13–15
period and prior to confirmation of conception.
Tiredness, breast tenderness, nausea, and mood
swings are some of the most common early signs
that appear in the first trimester of pregnancy. Oth-
er symptoms can also present in the first 12 weeks
but can be more severe and require close moni-
toring and quick and efficient treatment. The most
common early pregnancy complications are:
a. HG
b. Early embryonic demise and ectopic pregnancy
c. Molar pregnancy
d. Ovarian hyperstimulation syndrome (OHSS)
e. Ovarian accidents
f. Urinary tract infection
g. Abnormal vaginal discharge
h. Unplanned pregnancy occurred while using
contraception/intrauterine devices
i. Mental health problems
This review summarizes each of these key
presentations, expanding on investigations and
management for each.
Hyperemesis gravidarum
HG is defined as protracted vomiting asso-
ciated with a triad of weight loss of over 5%,
dehydration, and electrolyte imbalance (eg,
hyponatraemia, hypokalaemia, and hypochlo-
raemia). It can be diagnosed using the Preg-
nancy-Unique Quantification of Emesis (PUQE)
score (Table 1). This form of severe nausea and
vomiting in pregnancy affects about 0.3–3.6%
OBSTETRICS PEER REVIEWED
2–3 hours (3) 4–6 hours (4) More than 6
hours
3–4 times (3) 1–2 times (2) I did not throw
up (1)
3–4 times (3) 5–6 times (4) 7 or more times (5)
of pregnant women, while recurrence rates
vary. It usually starts between the 4th and 7th
week of gestation with a peak between the 9th
and 10th week, with 90% of cases resolving by
20 weeks. If initial onset is after 10 + 6 weeks
gestation, other causes need to be ruled out.
HG is primarily thought to be associated with
rising beta-hCG levels, with more severe cas-
es seen in trophoblastic disease and multiple
pregnancy where the hormone level is also
very high.
One hospital admission for HG is estimated
to cost £470 per day. The average length of
hospital stay is 3.5 days. It is estimated that
NHS funds diverted to treat hyperemesis
can reach £36,481,745 a year. This doesn’t
include the cost of the appointments with
midwives or GP prior to admission.
Ref: Statement on the cost of hyperemesis.
https://www.pregnancysicknesssupport.org.
uk/resources/literature-review/hyperemesis-
gravidarum-9/
Baseline assessment includes:
• A thorough history of nausea or vomiting in
pregnancy or HG, the use of the PUQE score,
and exclusion of other causes of the symp-
toms (urinary infections, drug history, etc).
• Examination for signs of dehydration, basic ob-
servations using the MEWS chart, abdominal
OBSTETRICS PEER REVIEWED
When pregnancy is complicated by HG, inpatient treatment should be provided.
palpation, and patient's weight plus BMI. Urine
dipstick analysis – with an MSU if required.
• Blood, including urea and electrolytes to as-
sess for electrolyte imbalance, dehydration,
and renal disease, a full blood count to as-
sess the risk of infection and anaemia, and
blood glucose if diabetic (to help rule out di-
abetic ketoacidosis).
• Ultrasound scan to confirm viability of preg-
nancy, or to diagnose multiple pregnancy or
trophoblastic disease.
Patients with recurrent admissions require
thyroid tests, liver function tests, calcium and
phosphate testing, amylase, and an arterial
blood gas.
Ideally, women with nausea and vomiting
but without dehydration should be managed in
the community with oral antiemetics, reassur-
ance, and advice on oral hydration and diet. If
this fails and the PUQE score is less than 13,
ambulatory daycare management can be im-
plemented to provide parenteral fluids, vitamins
MIMS JPOG 2019 VOL. 45 NO. 3 95
such as the B-complex, and antiemetics. This
regimen has been shown to improve symptoms
in up to 90% of cases.
When pregnancy is complicated by HG,
inpatient treatment should be provided. The
criteria used for admission of women with hy-
peremesis are:
• Inability to keep down any medication or an-
tiemetics.
• 
Associated comorbidities such as urinary
tract infections.
• Constant nausea and vomiting with ketonu-
ria, and/or weight loss of more than 5%, de-
spite antiemetics.
Medical treatment includes antiemetics,
antacids, thiamine and folic acid supplements,
thromboprophylaxis, and intravenous fluids.
Normal saline and potassium chloride are used
for rehydration as most women are hypon-
atraemic, hypochloraemic, hypokalaemic, and
ketotic. Dextrose can precipitate Wernicke’s en-
cephalopathy, therefore this is only appropriate
96 MIMS JPOG 2019 VOL. 45 NO. 3
CRL is 7 mm or above with no foetal activity or MGS is
25 mm or above and is empty
• Offer transvaginal ultrasound in 7 days
• Offer patient a second opinion
If the MGS is less than 25 mm
• Repeat scan after a minimum of 7 days
If the CRL is less than 7 mm with no foetal heart activity
• Repeat scan after a minimum of 7 days
Abbreviations: CRL = crown rump length; MGS = mean gestation sac
Figure 1. Management of miscarriage according to ultrasound findings.
if thiamine has been administrated and sodium
levels are normal.
First-line antiemetics are antihistamines
and phenothiazines, while second-line thera-
pies include metoclopramide (due to the risk of
extrapyramidal side effects) and ondansetron
(due to limited data available). Corticosteroids
are used only for resistant cases of hyperem-
esis where all the other treatments have failed
(100 mg intravenous hydrocortisone twice-dai-
ly, then oral prednisolone 40–50 mg daily once
clinical improvement occurs, with the dose
gradually tapered by 10 mg every 2–3 days un-
til the lowest maintenance dose that controls
symptoms is reached). Typically, prednisolone
will need to be continued at the lowest main-
tenance dose until the gestational age where
symptoms generally resolve, but in extreme
cases, this may be till delivery. Thiamine is ad-
ministered to all women with hyperemesis to
reduce the risk of Wernicke encephalopathy.
Associated gastro-oesophageal reflux is man-
aged with histamine H2 receptors antagonists
or proton pump inhibitors.
Thromboprophylaxis with low
lar weight heparin (LMWH) is indicated in hy-
peremesis where patients are admitted, and
oral iron supplements should be avoided in
OBSTETRICS PEER REVIEWED
cases of severe nausea and vomiting as they
can exacerbate symptoms.
Patients who want to avoid medical
therapies can consider the use of ginger in
mild-to-moderate nausea and vomiting. Studies
have shown that it reduces symptoms compared
with placebo therapies, although inferior to met-
oclopramide. Acupressure may also improve
symptoms and is safe in pregnancy. In compli-
cated cases of hyperemesis, where all medical
treatments have failed, enteral or parenteral ap-
proaches can be considered; in severe cases,
the option of termination of pregnancy should
be discussed with the patient. Patients who con-
tinue to have sickness in the second trimester
should be offered regular antenatal appoint-
ments and foetal growth scans. All these women
need a multidisciplinary approach to manage
and support them.
Early embryonic demise and ectopic
pregnancy
Although vaginal bleeding is associated with a
20% risk of miscarriage, it can also be a sign of
molar or ectopic pregnancy. Diagnostic trans-
vaginal ultrasound scan should be offered to
all pregnant women who present with vaginal
bleeding and are haemodynamically stable.
The diagnosis of early embryonic demise is
made using the crown rump length (CRL) and
mean gestation sac (MGS) measurements on
the ultrasound scan as shown in Figure 1.
A written report should be issued to the pa-
tient following her consultation. This should state
the clinical findings, diagnosis (Table 2), inves-
tigation results, and a clear management plan.
Women with vaginal bleeding and a viable
intrauterine pregnancy on scan need to be ad-
vised that if her bleeding worsens or persists for
more than 14 days, she should return for further
assessment. If the bleeding ceases, then she
molecu- should start or continue antenatal care.
After the cause of bleeding is estab-
lished as early embryonic demise in the first
trimester, the treatment options should be
OBSTETRICS PEER REVIEWED
Table 2. Terminology in Early Pregnancy
Terminology Vaginal bleeding
Threatened miscarriage Present
Inevitable miscarriage Present
Incomplete miscarriage Present
Complete miscarriage Absent
discussed with the patient. Expectant man-
agement should be offered as the first-line
treatment option for 7–14 days, where there
is no increased risk of haemorrhage, previous
adverse experience with pregnancy, history of
coagulopathies or evidence of infection. Wom-
en should be provided with oral and written
information on what to expect and how to get
help in case of an emergency. If the bleeding
and pain stops within the 7–14 days, this sug-
gests a complete miscarriage and the woman
should be advised to take a urinary pregnancy
test after 3 weeks and return if it is positive. A
repeat scan is offered if pain or bleeding has
not started after 7–14 days or if the symptoms
persist beyond this time indicating an incom-
plete miscarriage.
Medical management should be offered
to women if expectant management is not ac-
ceptable. The standard misoprostol regimen
includes 800 μg vaginally, or orally if preferred,
for a missed miscarriage or 600 µ g for an in-
complete miscarriage. Women should seek
advice if bleeding has not started 24 hours af-
ter treatment. Information should also be given
on what to expect, side effects, and when to
seek help. A urinary pregnancy test should be
taken after 3 weeks and the woman should be
advised to contact the hospital if it remains
positive.
Surgical management includes manual
vacuum aspiration under local anaesthetic in
an outpatient setting or in theatre under gen-
eral anaesthetic. Post-treatment advice should
MIMS JPOG 2019 VOL. 45 NO. 3 97
Vaginal findings Scan findings
Cervical os closed Normal
Cervical os open Normal/short cervix
Cervical os closed/open Retained product of conception
Cervical os closed Empty uterine cavity
again be clearly given with contact details in
case of an emergency, anti-D 250 IU/L should
be given to all rhesus-negative women under-
going a surgical intervention.
An ectopic pregnancy is defined as em-
bryonic implantation outside the uterine cavity
in the fallopian tube, ovary, interstitial portion,
caesarean section scar or myometrium. In the
UK, the incidence of ectopic pregnancies is
11/1000 with approximately 11,000 diagnosed
every year. The risk factors for ectopic preg-
nancy include tubal damage, previous tubal
surgery, previous pelvic infection, endometrio-
sis, and previous ectopic pregnancy.
The main symptoms of an ectopic preg-
nancy are pelvic, adnexal and abdominal pain,
vaginal bleeding, shoulder-tip pain, and gastro-
intestinal and urinary symptoms. The manage-
ment is based on the clinical picture, ultrasound
findings, and patient discussion and consent.
Medical management using methotrexate
is offered as first-line if the patient is asympto-
matic and haemodynamically stable, with an
unruptured ectopic mass <35 mm without a
visible heartbeat and no intrauterine pregnan-
cy. The bHCG levels should also be <1,500
IU/L. The healthcare professional should be
sure that the patient will be compliant with the
management plan. It is essential that bHCG is
monitored on day 4 and 7, and then weekly
until levels are undetectable. If the levels of
serum HCG are not decreasing by more than
15% between day 4 and 7, then a second
dose of methotrexate is recommended.
98 MIMS JPOG 2019 VOL. 45 NO. 3 OBSTETRICS PEER REVIEWED

bHCG levels

Day 1

Decrease by 50%, Repeat serum bHCG Raises above 63%

resolving pregnancy, 48 hrs after first test
repeat UPT in 2 weeks

A rise between 50% and 63%

– inconclusive
Refer to EPAGU wthin 24 hrs

If negative – If positive – Ongoing pregnancy Repeat scan if/when

no action reassessment is likely bHCG above
1,500 IU/L

Figure 2. bHCG monitoring: diagnosis and management in pregnancies of unknown location.

Surgical management is the preferred Pregnancy of unknown location is diagnosed

treatment if any of the criteria for medical man-
agement is not met or if they have a serum
hCG level of 5,000 IU/L or more, or the patient
chooses to have surgery. A choice of medical or
surgical options can be given if the serum hCG
levels are between 1,500 and 5,000 IU/L, and
all the other criteria for medical management is
met.
Laparoscopic salpingectomy is the sur-
gical option of choice unless the patient has
risk factors for infertility. The patient should be
advised to take a urinary pregnancy test at 3
weeks after the procedure and return if the test
remains positive. Laparoscopic salpingostomy
is preferred in patients with previous contralat-
eral tubal damage who wish to preserve fertility.
Patients are advised that this option has a fail-
ure rate of 20%. It is recommended that bHCG
levels are measured 7 days after the proce-
dure, and then weekly until a negative result is
obtained.
when the urine pregnancy test is positive but there
is no evidence of intrauterine or extrauterine preg-
nancy on the scan. Management involves commit-
ment to a clear algorithm as shown in Figure 2.
The rate of ectopic pregnancy is 11
per 1,000 pregnancies, with a maternal
mortality of 0.2 per 1,000 estimated
ectopic pregnancies (Cantwell, et al,
2011). Medical management of ectopic
pregnancy with methotrexate costs £613,
while laparoscopic surgery is estimated
to £2,313 and laparotomy is estimated to
£2,445.
NICE guidelines on cost of ectopic pregnancy –
https://www.nice.org. uk/guidance/cg154/resources/
costing-report-188359309
Molar pregnancy
Molar pregnancies are intrauterine pregnan-
cies characterized by abnormal trophoblast
OBSTETRICS PEER REVIEWED
proliferation and may present with vaginal
bleeding and severe hyperemesis in early
pregnancy. The incidence of a molar pregnan-
cy is 1:714.
Molar pregnancies are classified as:
• Complete molar
• Partial molar
• Invasive molar
• Choriocarcinoma
• Placental site trophoblastic tumour
Table 3 details the characteristics of com-
plete and partial molar pregnancies. The clin-
ical presentation of molar pregnancy includes
symptoms such as vaginal bleeding, abnormal-
ly enlarged uterus for the gestation, and severe
hyperemesis. On rare occasions, the clinical
presentation could include early pre-eclampsia,
hyperthyroidism, respiratory insufficiency, and
neurological signs.
The diagnosis of molar pregnancy is
strongly suggested by ultrasound and later
must be confirmed by histopathological assess-
ment of the products of conception. Surgical
evacuation of the products of conception is rec-
ommended as the first-line treatment of molar
pregnancies. Once a histopathological diagno-
sis is made, the patient should be referred to
the regional gestational trophoblastic centre for
further management and treatment.
An essential part of the management in-
volves serial bHCG measurements every 2
weeks. If the levels fall to normal values in the
first 8 weeks post-evacuation, then the patient’s
monitoring can stop at 6 months post-surgery.
If the levels take longer to fall, then follow-up
is usually recommended for 6 months from the
time when bHCG values first normalized. At this
stage, the patient can be discharged. It is recom-
mended that a future pregnancy is deferred for 1
year from the completion of treatment. The risk
of recurrence is quoted as approximately 1 in 80.
Ovarian hyperstimulation syndrome
OHSS is a complication of fertility treatments
which use pharmacological ovarian stimulation
MIMS JPOG 2019 VOL. 45 NO. 3 99
Table 3. Characteristics of Molar Pregnancies
Partial molar pregnancies Complete molar pregnancies
• Genetically triploid • Genetically diploid
• Results from fertilization of an • Result from fertilization
ovum by two spermatozoa of an empty ovum by one
spermatozoon
• Contain foetal parts • Absent foetal parts
to increase the yield of oocytes available during
assisted reproductive technology (ART).
OHSS is described as acute, if the onset oc-
curs in the first 7 days after the hCG injection, or
late, if the presentation is after day 10 of fertilization.
Risk factors for OHSS include:
• Previous history of OHSS
• Polycystic ovary syndrome
• Increased antral follicle count (AFC) or high
levels of anti-Mullerian hormone (AMH)
• Use of GnRH agonists or hCG
• Multiple embryo transfer
• Higher oocyte yields
• 
Greater counts of mature follicle develop-
ment prior to egg collection
While avoiding the variable risk factors
above (such as the use of GnRH antagonists in-
stead of agonists) may decrease the incidence
of OHSS, the syndrome can still occur in pa-
tients that do not meet any of the criteria deemed
“high-risk”. The incidence of OHSS is also high-
er in cycles where conception occurs compared
with regimens where conception does not, and
in even higher in multiple pregnancy, highlight-
ing the role of endogenous hCG.
The management of OHSS should be guid-
ed by the severity, and is dealt with in greater
detail in The Management of Ovarian Hyper-
stimulation Syndrome, Green-top Guideline
No.5, published February 2016. Figure 3 sum-
marizes the classification of OHSS and Table 4
sets out the key investigations.
Symptoms of OHSS should be managed
with adequate analgesia and antiemetics, while
100 MIMS JPOG 2019 VOL. 45 NO. 3 OBSTETRICS PEER REVIEWED

Mild Abdominal Mild Ovarian size

OHSS bloating abdominal pain usually < 8 cm

Moderate Nausea ± Moderate Ovarian size Ultrasound evidence

OHSS vomiting abdominal pain usually 8–12 cm of ascites

Haematocrit >0.45
Hyponatraemia
Severe Oliguria (≤300 mL/day
Hypo-osmolality
Ovarian size Clinical ascites
OHSS or <30 mL/hour) usually >12 cm (± hydrothorax)
Hyperkalaemia
Hypoproteinaemia

Haematocrit >0.55
Critical White cell count
Tense ascites/ Oliguria/anuria Acute respiratory
OHSS large hydrothorax Thromboembolism distress syndrome
>25,000/mL

Figure 3. Classification of OHSS.

should be advised to drink at least 1 L a day.

Table 4. Recommended Investigations in OHSS
• Full blood count
• Haematocrit
• C-reactive protein (severity)
• Urea and electrolytes (hyponatraemia and hyperkalaemia)
• Serum osmolality (hypo-osmolality)
• Liver function tests (elevated enzymes and reduced albumin)
• Coagulation profile (elevated fibrinogen and reduced antithrombin)
• hCG (to determine outcome of treatment cycle) if appropriate
• Ultrasound scan: Ovarian size, pelvic, and abdominal free fluid.
Consider ovarian Doppler, if torsion suspected
being careful to avoid medication contraindi-
cated in pregnancy. Paracetamol and opiates
are commonly used. Oral fluid replacement ac-
cording to thirst is the most appropriate way of
correcting intravascular dehydration. Women
Urine output of <1 L per 24 hours or a positive
balance of >1 L over 24 hours requires prompt
review of severity. This highlights the impor-
tance of strict fluid balance charts in an outpa-
tient and inpatient setting. Women with ongoing
haemoconcentration despite intravenous col-
loid replacement may need invasive monitoring
and anaesthetic input.
OHSS is a prothrombotic state due to
haemoconcentration and vascular endothelial
dysfunction. Women with OHSS who are man-
aged as outpatients, should be assessed for
thromboprophylaxis requirement and prescribed
compression stockings or LMWH as required.
The incidence of thromboembolic events in as-
sisted conception pregnancies varies between
0.7% and 10%. The rate of thromboembolic
events is 0.8:1000 for IVF pregnancies com-
pared with 0.2:1000 for those that have sponta-
neously conceived.
OBSTETRICS PEER REVIEWED MIMS JPOG 2019 VOL. 45 NO. 3 101

Paracentesis is considered when there is se-

vere abdominal distension with associated short-
ness of breath and oliguria. NSAIDs and diuretics
should be avoided as these could affect renal func-
tion. All patients with OHSS should be informed of
the risk of pre-eclampsia and preterm delivery.

OVARIAN ACCIDENTS IN
PREGNANCY
Approximately 80–95% of all adnexal masses
in pregnancy represent functional cysts, which
carry a very low risk of malignancy and are ex-
pected to resolve spontaneously by the end of
the first trimester. If an ovarian cyst is still pres-
ent beyond 12 weeks’ gestation, a different un-
derlying pathology becomes more likely, such
as a cystic mature teratoma. The incidence of
ovarian masses in pregnancy is 2%. Conserv-
ative management is recommended in ovarian
cysts with a diameter below 6 cm with no ma-
lignant features and negative tumour markers.
Acute ovarian accidents are treated surgically.
Overall, 10–15% of ovarian masses under-
go torsion and the diagnosis is confirmed intra- In pregnancy, bacterial vaginosis is associated with late miscarriage, preterm
operatively. If diagnosed early, detorsion of the birth, preterm premature rupture of membranes, and post-partum endometritis.
twisted ovary may be successful. Late diagno-
sis can be complicated by peritonitis and spon- times. In pregnancy, this is associated with an
taneous miscarriage. It is rare for ovarian cysts increased risk of premature rupture of mem-
to be operated on during pregnancy unless branes, premature labour, and low birthweight.
they are symptomatic or there is a high level of The most common causative organism is Es-
concern about the possibility of an underlying cherichia coli, occurring in 90% of cases.
malignancy. Persistent ovarian cysts do require It is recommended that asymptomatic
a follow-up plan post-birth however. bacteriuria and symptomatic UTI both receive
antibiotic treatment in pregnancy. Prior to com-
Urinary tract infections mencing treatment, one sample of urine should
Pregnancy predisposes to urinary tract in- be sent for microscopy, culture, and sensitivity
fection (UTI) due to the gravid uterus apply- testing. The antibiotic chosen should be decid-
ing pressure on the bladder and hormonal ed by local guidelines and the results of sensi-
changes reducing smooth muscle tone, both tivity testing on a urine culture. Repeated UTIs
of which cause relative urinary stasis. Bac- during pregnancy should prompt consideration
terial colonisation of the urethra may occur of a renal tract ultrasound scan.
secondary to sexual intercourse, urinary in-
continence, or poor personal hygiene. Asymp- Bacterial vaginosis in pregnancy
tomatic bacteriuria left untreated increases the In some populations, as many as 12% of all an-
risk of developing symptomatic UTIs by four tenatal patients have been diagnosed with bac-
102 MIMS JPOG 2019 VOL. 45 NO. 3
Depression and anxiety are the most common health problems, affecting 10–15%
of pregnant women.
terial vaginosis on vaginal swabs, or on clinical
picture alone. In pregnancy, bacterial vaginosis
is associated with late miscarriage, preterm
birth, preterm premature rupture of membranes,
and post-partum endometritis. Pregnant wom-
en with bacterial vaginosis should be treated
with either oral or topical low-dose metronida-
zole. Oral metronidazole 400 or 500 mg twice
daily is the treatment of choice for symptomatic
patients. For women who prefer topical treat-
ment, metronidazole gel 0.75% mg once a day
for 5 days can be prescribed. Testing should
be repeated after 1 month if the woman is still
symptomatic.
Unplanned pregnancy occurred while
using contraception/intrauterine devices
If a pregnancy occurs with an intrauterine de-
vice (IUD) in situ, removal should be consid-
OBSTETRICS PEER REVIEWED
ered before 12 weeks of gestation in order to
reduce the risk of miscarriage, preterm labour,
and infection. The incidence of pregnancy with
the progesterone intrauterine device is 0.2%
(1:500) and 0.8% (1:125) for the copper coil.
More than half of all pregnancies which have
developed with an IUD in situ, will result in mis-
carriage and approximately 6% of the pregnan-
cies will be ectopic. If the threads are visible at
vaginal examination, then the coil/IUD should
be removed before 12 weeks’ gestation. If the
threads are not visible, then confirmation of the
coil should be sought at delivery or at the time
of termination of pregnancy. Ultimately, a pel-
vic X-ray is helpful in diagnosing an extrauterine
coil.
Mental health problems in pregnancy
The majority of women have good mental
health throughout pregnancy. Some women
may have a past history of mental health issues
or be on treatment for mental health problems
when they become pregnant, while others have
mental health problems for the first time in
pregnancy.
Pre-existing mental illness can be exacer-
bated in early pregnancy due to the changes
and uncertainties this time brings. Women who
are on treatment often worry that the medica-
tion will affect the development of the baby and
cease to continue it once they find out that they
are pregnant. However, 7 of every 10 women
who stop antidepressants in early pregnancy
become unwell again. Education during the
preconceptual period, regarding the relative
safety of most treatments during pregnan-
cy, may help to prevent unsupervised cessa-
tion of psychotropic medications during early
pregnancy.
Depression and anxiety are the most
common health problems, affecting 10–15%
of pregnant women. Symptoms during preg-
nancy are similar to those occurring with
mental illness outside of pregnancy. However,
they can be confused with pregnancy-related
OBSTETRICS PEER REVIEWED
presentations, eg, broken sleep or lack of en-
ergy. When a woman first presents to primary
care or at her booking visit in the first trimes-
ter, depression identification questions will
help identify women at risk of mental health
issues in pregnancy. Other questionnaires
such as the GAD-2 scale can also be imple-
mented for anxiety identification. Women with
mental health problems in pregnancy require
information, support, and advice from early
pregnancy, whilst also supporting the family.
A multidisciplinary approach is vital in man-
aging these women and their families while
providing adequate monitoring and increased
contact with them. Non-pharmacological in-
terventions include self-help management
and CBT. If a woman who is taking TCA,
SSRI, or SNRI’s for anxiety becomes preg-
nant, discussion needs to be made regard-
ing stopping the medication gradually and
switching to high-intensity CBT, or continuing
the medication if she understands the risks
associated. If presenting with moderate or se-
vere depression in pregnancy, high-intensity
psychological intervention like CBT needs to
be considered, or medication such as TCA,
SSRI, or SNRI can be considered if they un-
derstand the risks associated. Women with a
history of severe depression presenting with
mild depression in early pregnancy need to
consider TCS, SSRI, or SNRI medications. All
of the above management discussed needs
to be implemented early in the pregnancy, if
identified.
CONCLUSION
Early pregnancy complications can be simple,
or far more complex and they require early di-
agnosis with multidisciplinary input. All health-
care professionals should have an understand-
ing of the common early pregnancy symptoms
that require further investigation and manage-
ment. Access to early pregnancy units and out
of hours GP practices has proven to be benefi-
cial, as well as cost-effective. Staff should be
MIMS JPOG 2019 VOL. 45 NO. 3 103
Practice Points
• Severe HG requires hospital admission and multidisciplinary team
involvement.
• 
Ectopic pregnancies can be managed medically or surgically
depending on presentation and test results.
• While under monitoring, it is recommended that patients diagnosed
with gestational trophoblastic disease should not get pregnant.
• OHSS is more common in IVF pregnancies.
• 
Both asymptomatic and symptomatic urinary tract infections
require treatment in pregnancy.
• Bacterial vaginosis diagnosed in pregnancy requires treatment.
• A multidisciplinary approach is vital in managing mental illness from
early on in the pregnancy.
compassionate and be specifically trained to
break bad news regarding early pregnancy fail-
ure and loss.
FURTHER READING
1. Antenatal and postnatal mental health: clinical management and ser-
vice guidance. https://www.nice.org.uk/guidance/cg192.
2. Bacterial vaginosis- Clinical Knowledge Summaries https://cks.nice.
org.uk/bacterial-vaginosis- scenario:1.
3. British Association of sexual health and HIV https://www.bashh.org/
documents/4413.pdf.
4. Ectopic pregnancy and miscarriage: diagnosis and initial manage-
ment https://www.nice.org.uk/guidance/cg154.
5. Faculty of Sexual and Reproductive Healthcare. Intrauterine contra-
ception. London: FSRH, 2007.
6.  Gestational Trophoblastic Disease (Green-top Guideline No. 38) -
RCOG https://www.rcog.org.uk/globalassets/documents/guidelines/
gtg_38.pdf.
7.  Guidelines for Diagnosis, Treatment, and Use of Laparoscopy
for Surgical Problems during Pregnancy: https://www.sages.
org/publications/guidelines/guidelines-for-diagnosis-treat-
ment-and-use-of-laparoscopy-for-surgical-problems-during-preg-
nancy/.
8. The Management of Nausea and Vomiting of Pregnancy and Hy-
peremesis Gravidarum (Green-top Guideline No. 69): https://www.
rcog.org.uk/globalassets/documents/guidelines/green-top-guide-
lines/gtg69-hyperemesis.pdf.
9.  The Management of Ovarian Hyperstimulation Syndrome RCOG
guidelines no. 5 https://www.rcog.org.uk/globalassets/documents/
guidelines/green-top-guidelines/gtg_5_ohss.pdf.
10. Trussell J. Contraceptive efficacy. In: Hatcher RA, Trussell J, Nelson
AL, Cates W, Kowal D, Policar M, eds. Contraceptive techology: twen-
tieth revised edition. New York NY: Ardent Media, 2011.
© 2018 Elsevier Ltd. All rights reserved. Initially published in Obstetrics,
Gynaecology and Reproductive Medicine 2019;29(2):29–35.
About the authors
Sai Gnanasambanthan is a Specialist Registrar in Obstetrics and Gynae-
cology at Guy’s and St Thomas’ NHS Trust, London, UK. Conflicts of in-
terest: none declared.
Shree Datta is a Consultant Obstetrician and Gynaecologist, King’s Col-
lege Hospital, London, UK. Conflicts of interest: none declared.
104 MIMS JPOG 2019 VOL. 45 NO. 3 GYNAECOLOGY PEER REVIEWED

Prevention and Treatment

of Osteoporosis in Women
Gabriella Shanks MBChB CMT 1; Devina Sharma MBChB; Vinita Mishra MBBS MD MPhil MRCPath

Osteoporosis is a disease with a significant disease burden worldwide,

affecting more than 75 million people in the US, Europe, and Japan. With an
ageing population, the incidence of osteoporosis is growing. Osteoporotic
fractures have significant individual morbidity but also strain healthcare
services. There is no screening service for osteoporotic fractures in the UK
and physicians must actively identify patients who are at risk of osteoporotic
fractures as well as managing appropriately patients who have sustained
osteoporotic fractures. Diagnosis of osteoporosis is done with dual-energy
X-ray absorptiometry (DXA) scans to measure bone mineral density (BMD).
The World Health Organization (WHO) Fracture Risk Assessment (FRAX)
score is used to identify patients who are at risk of fractures. Pharmacological
treatment is recommended for those who obtain a risk score sufficient
enough to warrant treatment. The treatment of osteoporosis includes
calcium and vitamin D replacement, bisphosphonates (BP), denosumab,
teriparatide, and hormone replacement therapy in women. Potential therapies
that are currently undergoing clinical trials include abaloparatide and
romosozumab.
GYNAECOLOGY PEER REVIEWED
CASE PRESENTATION
An 83-year-old female patient was diagnosed with
osteoporosis when she presented with fracture
right neck of femur at the age of 70 years. At the
time of diagnosis, she had vitamin D deficien-
cy and daily dietary calcium intake of less than
500 mg. Subsequently, she was commenced on
calcium and vitamin D supplements and oral BP
treatment for osteoporosis. However, she could
not tolerate the oral BP as she complained of gas-
trointestinal irritation type symptoms. Therefore,
she was subsequently commenced on intrave-
nous (IV) BP treatment. She had IV zoledronic
acid 5 mg once a year for the next 3 years. There
was apparent increase in BMD after 3 years of IV
BP treatment, based on DXA at treatment review.
Vertebral fracture assessment (VFA) showed no
vertebral fractures. The patient was given a drug
holiday (BP was stopped, and patient continued
on calcium and vitamin D supplements) due to
an apparent increase in BMD. After 2 years of
drug holiday, the BMD was reduced significant-
ly. The patient was commenced on IV zoledronic
acid 5 mg treatment once a year. After 2 years
of starting IV zoledronic acid treatment, the pa-
tient complained of sudden onset of back pain.
An X-ray spine showed minor anterior wedging
of thoracic vertebrae (T7, T8, and T9), as well as
biconcave fracture of T12 and lumbar vertebra
L3. The patient was commenced on teriparatide
therapy as the third-line management for her se-
vere osteoporosis. The BMD on DXA scanning
found significant increase in lumbar spine and no
significant change in the left femoral neck BMD,
after 2 years of teriparatide treatment. VFA did not
show any new vertebral fractures. The patient was
commenced on denosumab treatment to consol-
idate the effect of teriparatide therapy for the next
3 years.
EPIDEMIOLOGY AND IMPACT
Osteoporosis has a significant disease burden
and cost, and represents a major public health
problem worldwide. The WHO study group
found that it affects more than 75 million peo-
MIMS JPOG 2019 VOL. 45 NO. 3 105
ple in US, Europe, and Japan, and causes more
than 8.9 million fractures, globally. The lifetime
probability of osteoporotic fractures (hip, wrist,
and vertebral) is 30–40%. With an ageing popu-
lation, the prevalence of osteoporosis is expect-
ed to only increase.
The impact can be considered on an in-
dividual and collective basis. Collectively, the
economic burden is staggering. In high-income
countries, osteoporotic fractures account for
more bed days than myocardial infarctions, or
breast or prostate cancer. For individuals, hip
fractures alone are a cause for a significant dis-
ease burden. About 20% of hip fracture patients
require long-term nursing home care and only
40% fully regain pre-fracture mobility. Vertebral
fractures affect individual daily activity, produc-
ing postural changes, and chronic back pain.
Thoracic vertebral fractures indirectly cause mor-
bidity by increasing incidence of restrictive lung
disease. Psychosocially, osteoporotic fractures
account for reduced quality of life, seen most
clearly in those who are bedridden as a result.
The challenge arises as many are not sub-
jected to the appropriate testing to diagnose os-
teoporosis, nor are their early clinical risk factors
established at an early enough stage. Inherent
to its presentation, osteoporosis is asymptomat-
ic until fractures occur. Screening methods have
been difficult to establish and are not currently
employed in the UK. Further, many people are
not treated once having had osteoporotic frac-
tures. Only 23% of women aged 67 and over re-
ceive BMD test or prescription within 6 months
of fracture.
Hence, the aim of osteoporosis manage-
ment is to identify women who are at risk of os-
teoporosis, prevent fragility fractures, and initiate
appropriate treatment.
PATHOPHYSIOLOGY
Bone remodelling, essential for bone strength,
is mediated by osteoclasts and osteoblasts. Os-
teoclasts resorb mineralised bone (resorption
of old bone), which is then replenished by oste-
106 MIMS JPOG 2019 VOL. 45 NO. 3
Receptor
activator
NFKB
Osteoblast RANK Quiescent
RANKL
osteoclast
OP
G pathway (Figure 1). In post-menopausal women,
Inflammatory
T-cell
T creased osteoclastic activity and thereby bone
cytokines
Oestrogen
t oge
en Activated
deficiency osteoclast
Abbreviations: RANKL = receptor activator of nuclear factor kappa-B ligan; RANK = receptor
activator of nuclear factor k B; OPG = osteoprotegerin
Figure 1. Molecular biology of osteoporosis.
oblasts (formation of new bone matrix). Hence,
bone remodelling is a tightly controlled continu-
ous coupling process between osteoclasts and
osteoblasts, which sustains unremitting bone
repair and maintenance of bone strength.
Osteoporosis is caused by an imbalance of
the two biological processes (uncoupling of os-
teoblasts and osteoclasts), with an increase in
osteoclast activity, leading to overall bone loss.
There are molecular signals in the form of
cytokines which orchestrate the bone remod-
elling process. Most well-known is the recep-
tor activator of nuclear factor kappa-B ligand
(RANKL) and osteoprotegerin (OPG) signalling
system. RANKL is released from osteoblasts and
binds to the receptor activator of nuclear factor
k B (RANK) on the osteoclast, a receptor located
on quiescent osteoclasts. This binding results
in osteoclastogenesis, also known as the differ-
entiation and activation of osteoclasts. OPG is a
decoy receptor for RANKL, its release prevents
progression of this pathway by competing with
RANKL to bind with RANK, therefore preventing
osteoclastogenesis. Osteoclast-driven resorp-
tion of bone is mediated by the RANKL-OPG
imbalance, where increased RANKL leads to
GYNAECOLOGY PEER REVIEWED
increased osteoclastogenesis and subsequent
bone loss. RANKL release is regulated by sev-
eral cytokines and hormones: among these par-
athyroid hormone (PTH) and oestrogen have a
predominant role. PTH increases the osteoclas-
tic activity, whereas oestrogen suppresses the
osteoclast activity, by their effect on RANKL-OPG
an inevitable deficiency in oestrogen leads to in-
loss.
DIAGNOSIS, DEFINITION, AND RISK
ASSESSMENT OF OSTEOPOROSIS
WHO defines osteoporosis as “a progressive
systemic skeletal disease characterized by low
bone mass and micro architectural deteriora-
tion of bone tissue with consequent increase in
bone fragility and susceptibility to fracture”. Os-
teoporosis is characterized by low bone mass,
which is measured as BMD.
The WHO classifies BMD using a “T-score”
(standard deviation’s [SD] away from young
adult mean bone mass value). Osteoporosis
is defined as BMD with T-score equal to or
less than -2.5 and osteopenia with a T-score
between -2.5 and -1 SD (away from young
adult mean bone mass value). Severe osteo-
porosis is the presence of one or more bone
fragility fractures in addition to a low T-score.
The WHO, BMD T-score classification is only
applied to post-menopausal women and men
older than 50 years of age. In premenopau-
sal women and men younger than 50 years,
instead of the T-score, a “Z-score” (SD from
the age-matched normal bone mass value)
should be used. This figure adjusts for chron-
ological age, a Z-score of less than -2 as low
bone mass. BMD is an independent risk factor
for osteoporotic fracture. Hence, for each 1 SD
decrement in BMD, the risk of fracture increas-
es by twofold. Therefore, initial BMD calcula-
tion is vital for the confirmation of diagnosis,
prediction of fracture risk, and monitoring os-
teoporosis management.
GYNAECOLOGY PEER REVIEWED MIMS JPOG 2019 VOL. 45 NO. 3 107

The WHO recommends DXA scanning for

measuring the BMD. For diagnostic purposes Ageing

alone, DXA at the femoral neck is the preferred Increased Skeletal

bone loss fragility
site for generating a T-score, because of its high-
Menopause Fracture
est predictive value for fracture risk. Degenerative
changes in the spine, which are common in elder- Excessive
Falls risk
bone loading
ly patients, can falsely elevate the BMD, for this
reason the spine not the preferred site for diagno- Clinical risk factors
• Glucocorticoids
sis of osteoporosis in post-menopausal women. • Known fraglity
Nevertheless, BMD calculation at the spine is the fracture
• Family history
preferred site for assessing response to treatment.
• Low body mass
BMD has been shown to have a high specific- • Smoking, alcohol
ity but low sensitivity for osteoporosis, so it is not
used in population screening and should not be
routinely measured. Moreover, because of its low Figure 2. Risk factors for osteoporosis.
sensitivity, osteoporotic fractures are found to oc-
cur in women with a T-score of more than -2.5.
Table 1. Markers of Bone Remodelling
Hence, case finding methods are the preferred
option above screening. BMD measurement is
not recommended in young men (<50 years of Bone formation markers Bone resorption markers
age) or premenopausal women unless significant
Procollagen type 1 N-terminal N-terminal C-peptide (NTX)
risk factors are present. C-terminal C-peptide (CTX) Cross
propeptide (P1NP)
Advanced ageing and several clinical risk Procollagen type 1 C-terminal links (DPD: deoxypyridinoline;
factors contribute to fracture risk independent- propeptide (P1CP) PYD: pyridinoline)
ly of BMD (Figure 2). Hence, inclusion of risk Bone specific alkaline Hydroxyproline
factors increases sensitivity of testing, without phosphatase Hydroxylysine
compromising specificity. The tool to calculate Osteocalcin Bone sialoprotein
the fracture risk has been developed by the Cathepsin K
Osteoprotegerin (OPG)
WHO Collaborating Centre for Metabolic Bone
Receptor activator for nuclear
Disease at Sheffield as the “WHO FRAX”, which
factor kappa-B ligand (RANKL)
computes a 10-year probability of major osteo-
porotic or hip fracture. NICE recommends the
use of FRAX in post-menopausal women to as-
sess fracture risk; thereby identifying high-risk chines). Their discovery can completely change
patients for whom initiating treatment will pre- fracture risk. VFA can be repeated in cases of
vent fragility fractures. vertebral height loss, new back pain, or if there is
Other measures of risk assessment include consideration of a medication holiday.
vertebral imaging and bone turnover markers. Additionally, biochemical markers of bone
Low trauma vertebral fractures are consistent remodelling (bone turnover markers) are divid-
with a diagnosis of osteoporosis even in the ab- ed into bone formation and resorption markers
sence of low BMD and are an indication for phar- (Table 1). Bone formation markers are pro-
macological treatment. Most vertebral fractures duced by osteoblasts or by bone procollagen
are asymptomatic and remain undiagnosed for metabolism, whereas resorption markers are
many years; they may only be detected on ver- produced by degradation of osteoclasts or col-
tebral imaging (VFA, available on most DXA ma- lagen tissue in bone.
108 MIMS JPOG 2019 VOL. 45 NO. 3
The bone markers are predictive of fracture
risk or rate of bone loss. They can be used to
monitor efficacy of, and compliance with, oste-
oporosis treatment and to help as determine the
duration of a drug holiday.
PREVENTION OF OSTEOPOROSIS
Lifestyle advice and treating risk factors can re-
duce the likelihood of fracture in people at risk.
General measures such as increasing physical
activity, cessation of smoking, moderate alco-
hol consumption, optimal dietary calcium intake
(1,000–1,200 mg daily), and vitamin D sufficien-
cy at all ages reduces fracture risk. In the elderly
population, addressing modifiable factors has
a major role in preventing osteoporotic frac-
tures. These factors include visual impairment,
medications that alters alertness and balance,
home environmental hazards, and falls risks.
Post-menopausal osteoporotic patients, regard-
less of history of bone fragility fractures, should
be treated with pharmacological therapy.
PHARMACOLOGICAL TREATMENT
OF OSTEOPOROSIS
Pharmacological treatment is either antiresorp-
tive (targeting osteoclasts) or anabolic (target-
ing osteoblasts). All of the recommended med-
ications have been shown to increase the BMD
and reduce the risk of fracture.
The antiresorptive medications are BP (al-
endronate, risedronate, ibandronate, zoledro-
nate, etidronate) and denosumab. The anabol-
ic medication is parathyroid hormone peptide
(teriparatide).
Medications that are also useful in post-men-
opausal women include hormone replace-
ment therapy and selective oestrogen-receptor
modulators.
Bisphosphonates
BP interfere with the biochemical processes of
bone resorption, acting on osteoclasts and also
inducing their apoptosis. They are adsorbed into
the bones surface and remain embedded in the
GYNAECOLOGY PEER REVIEWED
mineralized bone surface. This allows them to con-
tinue to exert their effects even after cessation of
the medication. BP can be administered orally or
intravenously. The oral BP are alendronate, rise-
dronate, ibandronate, and etidronate (once a week
or monthly). Intravenous BP are zoledronic acid
(once a year) and ibandronic acid (once every 3
months). BP are no longer on patent and are wide-
ly available and cost-effective medications. NICE
recommends the use of oral BP as the first-line
treatment for post-menopausal osteoporosis. In
patients who are intolerant to oral BP or where BP
are contraindicated, IV BP should be considered.
BP are not licensed in patients with renal failure or
those who have an estimated glomerular filtration
rate (eGFR) of less than 45 mL/min/1.73 m2 as they
are considered to be nephrotoxic.
In the Fracture Intervention Trial, which in-
volved 2,027 women with known vertebral frac-
tures at the start of the trial, evidence found that
on completing 4 years of alendronate therapy,
new vertebral fractures were decreased by 47%
and hip fractures by 51%.
The HORIZON-PFT trial included 7,500
women with known osteoporosis. They were giv-
en 3 years of treatment with zoledronic acid and
this reduced new vertebral fractures by 70% and
hip fractures by 41%.
In summary, BP have been found to reduce
vertebral, hip, and non-vertebral fracture risk.
Oral and IV BP therapy should be reviewed
after 5 and 3 years, respectively. The continua-
tion of treatment should be assessed taking into
consideration the following: patient age (75 years
or above), T-score at the left femoral neck (2.5
SD or below), history of previous hip or vertebral
fractures, recurrent fractures on therapy, or re-
ceiving prolonged high doses of glucocorticoids.
The National Osteoporosis Guideline Group, UK
provides a decision algorithm at the end of 5 or 3
years of treatment with BP.
Denosumab
Denosumab is a human monoclonal antibody
that inhibits the bone resorption by binding to
GYNAECOLOGY PEER REVIEWED
the RANKL, thereby inhibiting the differentia-
tion of osteoclasts and inducing their apopto-
sis. As a result of decreased osteoclastogen-
esis, there is decreased bone resorption and
increased bone mineral density. Denosumab is
not renally cleared and can be safely adminis-
tered in patients with low eGFR. NICE recom-
mends denosumab treatment in patients with
severe osteoporosis who are intolerant to ini-
tial BP therapy.
The “Fracture Reduction Evaluation of
Denosumab in Osteoporosis Every 6 Months
(FREEDOM)” trial, an international randomized
controlled trial which ran over 36 months, found
that women benefitted from denosumab ther-
apy compared with placebo. Bone resorption
was reduced by a median of 86% at 1 month,
demonstrating superiority over all other bone
antiresorptive medications. The 7,868 women
with a T-score of less than -2.5 but more than
-4 at the lumbar spine or total hip involved in
the study, were seen to benefit from twice year-
ly denosumab therapy, with 68% less vertebral
fractures, 40% less hip fractures, and 20% less
non-vertebral fractures. A subsequent long-
term denosumab trial extending up to 8 years
(the FREEDOM extension trial) was associated
with continued gains in BMD and persistent re-
duction in bone turnover markers with ensuing
low fracture incidence. In contrast to BP, deno-
sumab has a shorter retention time in bone and
its effect disappears within 6 months of therapy
cessation. The post-hoc analysis after withdraw-
al of denosumab found significantly decreased
BMD, with rebound increase in bone turnover
and increased vertebral fractures within 1 year
of discontinuation. What can be learned from
this study is that BMD gains are lost if denosum-
ab treatment is stopped without consolidation
therapy.
Denosumab therapy is administered subcu-
taneously, 60 mg every 6 months. Patients should
have optimal calcium and vitamin D sufficiency
before and during the denosumab treatment as
there is a risk of consequential hypocalcaemia.
MIMS JPOG 2019 VOL. 45 NO. 3 109
Side effects associated with denosumab therapy
include hypocalcaemia, myalgia, diarrhoea, or
constipation, and an influenza-like illness.
Long-term adverse effects of
bisphosphonates and denosumab
Long-term treatment with BP and denosumab
is associated with atypical femoral fracture and
osteonecrosis of jaw. Atypical femoral fractures
occur in the sub-trochanteric or diaphyseal shaft
regions of the femur with minimal trauma and
can be bilateral. The fractures are transverse
and noncomminuted with lateral cortical thick-
ening. It is imperative to advise patients about
unexplained pain in the hips or lower limbs. On
assessment of hip/thigh pain in patients on BP
or denosumab, imaging should be bilateral.
Osteonecrosis of the jaw is characterized
by mucosal ulceration and exposure of necrotic
bone. Management is usually conservative. Prior
to initiating therapy, dental examination should be
considered with preventative dentistry therapy if
there are coexistent risk factors such as glucocor-
ticoid therapy, poor oral hygiene, or pre-existing
dental disease. Cases of osteonecrosis of the jaw
are rare and the benefits of therapy generally out-
weigh the risks. Invasive dental procedures should
be avoided if possible, although BP therapy is not
a contraindication to dental work.
Hormone replacement therapy
and selective oestrogen-receptor
modulators
Hormone replacement therapy (oestrogen)
inhibits bone resorption and maintains bone
formation. Oestrogen receptors have been
identified on osteoclasts, osteoblasts, osteo-
cytes, and bone marrow stromal cells. Oestro-
gen causes a decrease and reduction in the
lifespan of osteoclasts resulting in decreased
bone resorption. It also stimulates the activity of
osteoblasts and influences calcium homeosta-
sis. Because of its notable side effects, particu-
larly increased risk of breast cancer and cardi-
ovascular morbidity, it is not recommended in
110 MIMS JPOG 2019 VOL. 45 NO. 3
the elderly population. Early post-menopausal
women are shown to have beneficial effect in
terms of osteoporosis prevention and meno-
pausal symptoms.
Selective oestrogen-receptor modulators,
such as raloxifene, activate tissue receptors for
oestrogen in bone, preventing bone loss and
increasing BMD. Raloxifene has been shown to
reduce the vertebral fracture risk but not the hip
or non-vertebral fracture risk. It is recommended
in post-menopausal women who do not have a
history of menopausal symptoms.
The Women’s Health Initiative was an ob-
servational study involving 120,566 women aged
50−70 years old between 1993 and 1998. The
results found a significant reduction in new ver-
tebral, non-vertebral, and hip fractures with hor-
mone replacement therapy in post-menopausal
women.
Hormone replacement therapy is available
as oestrogen or as an oestrogen plus proges-
togen combination, either orally or via transder-
mal patches. Raloxifene is an oral medication
taken daily at a dosage of 60 mg and has been
found to decrease the risk of breast cancer.
Selective oestrogen-receptor modulators are
contraindicated in women of childbearing age,
previous history of venous thromboembolism,
unexplained uterine bleeding, and renal or he-
patic impairment.
Parathyroid hormone peptides
Teriparatide is a recombinant human para-
thyroid (PTH 1−34 amino acids) compound
licensed for use in severe post-menopausal
osteoporosis in Europe, containing the first 34
“active” amino acids. Teriparatide or intermit-
tent PTH (1−84 amino acids) administration
increases bone formation (anabolic effect) and
is recommended by NICE in the management
of severe osteoporosis in patients 65 years
or above with intolerance, contraindication,
or unsatisfactory response to BP. The most
marked effects are seen on cancellous bone.
The benefits of teriparatide are lost quickly af-
GYNAECOLOGY PEER REVIEWED
ter cessation so it is often succeeded by an an-
tiresorptive agent such as BP or denosumab.
A randomized trial found a significant increase
in BMD when 1 year of teriparatide therapy
was followed by 1 year of alendronate therapy.
Due to the high cost of this medication, it is
indicated for patients at very high risk of frac-
ture, namely vertebral fractures. A randomized
21-month trial, which included women with low
BMD that had suffered previous vertebral frac-
tures, found a reduction in vertebral fractures
by 65% and non-vertebral by 35% compared
with placebo. However, there was no reduction
in risk of hip fracture. Teriparatide is adminis-
tered subcutaneously, 20 μg, over a maximum
period of 24 months. Only mild side effects
have been seen with recombinant parathyroid
hormone, with reports of occasional nausea
and headache. The medication is generally
well tolerated.
Teriparatide is contraindicated in the pres-
ence of hypercalcaemia, metabolic bone disease
(other than osteoporosis), severe renal impair-
ment, prior radiation to the skeleton or malignant
disease of skeleton.
Miscellaneous therapy
Strontium ranelate was discontinued in the UK
in 2017 due to increased cardiovascular risk
in users. Calcitonin is no longer licensed in
Europe to treat osteoporosis as the European
Medicines Agency discovered an increased
risk of developing cancer with calcitonin use
over a prolonged period, and it was decided
that the limited benefits were outweighed by
the risks.
New therapies on the horizon
To date, antiresorptive therapy is the most com-
monly used treatment for osteoporosis. Nev-
ertheless, the prolonged use of this treatment
results in suppression of osteoclasts as well as
osteoblasts, resulting in reduced bone remod-
elling. This impairs the repair of micro-cracks in
bone and leads to atypical femoral fractures. In
GYNAECOLOGY PEER REVIEWED
the recent years, osteonecrosis of jaw has been
reported in patients on long term treatment with
BP and denosumab. The need for anabolic
therapy has become prominent in the last few
years as teriparatide is licensed only for 2 years
during each patient’s lifetime. Moreover, a need
for anabolic therapy has been identified in pa-
tients with severe osteoporosis presenting with
multiple vertebral fractures, failure of antire-
sorptive treatment or steroid-induced osteopo-
rosis. Anabolic therapy significantly increases
bone formation, which is followed by a period of
delayed bone resorption, called the “anabolic
window”. Hence, there is a net increase in bone
deposition and volume. To consolidate the ef-
fect of anabolic therapy, it should be followed
by antiresorptive treatment.
Abaloparatide is a synthetic analog of
PTH-related peptide (PTHrP), is identical to
PTHrP (1–22 amino acids) and acts through the
PTH receptor. The intermittent administration of
Abaloparatide has an anabolic action. A phase
3 clinical trial with Abaloparatide (Study to Eval-
uate the Safety and Efficacy of BA058 [Abalopa-
ratide] for Prevention of Fracture in Post-meno-
pausal Women, ACTIVE) reduced the vertebral
fractures by 86% compared to placebo.
Romosozumab is a humanised monoclonal
antibody to sclerostin (produced by osteocytes,
inhibits the bone formation, and induces bone
resorption). The phase 3 clinical trial (Fracture
Study in Postmenopausal Women with Osteopo-
rosis, FRAME) showed a significant reduction in
vertebral fractures by 75% in the Romosozumab
group compared to placebo.
The combination treatment with teriparatide
and denosumab showed a significant increase in
BMD in combination group compared to either
teriparatide or denosumab treatment alone after
12 months of treatment.
The sequential treatment where anabol-
ic therapy is followed by antiresorptive therapy
consolidates the anabolic bone density gains. In
a clinical trial, a switch from teriparatide to deno-
sumab after 24 months of teriparatide resulted
MIMS JPOG 2019 VOL. 45 NO. 3 111
in substantial gain in BMD whereas the switch
from denosumab to teriparatide resulted in loss
of bone density.
This suggests that combination and se-
quential treatment with teriparatide and deno-
sumab should be considered in the management
of severe osteoporosis.
THE CASE
This case demonstrates an example of second-
ary prevention in a postmenopausal woman.
Her right neck of femur fracture is indicative of
a characteristic osteoporotic fracture. As per
NICE guidance, DXA scan to measure BMD
(lumbar spine and left femoral neck T-score of
-3.8 and -2.5 respectively), a detailed assess-
ment of other risk factors such as use of sys-
temic glucocorticoids, low weight, history of
inflammatory disease and smoking and alcohol
consumption, were carried out. In light of her
age, fragility fracture and BMD (T-score of less
than -2.5), she falls in the treatment interven-
tional threshold.
First-line treatment according to NICE such
as Alendronate, an oral BP was commenced,
following exclusion of contraindications. Nation-
al Osteoporosis Guideline Group (NOGG) and
NICE guidelines recommend ensuring calcium
and vitamin D levels are replete prior to pharma-
cological therapies. As exemplified in our case,
supplementation of calcium and vitamin D is par-
ticularly recommended in older persons, but only
as an adjunct to other treatments. There should
be caution with calcium supplementation in those
with cardiovascular risk. The Institute of Medicine
(IOM) recommends that women over the age of
51 years consume 1,200 mg of calcium per day
and 800–1,000 IU of vitamin D per day for those
aged 50 or over. Along with this, modification of
other supportive measures should be taken into
regard. Falls prevention strategies and home
safety assessments by occupational therapists,
muscle strengthening exercises provided by
physiotherapists, along with smoking and alcohol
prevention strategies should all be considered.
112 MIMS JPOG 2019 VOL. 45 NO. 3
NICE guidelines recommend alendronate
as a first-line option. Before commencing al-
endronate, the presence of oesophageal ab-
normalities and renal impairment should be
ruled out. The risks of osteonecrosis of the jaw
and atypical fractures should be discussed. It
should be noted that these risks are significant-
ly outweighed by the potential benefit of fracture
risk reduction. Results from recent meta-analy-
sis show a highly favourable benefit to risk ra-
tio; treatment with up to 5 years in osteoporo-
sis, with fewer than one event caused per 100
fractures prevented, with a similar incidence for
osteonecrosis of the jaw.
As a result of gastrointestinal symp-
toms with alendronate, she was subsequently
changed to IV BP. Both Zoledronic acid and
denosumab are administered parentally and
are potential options in the case of gastroin-
testinal adverse effects. In this case, zoledronic
acid was given, the HORIZON-PFT trial showed
that after 3 years of treatment period, most of
the benefits in regard to BMD were maintained,
even after treatment cessation. Multiple pooled
analyses of long-term trials involving BP (FLEX,
HORIZON-PFT, VFERT-MN trials) found patients
who received 6 years or more of BP had a great-
er fracture rate than those compare to a place-
bo. The evidence points towards the use of a
drug holiday, to minimize the adverse effects of
BP. The adverse effects outweigh the antifrac-
ture benefits after a certain point. When BP are
discontinued, the benefit of BMD persists for at
least another 3 years.
The length of treatment prior to a drug holi-
day is case dependant, generally 3–5 years, de-
pending on the fracture risk. Some guidelines
suggest using the FRAX tool to recalculate risk
and those at an increased risk of fracture are
recommended continue treatment. In our case,
an increase in BMD was noted at 3 years and
a drug holiday commenced, as the patient was
deemed low risk.
NOGG guidelines suggest that after BP are
discontinued, fracture risk should be re-evaluat-
GYNAECOLOGY PEER REVIEWED
ed; after every new fracture or after 2 years if no
new fracture occurs. In our case, after 2 years,
a repeat DXA showed an apparent decrease in
BMD and IV zoledronic acid was reintroduced.
Despite this, she symptomatically represented
with anterior wedging and fractures at multiple
points of her thoracic and lumbar vertebrae. In
addition, she had a BMD of less than -2.5 at the
lumbar spine and femoral neck, and a low bone
turnover indicated by bone markers.
The presence of a vertebral fracture in-
creases subsequent risk of fracture by fivefold
and the risk of hip or other fractures by two to
threefold. Patients with multiple vertebral frac-
tures, as in our case, have shown to benefit from
the use of teriparatide. Teriparatide is a very po-
tent medication that is useful in reducing verte-
bral fracture risk when compared with placebo.
BP, raloxifene, and denosumab have also been
shown to reduce vertebral fragility fractures. The
benefits of teriparatide are quickly lost once it is
discontinued, so it should be followed by an an-
tiresorptive agent.
FURTHER READING
1. Miller PD, Hattersley G, Riis BJ, et al. Effect of Abaloparatide vs pla-
cebo on new vertebral fractures in postmenopausal women with
osteoporosis: a randomized clinical trial. J Am Med Assoc 2016;
316:722−33.
2. Felicia C, Crittenden DB, Adachi JD, et al. Romosozumab treat-
ment in postmenopausal women with osteoporosis. N Engl J Med
2016;375:1532−43.
3. Shepstone L, Lenaghan E, Cooper C, et al. Screening in the com-
munity to reduce fractures in older women (SCOOP): a randomized
controlled trial. Lancet 2017;391:741−7.
4. Bone HG, Wagman RB, Brandi ML, et al. 10 years of denosumab treat-
ment in postmenopausal women with osteoporosis: results from the
phase 3 randomised FREEDOM trial and open-label extension. Lancet
2017;5:513−23.
5. Kendler DL, Marin F, Zerbini CA, et al. Effects of teriparatide and rise-
dronate on new fractures in post-menopausal women with severe
osteoporosis (VERO): a multicentre, double-blind, double-dummy,
randomised controlled trial. Lancet 2017;391:230−40.
© 2019 Elsevier Ltd. All rights reserved. Initially published in Obstetrics,
Gynaecology and Reproductive Medicine 2019;29(7):201–206.
About the authors
Gabriella Shanks is a Doctor at Newham General Hospital, London, UK.
Conflicts of interest: none.
Devina Sharma is an Intern at St James’ University Hospital, Dublin, Ire-
land. Conflicts of interest: none.
Vinita Mishra is a Consultant Chemical Pathologist, Department of
Clinical Biochemistry and Metabolic Medicine, Royal Liverpool and
Broadgreen University Hospital NHS Trust, Liverpool, UK. Conflicts of
interest: none.
PAEDIATRICS PEER REVIEWED MIMS JPOG 2019 VOL. 45 NO. 3 113

Management of
Meningococcal Disease
Avishay Sarfatti BMBCh; Simon Nadel FRCP

In recent years, remarkable progress has been made in the development of vac-
cines against the different disease-causing serotypes of Neisseria meningitidis.
Despite this, invasive meningococcal disease (IMD) remains a life-threatening
illness with significant mortality, morbidity, and long-term sequelae. Prompt rec-
ognition and early treatment with antibiotics are the first steps in its management.
Professionals looking after children with suspected IMD should be familiar with its
clinical course, so that progression of the disease can be identified early, and its
complications including septic shock, coagulopathy, and raised intracranial pres-
sure (ICP) managed aggressively. This article summarizes the clinical features,
presentation, pathophysiology, and management of IMD focusing on its two com-
mon clinical presentations: septicaemia with associated shock and meningitis.

INTRODUCTION is an exclusively human gram-negative

Meningococcal infection is a disease diplococcus that is a common com-
with significant mortality, morbidity, mensal organism of the nasopharynx. It
and long-term sequelae. Neisseria spreads from person to person via the
meningitidis, the responsible pathogen, respiratory route. There are 13 sero-
114 MIMS JPOG 2019 VOL. 45 NO. 3
Table 1. Risk Factors for Invasive Meningococcal Disease
• Geographical location – eg, meningitis belt in sub-Saharan Africa
• 
Seasonality: Winter season in moderate climate zones, dry
season in sub-Saharan Africa
• Age (<5 and 15–24 years)
• Overcrowding: Poor housing/military/university dormitories
• Active/passive cigarette smoking
• Prior viral respiratory infection (eg, influenza A virus, RSV infection)
• Inherited complement deficiency
• Close (family/household) contact with index case
groups known to exist, some encapsulated and
unencapsulated. The polysaccharide capsule is
associated with pathogenicity. The serogroups
A, B, C, X, Y, and W are those implicated in IMD.
The commonest age for disease is in chil-
dren younger than 5 years, with the highest rate
in infants aged 3–12 months. However, disease
occurs throughout childhood, and the incidence
increases again in adolescence and young
adults.
While conjugate vaccines for serogroups A,
C, W, and Y have been available for some time,
the development of such a vaccine against se-
rogroup B proved more challenging. The sero-
group B meningococcal capsule is poorly immu-
nogenic as it resembles mammalian neural cell
adhesion molecules, a glycoprotein found on the
surface of foetal neuronal cells. A novel MenB
vaccine, however has been developed, and in
September 2015, the UK was the first country
to adopt the vaccine into a national routine im-
munization programme. This proved to be high-
ly effective. Public Health England surveillance
programme found a 50% incidence rate ratio
reduction in MenB cases in the vaccine eligible
group in the ten-month period after the vaccine
was introduced. Importantly, analysis of vaccine
safety data following the administration of 3 mil-
lion doses of the vaccine to 1.29 million children
in the UK did not raise any significant safety con-
PAEDIATRICS PEER REVIEWED
cerns. While initial data is encouraging, more
time is needed before we will be able to gauge
the efficacy of the vaccine. At present, serogroup
B meningococcal infection is responsible for the
majority of IMD in the developed world.
Approximately 10% of the population are col-
onised with commensal, non-encapsulated Neis-
seria meningitidis, some of which confer protection
against encapsulated virulent strains. The progres-
sion from colonization to invasive disease is not
fully understood. It is thought that meningococcal
virulence factors, environmental conditions, and
host susceptibility play an important role. A recent
(<10 days) acquisition of a pathogenic strain in a
susceptible host may lead to invasive disease. The
clinical manifestation of IMD in an individual host
is determined by the extent of activation of the im-
mune system. This in turn is affected by bacterial
factors, such as capsular serogroup, the amount
of circulating endotoxin and bacterial load, as well
as by genetic polymorphisms in constituents of the
complement system, the inflammatory response
and the coagulation cascade.
In some instances, there may be rapid onset
and progression of disease, and death may follow
within hours. Even when diagnosis is made early
and appropriate treatment is rapidly initiated, case
fatality is estimated at 5–10%. Of those who sur-
vive, approximately 30% suffer severe sequelae of
the disease, with one or more deficits in physical,
cognitive and psychological functioning, includ-
ing neurological defects, deafness, amputation of
limbs or digits, or skin scarring. Prompt recogni-
tion and early aggressive treatment with antibiot-
ics are paramount. Identifying systemic complica-
tions such as shock, raised ICP, and seizures are
imperative.
There are 3 main clinical manifestations of
disease: meningitis, sepsis, and pneumonia.
Pneumonia is primarily a disease of the elderly
and will not be discussed further.
RISK FACTORS
Risk factors can be stratified into the following
categories shown in Table 1.
PAEDIATRICS PEER REVIEWED
In general, meningococcal epidemiolo-
gy can be divided into endemic infections and
epidemic outbreaks. Endemic disease usually
occurs in developed countries and has an in-
cidence of 1–3 cases per 100,000. The highest
prevalence of endemic disease occurs during
the winter months, and is associated with in-
creases in the rate of viral upper respiratory in-
fection.
In the developing world, such as in sub-Sa-
haran Africa, epidemic outbreaks occur with an
incidence up to 10–100 times higher than that
seen in endemic disease. The predominant or-
ganism in this region is serogroup A. Epidemic
disease usually occurs during the dry season.
The risk of meningococcal disease is inverse-
ly related to age. Nearly half of all cases occur
in children <2 years of age. In epidemics, older
children are more likely to be infected. Crowding
especially among military recruits, or university
students is considered a major risk factor.
An association between smoking and in-
creased rate of meningococcal carriage has
been demonstrated. Passive smoking has been
implicated in increasing the risk of meningo-
coccal disease in children. Recent infection
with respiratory viruses has been documented
to increase susceptibility to meningococcal in-
fection. Respiratory viruses may disrupt the ep-
ithelial barrier and facilitate invasion of virulent
meningococci.
In general, antibodies and complement are
important in protection from meningococcal in-
fection, and deficiency of either is associated
with an increased risk of disease (see Table 2).
Terminal complement component and alterna-
tive pathway deficiencies have been reported
as predisposing to meningococcal disease.
Over the past 20 years, much effort has
gone into identifying individual genetic poly-
morphisms that may add to our understanding
as to why some individuals experience IMD
while others remain carriers, as well as account-
ing for the different clinical presentations and
varying severity of disease between individuals.
MIMS JPOG 2019 VOL. 45 NO. 3 115
Table 2. Host Factor Susceptibility and Severity
Complement deficiency
Hypogammaglobulinaemia
Hyposplenism
Various genetic polymorphisms in genes associated with the
complement, inflammatory response, and coagulation pathway
Single nucleotide polymorphisms (SNPs) in
genes controlling the host response to infection
are thought to be important. The strongest as-
sociations found to date are in SNPs in genes
involved in the fibrinolysis (SERPINE1) and
cytokine (IL1B, IL1RN) pathways. A large Ge-
nome Wide Association Study has determined
that variations in the complement factor H and
factor H-associated proteins are important
susceptibility factors. It is hoped that this area
of research will allow us in the future to tailor
treatment to individuals based on their genetic
makeup.
PRESENTATION
In the first few hours after disease onset, the
clinical picture is similar to one often seen in
common viral infections. While the classical
petechial/purpuric rash in a child with fever is
highly suggestive of meningococcal disease,
up to one fifth of children have no rash or a
non-specific maculopapular rash on presenta-
tion. Less specific features such as: fever, cold
peripheries, leg pain, tachycardia, and abnor-
mal skin colour present in the first 12 hours and
must not be ignored. In one large observational
study, myalgias were identified as an important
differential sign, with the pain being more in-
tense than expected in viral illnesses. The char-
acteristic haemorrhagic petechial/purpuric rash
occurs much later and may present up to 24
hours after illness onset.
Clinical presentation with signs and symp-
toms of meningism is more common in older chil-
dren with meningococcal meningitis. The classi-
116 MIMS JPOG 2019 VOL. 45 NO. 3
Table 3. Risk Factors Influencing Fatal Outcome
Rapidly progressing rash
Coma
Hypotension and shock
Low/normal peripheral WBC count
Low acute phase reactants
Low platelets
Coagulopathy
Absence of meningitis
Young age
cal symptoms of fever, headache, photophobia,
neck stiffness, and altered mental status are often
only partially present. A high level of suspicion is
crucial to making an early diagnosis. The clinical
features which are known to be associated with
risk of mortality are outlined in Table 3.
Physical examination
Pyrexia and an ongoing tachycardia are often
present. Physical signs are often non-specific.
Petechial rash and signs of meningeal irritation,
traditionally thought of as more specific find-
ings, may be present. However, their presence
or absence neither confirm nor exclude invasive
meningococcal disease.
As the disease progresses, signs and symp-
toms of shock and disseminated intravascular
coagulopathy (DIC) may become more obvious.
These include a worsening tachycardia and a
low blood pressure, altered mental state, pro-
found peripheral vasoconstriction – cold extrem-
ities, prolonged capillary refill time, and weak
peripheral pulses together with progression of a
petechial rash becoming more widespread, with
multiple lesions coalescing forming large purpu-
ric and ecchymotic lesions.
DIAGNOSTIC WORKUP
Microbiological confirmation is important for
disease identification and institution of pub-
PAEDIATRICS PEER REVIEWED
lic health measures. Definitive diagnosis of
meningococcal disease is established by iso-
lation of N. meningitidis, or its products from
a normally sterile body fluid such as blood or
CSF. Blood cultures are positive in 50–80% of
cases, and CSF cultures are positive in 80–
90% of cases of meningitis. Meningococci are
exquisitely sensitive to many antibiotics, with
penicillin-resistant strains only rarely reported.
Therefore, following administration of antibiot-
ics, blood, or CSF cultures are rarely positive.
Some studies suggest that the CSF becomes
sterile as soon as 2–8 hours after antibiotics
are given. Polymerase chain reaction (PCR)
assays in whole blood (using EDTA sample)
or CSF detect nucleic acids of the pathogen
and the test is highly specific (100% for blood,
and near 100% for CSF) and sensitive (approx-
imxately 88% in different studies). PCR testing
is useful up to 96 hours after antibiotics have
been given, but early samples are more likely
to be positive.
Non-specific laboratory tests such as
white blood cell (WBC) count and C-reactive
protein (CRP) may be elevated suggesting
bacterial infection. The few studies looking at
the diagnostic value of these markers found
them to have insufficient specificity and sen-
sitivity to distinguish IMD from other illnesses.
They should therefore have a supportive role
in the diagnostic work up, and they cannot be
relied on to exclude IMD. A low/normal WBC
and relatively low CRP are adverse prognostic
factors in patients with diagnosed meningo-
coccal disease.
Lumbar puncture
A lumbar puncture confirms a diagnosis of
meningococcal meningitis. This may be im-
portant in patients with meningism where the
diagnosis is in doubt. As well as confirming a
diagnosis of IMD, it can identify other causes for
a presentation with meningoencephalitis.
However, if a diagnosis of IMD is already
made, the presence of meningitis does not
PAEDIATRICS PEER REVIEWED MIMS JPOG 2019 VOL. 45 NO. 3 117

affect the duration of antimicrobial therapy Table 4. Contraindications to Performance of Lumbar Puncture
and all patients with meningococcal infection
should receive close follow up, including a
Clinical or radiological signs • Reduced or fluctuating level of
hearing test 4–6 weeks after diagnosis. of raised ICP consciousness (Glasgow Coma
Carrying out a lumbar puncture is not with- Scale score less than 9 or a drop
of 3 or more)
out risk and it should be postponed in patients
• Relative bradycardia and
with shock or coagulopathy and in patients with
hypertension
clinical features of raised ICP. There are well-doc-
• Focal neurological signs
umented instances of cerebral herniation follow-
• Abnormal posture or posturing
ing lumbar puncture and clear contraindications
• Unequal, dilated, or poorly
to the procedure exist (see Table 4).
responsive pupils
A lumbar puncture should be performed in
• Papilloedema
any stable patient where meningitis needs to be
• Abnormal “doll’s eye” movements
excluded, as long as no contraindications are
present. Cardiovascular instability/ • Tachycardia and/or hypotension
shock
The UK national guidelines use the follow- • Respiratory distress
ing normal ranges for CSF variables: • Toxic/moribund state
• Opening pressure: 10–100 mmH2O (age un- • Altered mental state or decreased
der 8 years); 60–200 mmH2O (over 8 years) conscious level (GCS <9)
• Appearance to the naked eye: clear and col- Extensive or spreading • Coagulopathy
purpura
ourless • Platelets <100
• Total protein concentration: 0.15–0.45 g/L • On anticoagulant therapy
• G lucose concentration: 2.78–4.44 millimole/L After convulsions until
(approximately 60% of the plasma value) stabilised
• Cell count (per microlitre): 0–5 WBCs (0–20 Infection at proposed site
in neonates), no RBCs (if RBCs are present of LP
and the blood WBC count is within the nor-
mal range, more than one WBC per 500–
1,000 CSF RBCs can be expected in a child the CT scanner. The decision to perform a lumbar
or young person with meningitis and should puncture should be made on clinical grounds, as
not be ignored) CT is unreliable at identifying raised ICP. In one
When a lumbar puncture is not performed study, 50% of patients with raised ICP confirmed
early, normal CSF results should not exclude bac- with invasive monitoring but did not have any
terial meningitis where clinical suspicion is high. radiological evidence supporting raised ICP on
CT.
Cranial imaging In recent years, the use of bedside ultra-
An urgent cranial computerized tomography sound to measure the diameter of the optic
(CT) scan is only justified in a patient with fo- nerve sheath has been shown potential in iden-
cal neurology or in a patient with unclear cause tifying raised ICP. However, further work is re-
for a reduced level of consciousness. It should quired before this can be relied on to rule in
only be performed once the patient has been or rule out intracranial hypertension in children.
stabilized, and patients should be transferred to
the CT scanner by an experienced team with full DISEASE PROGRESSION
monitoring to detect deterioration. It is danger- Meningococcal disease in children usually pre-
ous to transfer an unstable critically ill patient to sents in two major clinical syndromes, over-
118 MIMS JPOG 2019 VOL. 45 NO. 3
whelming host inflammatory response causing
shock and meningitis. These two clinical syn-
dromes may coexist and overlap.
In overwhelming host inflammatory re-
sponse the patient rapidly progresses to shock,
DIC, multiorgan failure, and death unless rapid
and aggressive resuscitation and organ sup-
port is carried out. This presentation occurs
in approximately 20% of patients with menin-
gococcal disease, but is associated with high
mortality and morbidity.
Meningitis is the most common manifesta-
tion of meningococcal disease. It often follows a
longer period of low-grade bacteraemia and a less
fulminant course, with patients exhibiting signs of
meningeal irritation, progressing to depression
of level of consciousness, coma, and seizures. A
small proportion of patients with meningococcal
meningitis may present very acutely with signs of
raised ICP, rapidly progressing to brainstem death.
MENINGOCOCCAL SEPTIC SHOCK
Shock in meningococcal disease results from a
combination of hypovolaemia, caused by cap-
illary leak syndrome, myocardial dysfunction,
altered vasomotor tone, and impaired cellular
metabolism, and in some instances, adrenal in-
sufficiency.
The clinical features of shock arise be-
cause perfusion of the vital organs (such as the
brain and heart) is maintained at the expense of
perfusion of the skin, kidneys, and gut. In the
early phases of shock, these processes com-
pensate for hypovolaemia and maintain central
circulating blood volume and cardiac output.
As a result, patients with meningococcal
septicaemia often present with cold peripher-
ies and prolonged capillary refill time, as well
as oliguria. In the most severe cases, ischaemia
of the skin or even whole limbs may occur, par-
ticularly if there is thrombosis in areas of vascu-
lar stasis. In addition, many patients with sep-
tic shock will develop renal dysfunction, often
leading to acute renal failure and may require
renal replacement therapy.
PAEDIATRICS PEER REVIEWED
Despite severe shock, preservation of
brain perfusion and function is often present
until decompensation occurs, so that the child’s
relatively alert state may make observers under-
estimate the degree of cardiovascular collapse.
Eventually, a decreased level of consciousness
indicates loss of cerebral vascular homeostasis
and reduced brain perfusion.
The onset of hypotension signifies a failure
of the compensatory mechanisms. It should be
remembered that the diagnosis of shock in chil-
dren is not dependent on the presence of arte-
rial hypotension. Children are able to compen-
sate for the loss of up to 40% of their circulating
blood volume without developing hypotension,
and may therefore have normal blood pressure
until shock is advanced.
Myocardial dysfunction arises as a result
of a number of different pathological processes.
Hypovolaemia causing decreased ventricular
filling; metabolic derangements including hy-
poxia, acidosis, hypokalaemia, hypocalcaemia,
hypophosphataemia, hypomagnesaemia, hy-
poglycaemia, and disturbed fatty acid metabo-
lism also affect myocardial contractility. Bacteri-
al products and inflammatory cytokines directly
suppress myocardial contractility. Interleukin 6
(IL-6) in plasma has specific myocardial depres-
sant properties.
Myocardial function improves with volume
resuscitation and correction of metabolic de-
rangements. However, patients in whom shock
persists will require inotropic support to im-
prove myocardial function.
INITIAL ASSESSMENT
AND MANAGEMENT
Management of shock
The goal of circulatory support in shock is the
maintenance of oxygenation and adequate tis-
sue perfusion. The priority in achieving this goal
is fluid resuscitation to restore intravascular vol-
ume. Early and aggressive fluid resuscitation is
associated with improved survival in paediatric
PAEDIATRICS PEER REVIEWED
septic shock. In addition, inotropic support is
frequently necessary in order to maintain cardi-
ac output and organ perfusion.
An initial bolus of 20 mL/kg of fluid should
be given over 5–10 minutes to children with
signs of shock. The expected response to vol-
ume replacement is reduction in heart rate,
improved peripheral perfusion and decreased
capillary refill time, and improving metabolic ac-
idosis. In mild cases, shock is rapidly reversed
by this initial fluid bolus, but repeated review is
mandatory as the disease may progress. In the
critically ill patient, aggressive fluid resuscita-
tion should continue, aiming to achieve thera-
peutic endpoints (see Table 5). The establish-
ment of central venous access is a priority. This
will aid and guide fluid resuscitation, and the
measurement of central venous oxygen satura-
tion (ScvO2) has been a useful guide to the ade-
quacy of oxygen delivery in shock, with the goal
of achieving a central venous pressure (CVP) of
8–12 mm Hg, and ScvO2 >70%.
If signs of shock persist after 40–60 mL/kg
of fluid, there is a significant risk of pulmonary
oedema developing. Elective tracheal intuba-
tion and mechanical ventilation is recommend-
ed at this stage, even in the absence of overt
respiratory failure. If performed early, before
signs of pulmonary oedema are manifest, this
procedure is associated with an improvement in
outcome. Early tracheal intubation and mechan-
ical ventilation is thought to be beneficial by al-
lowing reduction of myocardial and respiratory
muscle oxygen consumption and by facilitating
delivery of positive end-expiratory pressure
(PEEP) to aid oxygenation. The sedation and
muscle relaxation used in these circumstances
additionally facilitates the placement of arterial
and central venous catheters.
Fluid resuscitation therapy should be mon-
itored continuously using heart rate, blood
pressure, CVP, urine output, metabolic status,
and peripheral perfusion as indicators. Fluid
volumes much higher than 60 mL/kg are often
needed.
MIMS JPOG 2019 VOL. 45 NO. 3 119
Table 5. Initial Therapeutic Endpoints in the Resuscitation of Children
in Septic Shock (Data from the 2012 Surviving Sepsis Campaign
Guidelines for the Management of Septic Shock)
Capillary refill time <2 sec
Normal blood pressure for age
Normal pulses with no differential between peripheral and central
pulses
Warm extremities
Urine output >1 mL/kg/hr (A urinary catheter is required)
Normal mental status
ScVO2 >70%
There is controversy regarding the optimal
fluid for resuscitation in children with sepsis.
4.5% human albumin solution (HAS) has been
our preferred resuscitation fluid in meningo-
coccal sepsis, and its use has been associat-
ed with a reduction in morbidity and mortality.
Subgroup analysis from a large randomized
controlled study, comparing 4% HAS with nor-
mal saline in critically ill adults, suggested that
HAS may be beneficial in patients with septic
shock. However, no such studies have been
performed in children. Blood products may be
used to correct anaemia (aim for Hb >100 g/L
in the acute resuscitation), thrombocytopenia,
and coagulopathy.
As myocardial depression is invariably
found in persistent shock, inotropic support with
adrenaline or noradrenaline should be initiated
early, via a central vein. It is usually impractical
to gain central venous access in children before
tracheal intubation. The intraosseous route can
be used to deliver adrenaline and noradrenaline
until central venous access is obtained.
There is some evidence that refractory sep-
tic shock may be more common in children with
impaired adrenal responsiveness. Initial stud-
ies in adults with septic shock and document-
ed adrenal hyporesponsiveness suggested that
low-dose, steroid supplementation may improve
survival. However, a more recent study failed to
120 MIMS JPOG 2019 VOL. 45 NO. 3
In the child with raised ICP and coexistent shock, the priority is to correct shock
before addressing specific measures to control ICP.
confirm these findings. A meta-analysis of pae-
diatric studies found no benefit for steroids in
reducing mortality, duration of shock or length
of hospital stay. The Surviving Sepsis campaign
2012 guidelines suggest hydrocortisone therapy
in children with fluid-refractory and catechola-
mine-resistant shock with suspected or proven
adrenal insufficiency.
Respiratory support
High flow oxygen should be delivered routine-
ly from the outset. If no major airway or breath-
ing problem is present, priority is given to the
assessment and treatment of the circulation.
Indications for immediate endotracheal intuba-
tion and mechanical ventilation are hypoxia, with
severe respiratory distress indicating a progres-
sion of pulmonary oedema, severe persistent
shock, fluctuating or decreasing conscious level
(Glasgow Coma Score 8 or less, or a decrease
of 3 points within 1 hour), or signs of raised
ICP. When possible, the cardiovascular system
should be stabilized before intubation, and the
potential for acute decompensation should be
PAEDIATRICS PEER REVIEWED
anticipated. Inotropes when indicated, should
be started before intubation. It is our practice to
use ketamine and rocuronium for induction of
anaesthesia as they cause less cardiovascular
instability. A cuffed endotracheal tube is helpful
as pulmonary oedema is likely to develop in this
setting, and high ventilator pressures may be
needed.
DISSEMINATED INTRAVASCULAR
COAGULOPATHY
DIC is universal in severe sepsis, regardless of
the cause. Both procoagulant and anticoagulant
pathways of haemostasis are dysregulated as a
consequence of activation of the inflammatory
and coagulation cascades, in addition to en-
dothelial dysfunction.
It is likely that the coagulopathy seen in
meningococcal disease arises from a combi-
nation of loss of anticoagulant proteins such as
proteins C and S from the plasma, and the failure
of anticoagulant mechanisms on the endothelial
surface. The endothelial receptors required for
protein C activation (endothelial protein C recep-
tor and thrombomodulin) are down-regulated on
the endothelium of patients with meningococcal
septicaemia. In addition, levels of circulating
activated protein C and antithrombin III are re-
duced, the normal fibrinolytic mechanisms are
suppressed due to reduced production of en-
dothelial tissue plasminogen activator, and the
production of plasminogen activator inhibitior-1
(PAI-1) and other fibrinolysis inhibitors such as
thrombin-activatable fibrinolysis inhibitor (TAFI).
This results in intravascular clot formation, sup-
pression of the normal mechanisms which de-
grade intravascular thrombi, and the clinical
syndrome of DIC and the evolution of purpura
fulminans.
Spontaneous pulmonary, gastric, or cere-
bral haemorrhage may occur, particularly if there
is associated thrombocytopenia. Blood counts
and coagulation studies should be undertak-
en regularly. Correction of coagulopathy in the
presence of active bleeding with regular vitamin
PAEDIATRICS PEER REVIEWED
K, fresh frozen plasma, and platelets is advised.
Cryoprecipitate should be used when hypofi-
brinogenaemia is present. The aim is to prevent
life-threatening haemorrhage.
Knowing that abnormalities in both proco-
agulant and anticoagulant proteins contribute
to the development of DIC, research has looked
into interventions that will correct these abnor-
malities. Recombinant activated protein C (aPC)
is one example. Initially, it was shown to reduce
mortality in adults with severe sepsis and septic
shock. A study of the use of aPC in children with
severe sepsis, including purpura fulminans and
meningococcal disease, however did not show
any benefit, and aPC is no longer advocated as a
therapeutic option in sepsis. Other therapeutic in-
terventions which affect the coagulation cascade,
such as heparin, tissue plasminogen activator,
anti-thrombin III, and protein C concentrate have
no clear evidence for their continued routine use.
BIOCHEMICAL DERANGEMENTS
There may be profound derangements in blood
chemistry and acid-base balance. Important in-
vestigations to be repeated regularly include se-
rum sodium (particularly important in the context
of raised ICP), potassium, phosphate, calcium,
magnesium, urea, and creatinine.
Frequent blood gas analysis should be un-
dertaken. This will allow the treating physician
to identify evolving metabolic acidosis, monitor
blood glucose and electrolyte abnormalities,
and follow serial blood lactate levels. While the
correction of metabolic acidosis with Sodium bi-
carbonate is a matter of some controversy, the
authors believe that in cardiovascularly unstable
patients this is indicated.
In children with invasive meningococcal dis-
ease, both hyperglycaemia and hypoglycaemia
may be present. Any episodes of hypoglycaemia
should be corrected immediately, and a dextrose
containing maintenance fluid should be adminis-
tered. Hyperglycaemia should also be avoided,
although evidence for benefit of tight glucose
control is lacking following the CHiP trial (Control
MIMS JPOG 2019 VOL. 45 NO. 3 121
of Hyperglycaemia in Paediatric intensive care).
Therefore, a less tight glycaemic control is advo-
cated, aiming for a blood glucose <12mmol/L.
SKIN AND LIMBS
The skin may be severely compromised in menin-
gococcal disease through inadequate perfusion
and thrombosis. Decreased skin perfusion may
predispose pressure areas to ischaemic dam-
age, and tissue oedema from capillary leak may
cause a compartment syndrome. Multidiscipli-
nary input from orthopaedic, vascular, and plas-
tic surgeons may be needed for limb salvage.
RAISED INTRACRANIAL PRESSURE
Raised ICP occurs in meningitis due to inflam-
mation of the meninges and capillary leak in cer-
ebral vasculature, leading to cerebral oedema.
Clinically, significantly raised ICP is uncommon.
Although most critically ill children with menin-
gococcal infection have shock as their primary
clinical problem, a small proportion present with
signs of raised ICP as the predominant clinical
manifestation.
To understand the physiologic impact of
raised ICP on cerebral blood flow (CBF) one must
be familiar with the physiology of the intracranial
vault. CBF influences brain oxygenation. Three
major factors regulate CBF: Cerebral perfusion
pressure (CPP), partial pressure of arterial CO2,
and partial pressure of arterial O2. Hypoxia caus-
es cerebral vasodilation and increases CBF, and
therefore ICP. Hypercapnia causes cerebral vas-
odilation and similarly affects CBF and ICP.
CPP is taken as the difference between
mean arterial pressure (MAP) and ICP, and
represents the pressure gradient across the
cerebrovascular bed. (CPP = MAP - ICP). In
meningitis, it is assumed that cerebral vascular
autoregulation is abnormal, and therefore per-
fusion becomes critically dependent on CPP.
MAP can be increased by vasopressors to in-
crease CPP.
Reduction of ICP (and thus increased CPP)
may be accomplished by reducing brain vol-
122 MIMS JPOG 2019 VOL. 45 NO. 3
ume using agents such as the osmotic diuretic
mannitol or hypertonic saline to reduce cerebral
oedema. In addition, maintaining the head in the
midline, and elevated to 30° facilitates venous
drainage. Prevention of hypercarbia and hypoxia
reduces intracerebral blood volume and there-
fore mechanical ventilation can be useful in treat-
ing raised ICP.
Following intubation, adequate sedation is
essential in order to prevent acute rises in ICP
caused by agitation or coughing. Muscle relax-
ants may be needed but one must be aware that
the detection of seizures will be challenging and
EEG monitoring, while not widely available, is de-
sirable in these patients. Seizures when present
should be aggressively managed to avoid any
further increase in ICP. Other neuroprotective
measures include avoiding hyperthermia, and
hypoxia, and ventilating to normal range PaCO2.
In the child with raised ICP and coexistent
shock, the priority is to correct shock before ad-
dressing specific measures to control ICP. An ad-
equate blood pressure is necessary to maintain
cerebral perfusion. In this situation fluid resus-
citation may result in an improved level of con-
sciousness.
ANTIBIOTIC THERAPY
Cefotaxime (50 mg/kg) or ceftriaxone (100 mg/
kg) is preferred as initial antimicrobial therapy in
patients with a clinical diagnosis of meningococ-
cal disease. Ceftriaxone should not be admin-
istered simultaneously with calcium containing
solutions even if done through different infusion
lines. In children older than 28 days, ceftriaxone
and a calcium-containing solution can be given
sequentially, either through different infusion
lines, or through the same line so long as it is
flushed thoroughly between infusions.
Until definitive microbiological confirmation
is available, there remains the possibility of both
penicillin resistance and alternative bacterial di-
agnoses. Other rare bacterial causes of purpura
fulminans include Streptococcus pneumoniae,
Staphylococcus aureus, and Gram-negative
PAEDIATRICS PEER REVIEWED
bacteria. Broader antimicrobial cover may be
needed depending on local bacteria resistance
patterns. The recommended duration of antibi-
otic therapy for uncomplicated meningococcal
disease is 7 days.
ADJUNCTIVE THERAPIES
High-dose corticosteroids given prior to the first
dose of antibiotics appear to reduce the inci-
dence of neurological sequelae in both Haemo-
philus influenzae type b and pneumococcal men-
ingitis, and there is a trend to improved outcome
in meningococcal meningitis. A recent study
compared two prospective cohorts in the Neth-
erlands in two different periods of time: between
1998 and 2002 and between 2006 and 2011.
The main difference between the groups was
the routine use of dexamethasone in the latter
group. The study found no difference in mortality
and neurological sequelae between the groups.
The rates of death and hearing impairment were
slightly reduced in the later cohort but there was
no statistical significance. Current recommenda-
tions are to administer dexamethasone 0.15 mg/
kg 6 hourly for 4 days if started before or within
4 hours of the initial dose of parenteral antibiot-
ic in patients with proven or suspected bacterial
meningitis.
There have been two randomized, place-
bo-controlled studies of adjunctive therapies in
meningococcal septicaemia. Both have involved
antiendotoxin therapy.
A study of the antiendotoxin antibody, HA-
1A, showed that there was no significant reduc-
tion in mortality in children treated with HA-1A,
when compared with placebo. Studies in adults
with Gram-negative septicaemia also failed to
show benefit of therapy with HA-1A.
Recombinant bactericidal permeability in-
creasing protein (rBPI21), which binds to and
neutralizes endotoxin and blocks the inflam-
matory cascade, has been evaluated for use in
meningococcal disease. There was evidence
of improvement in outcome in a variety of pa-
rameters. Unfortunately, this study was not
PAEDIATRICS PEER REVIEWED MIMS JPOG 2019 VOL. 45 NO. 3 123

sufficiently powered to be able to detect a re-

duction in mortality. However, patients treated
with rBPI21 suffered fewer amputations, few-
er blood product transfusions, and improved
functional outcome compared with those re-
ceiving placebo. In addition, fewer children
died who had received a full 24-hour infusion of
rBPI21 (2% rBPI21 vs 6% placebo; p=0.07), com-
pared with those who had not received the full
infusion. This suggested that rBPI21 used ear-
lier in the course of disease may be beneficial
in children with meningococcal disease. How-
ever, the only published data at present would
not support its routine use and this agent is
currently not in production.

WHERE BEST TO MANAGE

CHILDREN WITH MENINGOCOCCAL
DISEASE?
Most patients with meningococcal disease will
not require intensive care. However, those who
present with shock or signs of raised ICP should
be managed in a high dependency area for close
monitoring or in a specialist paediatric intensive
care unit (PICU).
For those children who do not immediately
require transfer to PICU, careful monitoring of vi-
tal signs (pulse, blood pressure, transcutaneous
oxygen saturation, respiratory rate, urine output,
and conscious level) should be carried out for
the first 24–48 hours. This is likely to be better
facilitated by initial management in a high de-
pendency unit.
Failure to recognize deterioration following
hospital admission is associated with increased
mortality. A large case-control study demonstrat-
ed that suboptimal emergency care significantly
increased the likelihood of death in children with
meningococcal disease. In children who died,
there were significantly more departures from
protocolized optimal management compared
with control children with meningococcal dis-
ease who survived.
Three factors were independently associ-
ated with an increased risk of death: the fail-
For those children who do not immediately require transfer to PICU, careful
monitoring of vital signs should be carried out for the first 24–48 hours.
ure of patients under the age of 16 years to
be looked after by a paediatrician; inadequate
supervision of junior medical staff; and failure
to administer adequate inotrope doses. In ad-
dition, failure to recognize complications of the
disease was a significant risk factor for death,
although not independent of absence of paedi-
atric care. The authors concluded that subop-
timal healthcare delivery significantly reduced
likelihood of survival; and improved training
of clinical staff, adherence to published proto-
cols, and increased supervision of junior staff
by consultants may improve outcome for these
children as well as those with other life-threat-
ening illnesses.
The decision to transfer critically ill or un-
stable patients to a more specialized unit can be
difficult. A prolonged period of resuscitation may
be necessary in the Emergency Department be-
fore a child with severe shock is stable enough
124 MIMS JPOG 2019 VOL. 45 NO. 3
Practice Points
• Meningococcal disease remains an important cause of morbidity
and mortality in children.
• Early recognition and protocolized treatment are vital to improve
outcome.
• Recognition of the main complications – shock and raised ICP is
important to determine treatment priorities.
• 
Aggressive fluid resuscitation, early tracheal intubation and
mechanical ventilation, and appropriate use of vasoactive agents
improves survival.
• Early discussion and appropriate transfer to a specialist paediatric
intensive care unit is important.
• Children with meningococcal disease should initially be admitted
to a high dependency area for close monitoring and recognition of
clinical deterioration, even if they appear to be clinically stable.
• A novel serogroup B meningococcal vaccine was introduced in the
UK in September 2015. Its impact on disease incidence is yet to be
determined.
to move. Transporting children before they are
adequately resuscitated is hazardous and the
child should be fully stabilized, with monitoring
equipment securely in place, before transfer to
the PICU is undertaken.
Stabilization includes securing the airway,
controlled mechanical ventilation, central ve-
nous, arterial and urinary catheterization, and
full monitoring. Transport-related morbidity and
mortality is reduced by the use of a special-
ist paediatric intensive care transfer team. The
benefit of transferring patients to specialized
units for ongoing intensive care has been borne
out by significant reduction in mortality of chil-
dren with meningococcal disease.
CONCLUSION
The outcome of meningococcal disease has
improved in recent years due to enhancements
in the recognition, resuscitation, stabilization,
transfer, and ongoing care of individuals with
the disease. However, despite these advanc-
es, meningococcal infection remains a major
cause of morbidity and mortality throughout
the world. Introduction of serogroup C conju-
gated vaccines has been an impressive suc-
PAEDIATRICS PEER REVIEWED
cess. The initial data on the impact of the new
serogroup B vaccine on disease burden is
encouraging. However, more time and further
data is needed before firm conclusions can be
made.
FURTHER READING
1. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of re-
combinant human activated protein C for severe sepsis. N Engl J
Med 2001; 344: 699–709.
2. Booy R, Habibi P, Nadel S, et al. Reduction in case fatality rate from
meningococcal disease associated with improved healthcare deliv-
ery. Arch Dis Child 2001; 85: 386–90.
3. Brierley J, Carcillo JA, Choong K, et al. Clinical practice parameters
for hemodynamic support of pediatric and neonatal septic shock:
2007 update from the American College of Critical Care Medicine.
Crit Care Med 2009; 37: 666–88.
4. Carcillo JA, Davis AL, Zaritsky A. Role of early fluid resuscitation in
pediatric septic shock. J Am Med Assoc 1991; 266: 1242–5.
5. Derkx B, Wittes J, McCloskey R. Randomized, placebo-controlled
trial of HA-1A, a human monoclonal antibody to endotoxin, in chil-
dren with meningococcal septic shock. Clin Infect Dis 1999; 28:
770–7.
6. Faust SN, Levin M, Harrison OB, et al. Dysfunction of endothelial
protein C activation in severe meningococcal sepsis. N Engl J Med
2001; 345: 408–16.
7. Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R. A
comparison of albumin and saline for fluid resuscitation in the inten-
sive care unit. N Engl J Med 2004; 350: 2247–56.
8. Levin M, Quint PA, Goldstein B, et al. Recombinant bactericidal/
permeability-increasing protein (rBPI21) as adjunctive treatment for
children with severe meningococcal sepsis: a randomised trial. Lan-
cet 2000; 356: 961–7.
9. Macrae D, Grieve R, Allen E, et al. A randomized trial of hypergly-
cemic control in pediatric intensive care. N Engl J Med 2014 Jan 9;
370: 107–18.
10. Nadel S, Goldstein B, Williams MD, et al. Drotrecogin alfa (activated)
in children with severe sepsis: a multicentre phase III randomised
controlled trial. Lancet 2007; 369: 836–43.
11. National Institute for Health and Clinical Excellence. Bacterial men-
ingitis and meningococcal septicaemia: management of bacterial
meningitis and meningococcal septicaemia in children and young
people younger than 16 years in primary and secondary care. (Clin-
ical guideline 102.) 2010, www.nice.org.uk/CG102.
12. Ninis N, Phillips C, Bailey L, et al. The role of healthcare delivery
in the outcome of meningococcal disease in children: case-control
study of fatal and non-fatal cases. Br Med J 2005; 330: 1475–80.
13. Parikh SR, Andrews NJ, Beebeejaun K, et al. Effectiveness and im-
pact of a reduced infant schedule of 4CMenB vaccine against group
B meningococcal disease in England: a national observational co-
hort study. Lancet 2016 Dec 3; 388: 2775–82.
14. Pathan N, Hemingway CA, Alizadeh AA, et al. Role of interleukin 6
in myocardial dysfunction of meningococcal septic shock. Lancet
2004; 363: 203–9.
15. Pollard AJ, Nadel S, Ninis N, Faust SN, Levin M. Emergency man-
agement of meningococcal disease: eight years on. Arch Dis Child
2007; 92: 283–6.
16. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in
the treatment of severe sepsis and septic shock. N Engl J Med 2001;
345: 1368–77.
17. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for pa-
tients with septic shock. N Engl J Med 2008; 358: 111–24.
18. Thompson MJ, Ninis N, Perera R, et al. Clinical recognition of me-
ningococcal disease in children and adolescents. Lancet 2006; 367:
397–403.
19. van de Beek D, de Gans J, McIntyre P, Prasad K. Steroids in adults
with acute bacterial meningitis: a systematic review. Lancet Infect
Dis 2004; 4: 139–43.
© 2019 Elsevier Ltd. All rights reserved. Initially published in Paediatrics
and Child Health 2019;29(5):197–204.
About the authors
Avishay Sarfatti is a Consultant in Paediatric Intensive Care Medicine,
Oxford University Hospitals NHS Foundation Trust, Oxford, UK. Conflict
of interest: None declared.
Simon Nadel is Consultant and Adjunct Professor in Paediatric Intensive
Care, St Mary’s Hospital, Imperial College Healthcare NHS Trust and Im-
perial College London, London, UK. Conflict of interest: None declared.
CONTINUING MEDICAL EDUCATION MIMS JPOG 2019 VOL. 45 NO. 3 125

Moving Towards Evidence-

based Gestational Diabetes
Mellitus Screening
Kok Hian TAN, MBBS, MMed (O&G), FRCOG (London), FAMS

INTRODUCTION
Recent surveys showed that the Oral Glu-
cose Tolerance Test (OGTT), using the
International Association of the Diabetes
and Pregnancy Study Group (IADPSG)
criteria, is now a common screening
practice for gestational diabetes mellitus
(GDM).1 The surveys found that hospitals
in the Asia-Pacific region followed rec-
ommendation from international studies
calling for a universal method for screen-
ing GDM and using evidence from the
international HAPO (Hyperglycemia and
Adverse Pregnancy Outcome) study.
This change and standardization in prac-
tice enhance evidence-based practices
into GDM screening, allowing optimal
screening and encourages follow-up
management for better outcomes.

PREVALENCE
The World Health Organization (WHO)
defines GDM as hyperglycaemia first
detected at any time during pregnancy.2
The prevalence of GDM is about 15–20%
and has been steadily increasing world-
wide, which could be linked to increas-
ing obesity rates and maternal age in
various countries.3
HEALTH RISKS
GDM increases the health risks for
mothers and their infants given the as-
Screening pregnant women during pregnancy is the most effective way to detect and
manage GDM early.
sociated maternal and foetal compli-
cations such as macrosomia, cepha-
lopelvic disproportion, pre-eclampsia,
gestational hypertension, preterm la-
bour, caesarean section, and neonatal
hypoglycaemia. 4
Infants born to mothers with GDM
are at risk of macrosomia and may also
suffer from shoulder dystocia, birth trau-
ma, and hypoglycaemia, which could
lead to long-term negative health effects.
Women who have already had GDM are
also more likely to develop GDM again
in subsequent pregnancies and type 2
diabetes (T2D) later in life.5-6 Moreover,
children born to these women are more
likely to develop obesity and T2D in late
adolescence or adulthood.7
126 MIMS JPOG 2019 VOL. 45 NO. 3
EVIDENCE FOR ROUTINE
SCREENING
There is increasing evidence showing
that the need for routine screening for
GDM using standardized evidence-based
criteria for the diagnosis of GDM to opti-
mize the care of pregnant women. Tar-
geted or high-risk selective screening has
been practised for decades in different
countries, when advantages and benefits
of GDM screening were established. 13-14
Prior to 2018, most Singapore hospitals
have been offering targeted GDM screen-
ing to high-risk pregnant women, in line
with the Singapore Ministry of Health’s
clinical guidelines for GDM screening.
Women who are at high risk for GDM may
present with a body mass index (BMI)
of >25 kg/m2, history of first-degree rel-
atives with diabetes, personal history of
previous GDM, previous large babies of
>4 kg, and previous poor obstetric out-
comes, which were usually associated
with diabetes.15
Previous studies have shown that
up to 50% of women with GDM may
remain undiagnosed using targeted
screening alone.16-17 A birth cohort study
(GUSTO cohort of ≥1,000 Asian preg-
nant women who mostly completed their
entire pregnancy at Singapore KK Wom-
en’s & Children’s Hospital between 2009
and 2010) showed the substantial inad-
equacy of high-risk screening to detect
half of GDM cases in Asian population. 18
The American College of Obstetri-
cians and Gynecologists, American Di-
abetes Association, Australasian Diabe-
tes in Pregnancy Society, and IADPSG
have recommended universal (routine)
screening given the significant increase
in GDM detection rate as opposed to tar-
geted screening.19-21
There is increasing evidence to sup-
port the transition from targeted screen-
CONTINUING MEDICAL EDUCATION
ing to universal screening.18 In 2006,
Cosson, et al, showed that universal
screening for GDM not only increased
the number of diagnosed women with
GDM, it was also associated with de-
creased adverse foetal outcomes. 22
In
Singapore, Chen, et al, evaluated preg-
nant women who did and did not under-
go universal or targeted screening for
GDM.23 The results showed that univer-
sal GDM screening is a cost-effective ap-
proach in reducing GDM complications
in the Asian population compared with
targeted screening or no screening. This
study validated other international study
findings showing universal screening
as a key and cost-effective method for
detecting GDM, leading to better health
outcomes.24-25
In Singapore, as part of the OBGYN
Academic Clinical Programme in Sing-
Health-Duke NUS Academic Medical
Centre, KKH Obstetrics & Gynaecology
Division, and SGH Obstetrics & Gynae-
cology Department units started offering
GDM screening to all pregnant patients
in their 24–28 weeks of gestation in 1
January 2016, using the IADPSG screen-
ing criteria.
26-27
This shift to universal
screening (routine screening for all) fol-
lows similar recommendations in Octo-
ber 2015 by the International Federation
of Gynecology and Obstetrics. 24
EVIDENCE-BASED CRITERIA
FOR ORAL GLUCOSE
TOLERANCE TEST
Many hospitals have adopted the
IADPSG criteria, a diagnostic criterion
for OGTT based on evidence derived
from an international HAPO study,
which evaluated women from 15 partic-
ipating centres.28 Of these, three were
Asian HAPO centres, namely Prince
of Wales Hospital–Chinese University
of Hong Kong in Hong Kong, Rajavithi
Hospital, Bangkok in Thailand, and KK
Women’s and Children’s Hospital in
Singapore.
Based on the HAPO study, each gly-
caemic value time point is independently
pegged to a certain odds ratio (OR) of
adverse outcome, on a linear progressive
basis. The threshold criteria of IADPSG
were fasting plasma glucose (FPG) 5.1
mmol/L (92 mg/dL), 1-hour plasma glu-
cose (PG) 10.0 mmol/L (180 mg/dL), and
2-hour PG 8.5 mmol/L (153 mg/dL), cor-
responding to the predefined value for
OR of 1.75 for adverse outcomes. The
cut-off OR of 1.75 was decided based
on the consensus of the IADPSG. Each
of the three IADPSG time points is vital
and contributes independently to the
detection of GDM.29 In 2014, Duran A, et
al, found that the introduction of IADPSG
criteria for screening and diagnosis of
GDM results in improved pregnancy out-
comes at a lower cost in a large cohort of
pregnant women.30
These changes (universal screen-
ing with IADPSG criteria) enhance pa-
tient care by ensuring that pregnant
women who develop GDM are promptly
identified and provided with timely inter-
ventions. Both Singapore (see Figure
1 – Summary of Guidelines) and Hong
Kong, as well as various hospitals in the
Asia-Pacific region have adopted the
guidelines, incorporating IADPSG crite-
ria in universal GDM screening.1,31-34
ORAL GLUCOSE TOLERANCE
TEST PREPARATION
Screening pregnant women during preg-
nancy is the most effective way to detect
and manage GDM early. The screening
test for GDM is a three-point OGTT. Af-
ter fasting overnight, blood is drawn
and tested at three time-points: start
CONTINUING MEDICAL EDUCATION MIMS JPOG 2019 VOL. 45 NO. 3 127

Diagnostic criteria for diabetes in pregnancy (DIP) and GDM
• DIP should be diagnosed, if one or more of the following criteria are met:
o FPG ≥7.0 mmol/L
o 2-hour PG ≥11.1 mmol/L following a 75-gram oral glucose load
o Random PG ≥11.1 mmol/L in the presence of diabetes symptoms

• GDM should be diagnosed during the second and third trimesters, if one or more of the following criteria are
met using a 75-gram OGTT – IADPSG Criteria:
o FPG 5.1–6.9 mmol/L
o 1-hour PG ≥10.0 mmol/L
o 2-hour PG 8.5–11.0 mmol/L

Screening for hyperglycaemia in pregnancy

• Universal screening by 75-gram OGTT at 24–28 weeks of gestation is recommended using the full three-point
IADPSG criteria (0 hour, 1 hour, and 2 hours).

Management of GDM in pregnancy

• A multidisciplinary team approach (dietician, diabetic nurse, obstetrician, and endocrinologist) is recommended.
• Refer all women to a dietician.
Advise on eating a healthy diet and recommend meals with low glycaemic index.
o

• Advise regular exercise (such as walking for 30 minutes after a meal) to improve glycaemic control.
• Educate on capillary blood glucose monitoring to maintain glucose levels with the following targets:
o Fasting: 4.4–5.5 mmol/L and either
o 1-hour post-prandial: <7.8 mml/L or
o 2 hours post-prandial: 5.5–6.6 mmol/L
• Consider metformin and/or insulin as indicated
• There should be a regular foetal growth surveillance
• Timing and mode of delivery should be based on clinical assessment no later than 40 weeks and 6 days
gestation.

Post-natal management
• Breastfeeding is encouraged and supported.
• Metformin and glibenclamide can be continued while breastfeeding (but avoid all other hypoglycaemic
agents).
• Inform women diagnosed with hyperglycaemia in pregnancy of the risk of future diabetes and hyperglycae-
mia in future pregnancies and offer lifestyle advice that includes weight control, diet, and exercise.
• Post-natal test at 6–12 weeks should be performed to exclude diabetes or IGT, preferably with the 75-gram
2-point OGTT.
• Women diagnosed with hyperglycaemia in pregnancy should be screened for diabetes at regular intervals
thereafter. Women at higher risk for progression to diabetes should be screened yearly, while those at lower
risk should be screened at least three yearly.

Figure 1. Summary of College of Obstetricians and Gynaecologists, Singapore GDM recommendations.

128 MIMS JPOG 2019 VOL. 45 NO. 3
Women with GDM should be encouraged and supported to breastfeed, as breastfeeding
reduces the risk of obesity and diabetes in children.
(fasting), 1 hour, 2 hours; and after tak-
ing a flavoured sweet drink calibrated at
75-gram glucose load. Any blood sugar
levels equal to or above a certain criteria
value for each of the three time-points is
considered GDM.
The previous practice in KKH is
manual preparation of the drink with glu-
cose powder and boiled water. Howev-
er, this was time and labour consuming,
hence the shift to a premixed 75-gram,
more palatable OGTT drink. This has
enabled the facility to cope better with
the increased load of OGTT from routine
testing of all pregnant women.
Follow-up actions for women
with GDM
The treatment of GDM varies depending
on the result of the OGTT. If the condi-
tion is mild, controlling the diet is often
enough. For more severe cases, oral
medications (metformin) or insulin in-
jections (depending on severity) may be
required for the remainder of the preg-
nancy. Women with GDM should be ed-
ucated on capillary blood glucose moni-
CONTINUING MEDICAL EDUCATION
toring to maintain glucose levels closely
to target range (Fasting: 4.4–5.5 mmol/L;
1-hour post-prandial: <7.8 mml/L; and
2-hour post-prandial: 5.5–6.6 mmol/L). 31
The HbA1c test measures glycated
haemoglobin to determine the average
blood glucose over the past 8–12 weeks.
HbA1c is not used for screening or diag-
nosing GDM, and it should also not be
used for assessing blood glucose con-
trol during the second and third trimes-
ters of pregnancy.35 It is not sensitive in
detecting post-prandial hyperglycaemia
and is generally lower during pregnan-
cy because of increased red blood cell
turnover.
A multidisciplinary team approach
(dietician, diabetic nurse, obstetrician,
and endocrinologist) is recommended.
A dietitian will advise on a sensible eat-
ing plan focusing on healthy meals with
a low glycaemic index. Regular exercise
(such as walking for 30 minutes after
a meal) to improve glycaemic control
is recommended. Women with GDM
should have regular monitoring of foetal
growth and deliver by full-term.
Women with GDM should be en-
couraged and supported to breastfeed,
as breastfeeding reduces the risk of obe-
sity and diabetes in children. The dose of
metformin, glibenclamide, and/or insulin
may be reduced or stopped after birth as
indicated.
A repeat OGTT (two-point test)
should be performed 6 weeks after de-
livery, with a follow-up in the clinic to en-
sure that high sugar level was resolved.
This can exclude existing T2D and will
also identify women with impaired glu-
cose tolerance (IGT), for whom referral
for more active follow-up and interven-
tion is required.
Although GDM resolves in most
women after their pregnancy, they are
still exposed to a much higher risk of
developing T2D in their lifetime. T2D, if
not detected early or not well-controlled,
is associated with permanent compli-
cations to the kidneys, eyes, and blood
vessels.
Even if the post-natal OGTT is
normal, women with a history of GDM
should be informed about the increased
risk of developing T2D later in their life-
time or hyperglycaemia in subsequent
pregnancies. Thus, lifestyle advice that
includes weight control, diet, and exer-
cise should be offered.
Women with background risk fac-
tors (eg, obesity, strong family history of
T2D, insulin required during pregnancy,
metabolic syndrome, etc) should have
more frequent screening (yearly).
Follow-up after delivery is important
for detecting persistent GDM? or the on-
set of T2D, in order to achieve prompt
and optimal control and treatment of the
condition. A high BMI is associated with
an increased risk of developing T2D.
Sensible eating and regular exercise
may contribute to body weight and BMI
CONTINUING MEDICAL EDUCATION MIMS JPOG 2019 VOL. 45 NO. 3 129

reduction, thus reducing the risk or even
preventing the development of T2D after
GDM.36
THE NEXT LAP
Although the call for utilizing evi-
dence-based screening has reached
global proportions, more research and
evaluation of the IADPSG criteria is still
warranted to optimize the screening
process in various poulations.
next lap for GDM management is to
enhance practice-based evidence and
further accelerate evidence-based prac-
tices into GDM screening. An effective
universal screening programme should
be implemented to optimize treatment
for our patients.
Although patients with a history of
GDM have a very high risk of develop-
ing T2D, follow-up rates for such patients
worldwide has been poor. It is important
38
to audit the GDM screening process and
follow-up management to ensure that the
evidence-based standard of process and
follow-up practice are achieved.
The availability of data from routine
screening of mothers for GDM will be
37
The a boon for our health service improve-
ment and research. It will help us to bet-
ter define our pregnant population for
any pregnancy studies and allows us to
embark on the next level of research to
tackle the challenges of diabetes. These
include determining the best follow-up
strategy for patients with GDM and also
formulating better strategies for preven-
tion of diabetes in our population starting
from preconception, to conception, birth,
and the early years of life.
CONCLUSION
The prevalence of GDM has been stead-
ily increasing worldwide, making it
the most common medical disorder in
pregnancy. With the adoption of univer-
sal (routine) screening practice, GDM
screening, and the use of the IADPSG
criteria, the screening for GDM has be-
come more evidenced based.
About the author
Professor Kok Hian TAN is a Senior Consultant in the De-
partment of Maternal Fetal Medicine at KK Women’s and
Children’s Hospital, Singapore.

REFERENCES
1. Li LJ, Yu Q, IPRAMHO-INTERNATIONAL
Study Group, Tan KH. Clinical practice of
diabetic pregnancy screening in Asia-Pacif-
ic Countries: a survey review. Acta Diabetol
2019;7:815-817.
2. World Health Organization. Diagnostic
Criteria and Classification of Hyperglycaemia
First Detected in Pregnancy. World Heal Or-
ganization 2013;1–63.
3. IDF Diabetic Atlas (7th Edition). Inter-
national Diabetic Federation 2015. http://
www.diabetesatlas.org/component/attach-
ments/?task=download&id=116. Accessed
18 Mar 2016.
4. Reece EA. The fetal and maternal conse-
quences of gestational diabetes mellitus. J
Matern Fetal Neonatal Med 2010;23:199–203.
5. Metzger BE. Long-term outcomes in
mothers diagnosed with gestational diabetes
mellitus and their offspring. Clin Obstet Gyne-
col 2007;50:972–979.
6. Center for Disease Control. National
agenda for public health action: A national
public health initiative on diabetes and wom-
en’s health. Retrieved April 17, 2003.
7. American Diabetes Association. Gesta-
tional diabetes mellitus. Diabetes Care. 26
Suppl:S103-5.
8. Landon MB, Spong CY, Thom E, et al.
A multicenter, randomized trial of treatment
for mild gestational giabetes. N Engl J Med
2009;361:1339–1348.
9. Crowther CA, Hiller JE, Moss JR, McPhee
AJ, Jeffries WS, Robinson JS. Effect of treatment
of gestational diabetes mellitus on pregnancy
outcomes. N Engl J Med 2005;352:2477–2486.
10. Bonomo M, Corica D, Mion E, et al. Eval-
uating the therapeutic approach in pregnan-
cies complicated by borderline glucose in-
tolerance: a randomized clinical trial. Diabet
Med 2005;22:1536–1541.
11. Karlsson K, Kjellmer I. The outcome of
diabetic pregnancies in relation to the moth-
er’s blood sugar level. Am J Obstet Gynecol
1972;112:213-220.
12. Metzger BE, Buchanan TA, Coustan
DR, de Leiva A, Dunger DB, Hadden DR, et
al. Summary and recommendations of the
Fifth International Workshop-Conference on
Gestational Diabetes Mellitus. Diabetes Care
2007;30 Suppl 2:S251–S260.
13. Tee CS, Wang KW, Tho CK, et al. Manage-
ment and outcome of gestational diabetes in
Alexandra Hospital, Singapore. Ann Acad
Med Singapore 1990;19:459–462.
14. MOH Clinical Practice Guidelines on
Diabetes Mellitus. Published: Mar 2014.
https://www.moh.gov.sg/content/moh_web/
healthprofessionalsportal/doctors/guidelines/
cpg_medical/2014/cpgmed_diabetes_melli-
tus.html.
15. O’Sullivan JB, Mahan CM, Charles D,
Dandrow R V. Screening criteria for high-risk
gestational diabetic patients. Am J Obstet Gy-
necology 1973;116:895–900.
16. Coustan DR, Nelson C, Carpenter MW,
Carr SR, Rotondo L, Widness JA. Maternal
age and screening for gestational diabetes:
a population-based study. Obstet Gynecol
1989;73:557–561.
17. Chong YS, Cai S, Lin H, Soh SE, Lee YS,
Leow MKS, et al. Ethnic differences trans-
late to inadequacy of high-risk screening
for gestational diabetes mellitus in an Asian
population: a cohort study. BMC Pregnancy
Childbirth 2014;14:345.
18. ACOG. Practice Bulletin No. 137: Ges-
tational diabetes mellitus. Obstet Gynecol
2013;122:406–416.
19. American Diabetes Association. Stand-
ards of Medical Care in Diabetes-2015. Dia-
betes Care 2015;38:1–94.
20. Australasian Diabetes in Pregnancy So-
ciety. 2014. ADIPS Consensus Guidelines for
the Testing and Diagnosis of Hyperglycaemia
in Pregnancy in Australia and New Zealand
(modified November 2014).
21. International Association of Diabetes and
Pregnancy Study Groups Consensus Panel,
Metzger BE, Gabbe SG, Persson B, Bu-
chanan TA, Catalano PA, et al. International
association of diabetes and pregnancy study
groups recommendations on the diagnosis
and classification of hyperglycemia in preg-
nancy. Diabetes Care 2010;33:676–682.
22. Pin Yu Chen, Eric A. Finkelstein, Mor Jack
Ng, Fabian Yap, George S. H. Yeo, Victor
Samuel Rajadurai, Yap Seng Chong, Peter
D. Gluckman, Seang Mei Saw, Kenneth Y. C.
Kwek, and Kok Hian Tan. Incremental Cost-Ef-
fectiveness Analysis of Gestational Diabetes
Mellitus Screening Strategies in Singapore.
Asia Pac J Public Health 2016;28:15–25.
23. Hod M, Kapur A, Sacks DA, Hadar E,
Agarwal M, Di Renzo GC, Roura LC, McIntyre
HD, Morris JL, Divakar H. The International
Federation of Gynecology and Obstetrics
(FIGO) Initiative on gestational diabetes mel-
litus: A pragmatic guide for diagnosis, man-
agement, and care. Int J Gynaecol Obstet
2015;131 Suppl 3:S173–S211.
24. Moyer VA; U.S. Preventive Services Task
Force. Screening for gestational diabetes
mellitus: U.S. Preventive Services Task Force
recommendation statement. Ann Intern Med
2014;160:414–420.
25. Seow BY. Diabetes screening for expect-
ant mums. The Straits Times 18/11/2015.
26. Tan J. Gestational diabetes screening to
be offered to pregnant patients at KKH, SGH.
Channel News Asia 18/11/2015.
27. HAPO Study Cooperative Research
Group, Metzger BE, Lowe LP, Dyer AR, Trim-
ble ER, Chaovarindr U, Coustan DR, Hadden
DR, McCance DR, Hod M, McIntyre HD, Oats
JJ, Persson B, Rogers MS, Sacks DA. Hyper-
glycemia and adverse pregnancy outcomes.
N Engl J Med 2008;358:1991–2002.
28. Coustan DR, Lowe LP, Metzger BE, Dyer
AR. The HAPO Study: Paving The Way For
New Diagnostic Criteria For GDM. Am J Ob-
stet Gynecol 2010;202:654 e1–e6.
29. Duran A et al. Introduction of IADPSG
Criteria for the Screening and Diagnosis of
Gestational Diabetes Mellitus Results in Im-
proved Pregnancy Outcomes at a Lower Cost
in a Large Cohort of Pregnant Women: The St.
Carlos Gestational Diabetes Study. Diabetes
Care 2014;37:2442–2450.
30. HKCOG Guidelines - Guidelines for the
Management of Gestational Diabetes Melli-
tus The Hong Kong College of Obstetricians
and Gynaecologists. A Foundation College of
Hong Kong Academy of Medicine Number 7
Revised November 2016.
31. Tan KH, Tan T, Chi C, Thian S, Tan LK &
Yong TT. Guidelines for the Management
of Gestational Diabetes Mellitus. College of
Obstetricians and Gynaecologists, Singa-
pore Journal of Obstetrics & Gynaecology
2018;49:9–13.
32. Appropriate Care Guide. Gestational Dia-
betes Mellitus (GDM). An update on screen-
ing, diagnosis and follow-up. The Agency for
Care Effectiveness (ACE) Ministry of Health
(MOH). Published: 28 May 2018. www.ace-
hta.gov.sg.
33. Hyperglycemia in Pregnancy Consensus
Working Group. Asia & Oceania Federation of
Obstetrics and Gynaecology, Maternal Fetal
Medicine Committee’s consensus statements
on screening for hyperglycemia in pregnancy.
J Obstet Gynaecol Res 2018;44:2023–2024.
34. Diabetes Prevention Program Research
Group. 10-year follow-up of diabetes inci-
dence and weight loss in the Diabetes Pre-
vention Program Outcomes Study. Lancet
2009;374:1677–1686.
35. Diabetes in pregnancy: management
from preconception to the postnatal period.
NICE guideline Published: 25 February 2015.
36. Dias T, Siraj SHM, Aris IM, Li L-J and Tan
KH. Comparing different diagnostic criteria
for gestational diabetes mellitus in relation to
birthweight in Sri Lankan women. Frontiers
Endocrinol 2018;9:682.
37. Bernstein JA, Quinn E, Ameli O, et al.
Follow-up after gestational diabetes: a fixable
gap in women’s preventive healthcare. BMJ
Open Diab Res Care 2017;5:e000445.
130 MIMS JPOG 2019 VOL. 45 NO. 3 CME QUESTIONS

This continuing medical education service is brought to you by MIMS. Read the article
‘Moving Towards Evidence-based Gestational Diabetes Mellitus Screening’ and answer the
following questions. Answers are shown at the bottom of this page. We hope you enjoy
learning with MIMS JPOG.

CME ARTICLE

Moving Towards Evidence-based

Gestational Diabetes Mellitus
Screening
Answer True or False to the questions below.

True False
1. GDM is now the most common medical disorder in pregnancy.
2. GDM is associated with increased risks of macrosomia, cephalopelvic
disproportion, shoulder dystocia, birth trauma, and caesarean section.
3. GDM is associated with an increased risk of neonatal hyperglycaemia.
4. Women with GDM are more likely to develop GDM in subsequent pregnancy and
T2D later in life.
5. Universal screening for GDM has not only increased the number of diagnosed
women with GDM, it was also associated with a decrease in adverse foetal
outcomes.
6. The threshold criteria of IADPSG were FPG 5.1 mmol/L (92 mg/dL), 1-hour PG
10.0 mmol/L (180 mg/dL), and 2-hour PG 8.5 mmol/L (153 mg/dL), corresponding
to the predefined value for OR of 1.75 for adverse outcomes.
7. Women with GDM should be encouraged and supported to breastfeed as
breastfeeding reduces the risk of obesity and diabetes in the children.
8. A repeat OGTT (two-point test) should be performed at 12 weeks after delivery,
with a follow-up in the clinic to ensure that high sugar level was resolved.
9. HbA1c is not used for screening or diagnosing gestational diabetes.
10. Women with GDM should have regular monitoring of foetal growth and be delivered
preterm.

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