Get your copy of JPOG today and earn SKP IDI ISSN 1016-0124 (INDONESIA) www.jpog.com JAN/FEB 2012 Vol. 38 No. 1 JOURNAL OF PAEDIATRICS, OBSTETRICS & GYNAECOLOGY Your partner in paediatric and O&G practice SEP/OCT 2013 Vol. 39 No. 5 Your partner in paediatric and O&G practice CME ARTICLE 5 SKP Screening for Group B Streptococcus in Pregnancy JOURNAL WATCH OBSTETRICS Renal Disease in Pregnancy Carbetocin in the Prevention of Postpartum Haemorrhage GYNAECOLOGY Prevention & Treatment of Osteoporosis in Women
Transcript
Get your copy of JPOG today and earn SKP IDI
ISSN 1016-0124(INDONESIA)
www.jpog.com
IndonesiaJAN/FEB 2012 Vol. 38 No. 1
JOURNAL OF PAEDIATRICS, OBSTETRICS & GyNAECOLOGy
Your partner in paediatric and O&G practice
SEP/OCT 2013 Vol. 39 No. 5 Your partner in paediatric and O&G practice
CME ARTICLE
5 SKP Screening for Group B Streptococcus
in Pregnancy
JOURNAL WATCH
OBSTETRICS
Renal Disease in Pregnancy
Carbetocin in the Prevention of
Postpartum Haemorrhage
GyNAECOLOGy
Prevention & Treatment of Osteoporosis
in Women
JPOG_SepOct13_CVR_FINAL.indd 5 10/4/13 2:47 PM
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Dr Markus Cornbergdiscusses the management of chronic hepatitis B.“The aim of therapy should be the cure or control of HBV infection without the need for life-long treatment.”
In this Series, find out what these medical experts have to say about latest updates in the management of refractory GERD, the management of chronic hepatitis B and the present & future of colorectal cancer screening.
Current Opinion in Gastroenterology
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181 Prevention and Treatment of Osteoporosis in Women: An Update
Osteoporosis is a growing health problem in the ageing population. A postmenopausal woman has an approximately 50% lifetime risk of suffering an osteoporotic fracture with hip fractures carrying the highest morbidity and mortality. Non-pharmacological prevention strategies focus on attainment and maintenance of a high peak bone mass. Pharmacological interventions include hormone replacement therapy in women with early menopause and postmenopausal women until the age of 60 in the absence of contraindications.
Anna Daroszewska
Review ArticleObstetrics
195 Renal Disease in Pregnancy
Pregnancy in women with chronic kidney disease is associated with risks of accelerated decline in renal function in the mother and adverse outcomes for the infant, including prematurity and growth restriction. Managing these risks requires collaboration between patient, nephrologist, neonatologist, and obstetrician. This review discusses the approaches to managing pregnancy in women with chronic kidney disease.
Matt Hall, Nigel J Brunskill
In Practice
206 Dermatology Clinic: Sudden Onset of Blistering Lesions in a Young Boy
Gayle Fischer
195
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SEP/OCT 2013
Vol. 39 No. 5
JOURNAL OF PAEDIATRICS, OBSTETRICS & GYNAECOLOGY
JPOG SEP/OCT 2013 • iv
Review ArticlesComprehensive reviews providing the latest clinical information on all aspects of the management of medical conditions affecting children and women.
Case StudiesInteresting cases seen in general practice and their management.
Pictorial MedicineVignettes of illustrated cases with clinical photographs.
For more information, please refer to the Instructions for Authors on our website www.jpog.com, or contact:The EditorMIMS Pte Ltd, 6 Shenton Way, #15-08 Tower 2, Singapore 068809Tel: (65) 6290 7400 Fax: (65) 6290 7401 E-mail: [email protected]
Review ArticleObstetrics
207 Carbetocin in the Prevention of Postpartum Haemorrhage: An Asian Perspective
Postpartum haemorrhage (PPH) is one of the leading causes of maternal morbidity and mortality. While the rate of PPH varies widely among different countries, it accounts for approximately 30% of maternal deaths in Asia. Carbetocin, an oxytocin agonist with pharmacological properties similar to natural oxytocin, is a promising alternative uterotonic agent for the prevention of PPH.
Shilla Mariah Yussof, Horng Yen Wee
211 In Practice (Answers)
Continuing Medical Education
213 Screening for Group B Streptococcus in Pregnancy
Group B Streptococcus (GBS) is the most frequent cause of severe early-onset neonatal infection, which is associated with a high rate of morbidity and mortality. Because the early-onset disease develops shortly and rapidly after birth, there has been little improvement in the disease treatment, and the focus thus lies in disease prevention. This review article discusses the current screening methods for GBS in pregnancy, the guidelines by the Centers for Disease Control and Prevention, the improvement in laboratory techniques, and a pilot study in Hong Kong.
KY Leung, Teresa WL Ma, KKW To, KY Wong, Thomas Li, CW Law, Sarah Morag McGhee
Dry vaginal swabs feasible alter-native for self-screening for HPV
Cervical screening has reduced the incidence and
mortality of cervical cancer in Western countries,
but it remains an issue in developing countries.
Self-sampling for human papillomavirus (HPV) in-
fection has been suggested as a means of resolv-
ing cost and availability concerns, but the use of a
liquid medium for specimen collection risks spill-
age and medium availability may be problematic in
under-resourced countries. The recent report that
self-collection of cervical samples using dry vaginal
swabs has comparable efficacy to self-collection of
samples in liquid medium and physician-collected
samples is thus a welcome development.
In the study, 120 women attending a colpos-
copy clinic were assigned to collect two consecu-
tive self-samples using a dry swab (S-Dry) and a
wet transport medium (S-Wet), in random order. The
samples were tested for HPV using real-time poly-
merase chain reaction. Questionnaires were also
administered to determine preferences and test
acceptability. Thereafter, standard colposcopy ex-
aminations were performed, during which a physi-
cian obtained a cervical sample using a broom-like
device. The samples were stored in liquid cytology
medium and were subsequently used to prepare
cytology slides; the residual liquid was tested for
HPV using a Hybrid Capture HPV DNA test (HC). Bi-
opsies were performed as needed. Analyses were
based on 112 women with 224 paired samples and
completed questionnaires.
The overall HPV prevalence was 68.7% (95%
CI, 59.3–77.2) with the S-Wet technique, 54.4%
(95% CI, 44.8–63.9) with the S-Dry technique, and
53.8% (95% CI, 43.8–63.7) by HC. Overall agree-
ment between the paired S-Wet and S-Dry samples
was good (85.7%; 95% CI, 77.8–91.6), and kappa
statistic was 0.70 (95% CI, 0.53–0.88). Positive
agreement for type-specific HPV was 77.3% (95%
CI, 68.2–84.9). In addition, no statistically signifi-
cant differences were observed among the three
techniques in terms of their sensitivity for cervical
intraepithelial neoplasia grade 1 or higher lesions.
Both the S-Wet and S-Dry tests were rated accept-
able.
Dry vaginal swabs thus appear to be a fea-
sible option for self-screening for HPV.
Eperon I et al. Randomized comparison of vaginal self-sampling by standard vs. dry swabs for human papillomavirus testing. BMC Cancer 2013;13:353.
Vaginal vitamin C effective prophylactic against recurrent bacterial vaginosis
Bacterial vaginosis affects approximately 29% of
women of childbearing age. The aetiology of the
disorder is unclear, but it is characterized by an al-
teration in the vaginal microflora and the replace-
ment of Lactobacillus spp with anaerobic vaginal
bacteria such as Gardnerella vaginalis, Prevotella
spp, Mobiluncus spp, Mycoplasma hominis, and
Atopobium vaginae. The disorder can become
chronic, but a recent study has shown that the ap-
plication of vaginal ascorbic acid (vitamin C) tablets
has a prophylactic effect.
The randomized, multicentre, double-blind
trial assessed the efficacy of vaginal vitamin C ver-
sus placebo in 142 women (age, 18–50) who had a
history of recurrent bacterial vaginosis. The women
were randomly assigned to receive vitamin C 250
mg/day (n = 74) or placebo (n = 68) for 6 consecu-
tive days after menses once a month for 6 months.
Patients were discontinued from the study once a
relapse occurred. The intention-to-treat population
included all women who met the study inclusion
criteria and who received at least one dose of
medication.
No significant differences in recurrence
rate were observed among vitamin C and placebo
recipients in the intention-to-treat population at
3 months (6.8% vs 14.7%), but after 6 months of
treatment significantly fewer women in the vitamin
JPOG_SepOct_2013_Final_COMBINE.indd 177 10/4/13 9:18 AM
JPOG SEP/OCT 2013 • 178
C group experienced a recurrence compared with
those in the placebo group (16.2% vs 32.4%; P =
0.024). The vitamin C recipients also had a signifi-
cantly lower risk of recurrence (odds ratio, 0.405;
95% CI, 0.182–0.901). Moreover, Kaplan-Meier
survival analysis indicated that the women had a
greater probability of being free of relapse after 5
months of treatment (P = 0.039) and that this prob-
ability increased after 6 months of treatment (P =
0.029).
The researchers concluded that 6-month
prophylactic treatment with vitamin C effectively
halves the risk of recurrence of bacterial vaginosis.
Krasnopolsky et al. Efficacy of vitamin C vaginal tablets as prophylaxis for recurrent bacterial vaginosis: a randomised, double-blind, placebo-controlled clinical trial. J Clin Med Res 2013;5(4):309–315
Low risk of mental disorders in children born by assisted reproduction
The risks of perinatal outcomes, such as low birth
weight, shorter gestational age, and congenital
malformations, are known to be increased among
children conceived by assisted reproduction, but
little is known about their long-term development.
Now, researchers in Denmark have shown that
children conceived via fertility treatments show
comparable development to children conceived
naturally, although induced ovulation is associated
with a slightly increased risk of mental disorders.
The prospective cohort study compared the
risk of mental disorders among children born in
Denmark between 1995 and 2003 to mothers older
than 20 years, using information from the Danish
National Health Registers; 33,139 children were
conceived after fertility treatment and 555,828
children were spontaneously conceived. Follow-up
was in 2012 when the children were aged 8–17.
Risks associated with in vitro fertilization
(IVF) and intracytoplasmic sperm injection (ICSI)
were low and comparable to those in spontane-
ously conceived children, except for a borderline
significant increase in the risk of tic disorders (haz-
ard ratio [HR], 1.40; 95% CI, 1.01–1.95; absolute
risk, 0.3%). However, children born after ovulation
induction (with or without intrauterine insemina-
tion) had low but significantly increased risks of
1.40; absolute risk, 1.7%); conduct, emotional, or
social disorders (HR, 1.21; 95% CI, 1.02–1.45; ab-
solute risk, 0.8%); and tic disorders (HR, 1.51; 95%
CI, 1.16–1.96; 0.4%). No risk was systematically
related to a specific drug or hormone treatment.
The overall long-term development of chil-
dren born after IVF/ICSI appears to be comparable
to that of children conceived spontaneously. How-
ever, children born after induced ovulation appear
to have a small increased risk of autism; hyperki-
netic disorders; conduct, emotional, or social disor-
ders; and tic disorders.
Bay B et al. Fertility treatment and risk of childhood and adolescent mental disorders: register based cohort study. BMJ 2013;34(Jul 5):f397.
Incidence density and aetiology of acute febrile illnesses among children in Asia
Children living in tropical countries, such as those
in the Asia-Pacific region, often experience acute
febrile illnesses. Differential diagnosis of these
illnesses and estimation of the disease burden in
a region can be difficult because the presenting
symptoms of these illnesses are similar. Recently,
a multicentre study among children in the dengue-
endemic countries of Indonesia, Malaysia, Philip-
pines, Thailand, and Vietnam identified chikun-
gunya, Salmonella Typhi, and dengue as the most
common causes of acute fever.
PAEDIATRICS
JPOG_SepOct_2013_Final_COMBINE.indd 178 10/4/13 9:18 AM
Journal Watch
JPOG SEP/OCT 2013 • 179
Peer reviewedPeer reviewed
A cohort of 1,500 healthy children aged 2–14
years were followed up in a prospective, active fe-
ver surveillance study for a mean of 237 days dur-
ing 2010–2011. Sera samples were collected from
289 participants (19.3%) who experienced at least
one acute febrile episode and tested for dengue,
chikungunya, hepatitis A, influenza A, leptospiro-
sis, rickettsia, and S Typhi using commercial tests.
The overall incidence density of acute fever
was 33.6 (95% CI, 30–37.8) per 100 person-years
of follow-up. Serological analysis indicated that
57% of the febrile children were positive for at
least one of the listed diseases with chikungunya
(35%) and S Typhi (29.4%) being the most common.
The overall incidence density of chikungunya and
S Typhi was 10.8 (95% CI, 8.9–13.1) and 9.1 (95%
CI, 7.3–11.2) per 100 person-years, respectively.
The overall incidence density of dengue was 3.4
(95% CI, 2.4–4.8) per 100 person-years based on
non-structural protein 1 (NS1) antigen positivity
and 7.3 (95% CI, 5.7–9.2) based on serology. Not
all cases of dengue were clinically diagnosed and
some cases were misdiagnosed.
Chikungunya, S Typhi, and dengue appear to
be the most common causes of acute fever in the
region. Laboratory confirmation is required for an
accurate assessment of disease burden.
Capeding MR et al. Dengue and other common causes of acute febrile illness in Asia: an active surveillance study in children. PLOS Negl Trop Dis 2013;7(7):e2331.
Hypertrophic cardiomyopathy in infants with congenital hyperinsulinism
Hypertrophic cardiomyopathy is a recognized com-
plication in infants of diabetic mothers, but the
disorder may be underreported among infants with
congenital hyperinsulinism, say researchers from
the Children’s Hospital of Philadelphia.
In their retrospective study, the researchers
infants who were not diagnosed with hypertrophic
cardiomyopathy after an echocardiogram, foetal
hyperinsulinism, rather than a KATP channel muta-
tion, was considered the likely mediating factor in
the development of hypertrophic cardiomyopathy.
Among the infants who required surgery, the only
significant risk factor differentiating those with
and without hypertrophic cardiomyopathy was a
younger gestational age (36 vs 38 weeks; P = 0.02).
However, birth weight approached statistical sig-
nificance (P = 0.063).
Given the relatively common incidence of hy-
pertrophic cardiomyopathy among infants with con-
genital hyperinsulinism, the researchers suggest
that routine echocardiogram and electrocardiogram
of such infants be considered, particularly for those
with a murmur or respiratory distress.
Huang et al. Hypertrophic cardiomyopathy in neonates with congenital hyperinsulinism. Arch Dis Child Fetal Neonatal Ed 2013;98(4):F351–F354.
Eating behaviours among young children positively associated with serum non-HDL cholesterol
The new focus on preventive care has led to nu-
merous studies of early risk indicators of disorders
such as cardiovascular disease among young chil-
dren. Recently, one such study found that eating
behaviours among young children were significant-
ly associated with serum non-high-density lipopro-
tein (non-HDL) cholesterol, a surrogate indicator of
cardiovascular risk.
A total of 1,856 children aged 3–5 years
were recruited to the cross-sectional study from
primary care practices in Toronto, Canada, be-
tween 2008 and 2011. The parents of the children
completed the Nutritional Screening Tool for Every
Preschooler (NutriSTEP) questionnaire, and their
responses were compared with laboratory analy-
ses of non-fasting blood samples drawn from the
children.
reviewed the charts of all infants younger than 3
months who were treated at their institution over
a 3.5-year period (February 2000 to May 2004). Hy-
poglycaemia was detected within the first week of
life in 68 infants who were subsequently diagnosed
with congenital hyperinsulinism, 25 of whom un-
derwent an echocardiogram for a variety of indica-
tions including murmur, cardiomegaly, respiratory
distress, and arrhythmia.
Hypertrophic cardiomyopathy was identi-
fied in 10 of the 25 infants (40%), all of whom had
been born large for gestational age and required
a pancreatectomy for focal or diffuse hyperinsulin-
ism after failed diazoxide and octreotide therapy.
Eight of the 10 infants also underwent a genetic
analysis, and all were found to have ATP-sensitive
potassium (KATP) channel mutations. Since KATP
channel mutations were also detected in the 13
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JPOG SEP/OCT 2013 • 180
Among the 1,076 children with sufficient
data for analysis, the mean (± SD) laboratory in-
dices were as follows: non-HDL cholesterol, 2.8 (±
mmol/L; total cholesterol, 4.1 (± 0.7) mmol/L; apo-
lipoprotein A1, 1.3 (± 0.2) g/L; and apolipoprotein
B, 0.6 (± 0.1) g/L. The eating behaviours subscore
of the NutriSTEP questionnaire was significantly
associated with the serum non-HDL cholesterol
level (P = 0.03), and for each unit increase in this
score, serum levels of non-HDL cholesterol were in-
creased by 0.02 mmol/L (95% CI, 0.002–0.05). The
association between eating behaviours and serum
non-HDL cholesterol level persisted after adjusting
for age, sex, birth weight, z score body mass index,
parental body mass index, gestational diabetes,
and parental ethnicity. No other subscales of the
nutritional questionnaire were associated with
serum non-HDL, including dietary intake. However,
the eating behaviours subscore was also signifi-
selves and their children. Data from 148 children
were evaluated; a carry-over effect was noted, and
so data were compared for day 1 as well as across
all 4 days.
The mean VAS scores on day 1 and across
all 4 days were as follows: tablet, 9.39 and 9.01;
powder, 8.84 and 8.20; suspension, 8.26 and 7.90;
syrup, 8.35 and 8.19. The mean scores for the tablet
were significantly higher than those for the suspen-
sion on day 1 as well as across all 4 days; they
were significantly higher than those for the powder
and syrup on day 1. In addition, significantly more
administrations were swallowed in full for the tab-
let (1.96) compared with the powder (1.58), suspen-
sion (1.70), and syrup (1.67) formulations. Both the
parents and their children preferred the tablet and
syrup formulations.
Van Riet-Nales et al. Acceptability of different oral formulations in infants and preschool children. Arch Dis Child 2013;98:725–731.
cantly associated with LDL cholesterol and apoli-
poprotein B levels, both of which were correlated
with serum non-HDL cholesterol (correlation coef-
ficients, 0.90 and 0.89, respectively; P < 0.001).
The researchers concluded that eating be-
haviours may be more closely related to health
outcomes than dietary intake, and may thus be an
important target for interventions promoting car-
diovascular health in young children.
Persaud et al. Association between serum cholesterol and eating behaviours during early childhood: a cross-sectional study. CMAJ 2013;185(11):E531–E536.
Small tablets, syrup preferred oral formulations among preschool children
Infants and preschool children are often admin-
istered oral medications in a liquid formulation,
but these may have a bad taste and often require
refrigerated storage. In an attempt to determine
the optimal formulation among children and their
parents, researchers from The Netherlands studied
the acceptability of a placebo with a neutral taste
administered as a small tablet, a syrup, a suspen-
sion, and a powder. They report that the tablets
and syrup were preferred by both the parents and
their children, and that intake was higher with the
tablets.
In the randomized cross-over study, an oral
placebo was administered twice a day to 183 chil-
dren aged 1–4 years at home by a parent in the
form of a small tablet (< 4 mm diameter), a syrup, a
suspension, and a powder. The formulations were
administered on four consecutive days, but the
parents were allowed to skip a day if necessary.
Acceptability was assessed by score on a 10-cm
Visual Analogue Scale (VAS) and by parental report
of whether the dose was swallowed in full, in part,
or not at all. At the end of the study, the parents
also reported the formulation preferred by them-
JPOG_SepOct_2013_Final_COMBINE.indd 180 10/4/13 9:18 AM
Autism Spectrum Disorders Patricia Howlin, BA MSc PhD FBSP, Professor of Clinical Child Psychology
GYNAECOLOGY I Peer revIewed
JPOG SEP/OCT 2013 • 181
INTRODUCTION
Owing to significant advances in biomedical research, women enjoy better health and
live longer than ever before. As life expectancy increases, larger numbers of women
reach old age, and paradoxically more and more women suffer from age-related chronic
diseases, such as osteoporosis. It is estimated that osteoporosis currently affects ap-
proximately 200 million women worldwide.
Osteoporosis is the most common metabolic bone disease. Over 2 million women in
the United Kingdom have osteoporosis, and a woman aged 50 has an approximately 50%
lifetime risk of suffering an osteoporotic fracture. The cost of osteoporotic fractures in
the UK has been estimated at £2.3 billion in 2011 and predicted to increase to over 6
billion per year over the next 25 years. Approximately 80% of this cost relates to hip
fractures, which carry the highest morbidity and mortality: 10% of patients die within a
month and 33% within a year, 25% lose the ability to live independently, up to 50% have
permanently impaired mobility, and only 30% make a full recovery.
Osteoporosis is characterized by low bone mass and deterioration in bone archi-
tecture, which predispose to fragility fractures. Bone mineral density (BMD) is the most
important predictor of fracture risk and is highly heritable with heritability estimates
of 0.60–0.90. To date, dozens of genes and loci associated with osteoporosis have
been identified by genome-wide association studies. Other contributing factors to bone
strength, some of which are heritable, include bone turnover, bone architecture, and
skeletal geometry (eg, long femoral necks fracture easier than short ones). The risk of
falls, which depends on postural stability, frailty, rate of response, padding, and environ-
mental factors, also contributes to fracture risk. Thus, the 10-year hip fracture probabil-
ity (averaged for age and gender) varies between geographical regions and countries,
Prevention and Treatment of
Osteoporosis in Women: An Update
Anna Daroszewska, MRCP(UK), FRCP Edin, PhD
GYNAECOLOGY i Peer reviewed
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JPOG SEP/OCT 2013 • 182
GYNAECOLOGYGYNAECOLOGY I Peer revIewed
with the highest in Scandinavia, lowest in South
America and Asia, and the UK in between.
Bone is a dynamic tissue, which undergoes
renewal in the process known as the bone remod-
elling cycle, which, in physiological conditions, is
initiated by bone-resorbing cells (osteoclasts). Os-
teoclasts secrete hydrochloric acid and cathepsin K,
which dissolve bone mineral and collagen, respec-
tively. Bone resorption is followed by osteoblastic
bone formation whereby osteoblasts lay new bone
matrix, which then undergoes mineralization. Oste-
oclast and osteoblast function is coupled owing to
bidirectional communication. At a molecular level,
osteoclastogenesis and consequently bone resorp-
tion are initiated by the stimulation of the receptor
activator of nuclear factor-κB (RANK), expressed on
preosteoclasts, with its ligand (RANKL), expressed
by osteocytes, osteoblasts, bone marrow stromal
cells, and T and B lymphocytes. An endogenous
soluble RANKL-decoy receptor, osteoprotegerin in-
hibits this process by binding to RANKL. Osteoblast
differentiation and bone formation are triggered by
the activation of the Wnt-signalling pathway, which
leads to nuclear accumulation of β-catenins. This
process is mainly controlled by two naturally occur-
ring Wnt-antagonists: sclerostin expressed by oste-
ocytes and dickkopf-1 (Dkk-1) mainly expressed by
osteoblasts and osteocytes. Understanding of these
signalling pathways has lead to the development of
novel treatments for osteoporosis (see below).
The major contributing factor to bone loss af-
ter the menopause is the drop in oestrogen concen-
tration by approximately 75%, which induces ex-
pression and production of RANKL. A similar effect
is seen with therapeutic inhibition of oestrogen in
women treated for receptor-positive breast cancer.
High RANKL activity is also observed in certain au-
incidence of new clinical vertebral fractures but not
morphometric vertebral fractures or non-vertebral
fractures as compared with 5 years of alendronate.
However, a significant reduction of non-vertebral
fracture risk was observed in a subgroup of women
with a femoral neck T-score of –2.5 or lower (RR,
0.50; 95% CI, 0.26–0.96) as compared with women
with higher femoral neck T-scores, suggesting that
women who remain at high risk of osteoporotic
fractures after 5 years treatment with alendronate
would benefit from an additional 5 years of treat-
ment. The recently extended 3-year zoledronate
HORIZON-PFT trial demonstrated prolonged effect
on BMD lasting for up to 3 years after discontinua-
tion of zoledronate; however, significantly less mor-
phometric vertebral fractures were seen in women
treated for 6 years.
At the time of writing, there is an ongoing de-
bate in the field with regard to long-term bisphos-
phonate use primarily driven by limited evidence;
however, most authorities suggest treatment with
bisphosphonates for 5–10 years, depending on pa-
tient’s fracture risk, and withdrawal of treatment
for 1–2 (up to 5 years) or until there is significant
loss of BMD or the patient has a fracture, which-
ever comes first. If after 10 years of treatment, frac-
ture risk remains high, some consider an interval
treatment with raloxifene or teriparatide.
CALCITONIN
Calcitonin, a peptide hormone produced by the C
cells of the thyroid gland, has an antiresorptive ef-
fect, which is mediated through calcitonin recep-
tors abundant on osteoclasts. The salmon calciton-
There have been concerns about the association of long-term bisphosphonate use with atypical femoral fractures.
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JPOG SEP/OCT 2013 • 191
GYNAECOLOGYGYNAECOLOGY I Peer revIewed
in, which is used in the treatment of osteoporosis,
is approximately 20–40 times more potent than
human calcitonin. It is administered intranasally at
a dose of 200 units per day (to alternate nostrils)
and is generally well tolerated, although flushing,
nausea, diarrhoea, and local irritation can occur.
Calcitonin administered as nasal spray at 200 units
a day has been shown to reduce the risk of verte-
bral fractures by 33% over 5 years in a placebo-
controlled study. However, no effect was shown on
non-vertebral fracture rate. Calcitonin can be used
in patients with osteoporosis and renal impairment
in whom bisphosphonates are contraindicated.
DENOSUMAB
Denosumab is a novel fully human monoclonal an-
tibody, which binds to RANKL and prevents RANKL
from binding to RANK, thereby inhibiting osteoclas-
togenesis and osteoclast survival. Denosumab’s
half-life is approximately 26 days, and it is detect-
able in the system for several weeks. The usual
dose is 60 mg given subcutaneously at 6-monthly
intervals. As the clearance of denosumab occurs
through the reticuloendothelial system and not
through renal excretion, denosumab can be given to
patients with renal impairment. The FREEDOM tri-
al, a 3-year randomized placebo-controlled trial of
denosumab in the treatment of postmenopausal os-
teoporosis, revealed a significant reduction in ver-
tebral, hip, and non-vertebral fracture risk of 68%,
40%, and 20%, respectively, when compared with
placebo. Although no head-to-head trial comparing
the effect of denosumab and bisphosphonates on
fracture risk has been performed, two double-blind,
randomized clinical trials evaluating the efficacy
and safety of denosumab vs alendronate showed
significantly greater increase of BMD at all meas-
ured sites in denosumab treated patients of approx-
imately 1%. This increase in BMD corresponded to
significantly greater suppression of bone turnover
markers in patients treated with denosumab. How-
ever, after denosumab discontinuation, a rebound
effect of rapid increase of bone turnover markers
and decline in BMD is observed, in keeping with a
relatively short offset of action in comparison with
bisphosphonates, which can persist in the skeleton
for years. Denosumab has a good safety profile,
with clinical data available for over 8 years of use.
In the phase III FREEDOM trial, a higher number of
cases with cellulitis were reported in patients tak-
ing denosumab as compared with placebo (0.3% vs
< 0.1%), although the absolute risk was very low.
In patients receiving denosumab for treatment of
postmenopausal osteoporosis not unlike with bi-
sphosphonates, rare cases of ONJ have been re-
ported; but so far, there have been no reports of
atypical fractures.
STRONTIUM RANELATE
Strontium ranelate contains two atoms of stron-
tium, which have a higher atomic number than
calcium and ranelic acid. Strontium ranelate com-
bines antiresorptive and anabolic activity and may
dissociate bone resorption from bone formation,
as suggested by decreased bone resorption mark-
ers and increased bone formation markers during
treatment. The exact mechanism of action of stron-
tium ranelate, however, remains to be elucidated.
The Spinal Osteoporosis Therapeutic Intervention
(SOTI) trial of strontium ranelate in the treatment
of postmenopausal osteoporosis demonstrated a
reduction of the risk of vertebral fractures by 49%
in the first year and 41% after 3 years of treatment.
An increase in the lumbar, femoral neck, and total
hip BMD by 14.4%, 8.3%, and 9.8%, respectively,
over 3 years was observed as well; however, it has
been estimated that up to 50% of the BMD changes
may be due to increased X-ray absorption of stron-
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GYNAECOLOGYGYNAECOLOGY I Peer revIewed
tium compared with calcium. The subsequent Treat-
ment of Peripheral Osteoporosis (TROPOS) study
also showed a reduction of non-vertebral fractures
by 19%, and in the subgroup of women at high risk
of hip fracture, there was a 36% reduction of the
relative risk of hip fractures seen after 3 years of
treatment. An open-label 5-year extension of the
SOTI and TROPOS studies demonstrated continuous
increase in BMD, anti-fracture efficacy, and safety
of taking strontium ranelate for 10 years.
Strontium ranelate is given orally at a dose of
2 g a day. It has to be administered after and fol-
lowed by a 2-hour fast; thus, it is given last thing
at night. Strontium ranelate is generally well tol-
erated, and the most common side effects include
nausea and diarrhoea, which usually subside with
continuous treatment. Mild and transient elevation
in creatine kinase can occur. Strontium ranelate
is contraindicated in patients with risk factors for
thromboembolic disease in view of a small increase
of venous thromboembolic events observed after
pooling the SOTI and TROPOS trial data. Severe
allergic reactions to strontium ranelate have been
reported (including the drug reaction with eosino-
philia and systemic symptoms [DRESS syndrome]);
therefore, patients developing a rash must discon-
tinue the treatment immediately. NICE recommends
strontium ranelate as an alternative treatment to
bisphosphonates in primary and secondary preven-
tion of fractures in postmenopausal osteoporosis.
PTH PEPTIDES
Intermittent administration of low-dose PTH has
an anabolic effect on bone as it enhances osteo-
blast activity and bone formation in stark contrast
to the action of antiresorptive agents. Two PTH de-
rivatives have been approved for treatment of post-
menopausal osteoporosis in Europe—teriparatide
(PTH 1-34) and PTH 1-84—whereas only teripara-
tide has the Food and Drug Administration approval
in the US. Teriparatide administered as a 20-µg
subcutaneous injection daily has been shown to in-
crease lumbar and femoral BMD by about 9% and
3%, respectively, over 21 months. There was a 65%
and 54% fracture risk reduction seen in vertebral
and non-vertebral sites as well. The number of hip
fractures was lower; however, a significant fracture
risk reduction was not seen, possibly because of
small numbers.
Teriparatide is licenced for use in postmeno-
pausal osteoporosis. Teriparatide has been also
shown in clinical trials to be of particular value in
steroid-induced osteoporosis, which is character-
ized by suppressed bone turnover, in which state
the anabolic action of teriparatide is of particular
benefit. Teriparatide has also been shown to re-
duce pain associated with osteoporotic vertebral
fractures. NICE recommends its use in patients
with severe osteoporosis for secondary preven-
tion of fractures in patients who are intolerant of,
have contraindications to, or have an unsatisfac-
tory response to bisphosphonates and/or strontium
ranelate, and have a T-score of –4 or lower (or in
patients with a T-score of –3.5 who had already
sustained two fragility fractures).
Administration of PTH peptides can rarely
cause transient hypercalcaemia, which has been
reported more commonly with PTH 1-84. PTH pep-
tides are contraindicated in other metabolic bone
diseases than osteoporosis, in patients with skel-
etal malignancy (in patients with a history of can-
cer, utmost caution is advised owing to reports of
the presence of occult micrometastases in the bone
marrow in many cancers including breast cancer
and non-small-cell lung cancer), and in patients
with a history of skeletal irradiation. Teriparatide
should be given to patients who are vitamin D re-
plete and is licenced to be used for 24 months, af-
ter which time an antiresorptive agent should be
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GYNAECOLOGYGYNAECOLOGY I Peer revIewed
considered in order to maintain bone gain achieved
with teriparatide treatment.
NEW DEVELOPMENTS
The use of combination therapy in treatment of
postmenopausal osteoporosis has been addressed
by several studies. The combined use of bispho-
sphonates and HRT overall results in greater in-
creases in BMD than either therapy alone; however,
owing to lack of evidence for greater fracture reduc-
tion, such regimens are generally not recommend-
ed. Treatment with bisphosphonates followed by
strontium ranelate or PTH peptides initially blunts
the BMD response, whereas studies of concurrent
treatment with bisphosphonates and PTH peptides
yielded conflicting results. Concurrent treatment
with a single zoledronate infusion followed by daily
PTH injections resulted initially in faster BMD incre-
ments than monotherapy. However, by 12 months,
this effect was lost, and compared with combina-
tion therapy, PTH alone and zoledronate alone
yielded similar BMD increase in the lumbar spine
and femoral neck, respectively. Thus, zoledronate
followed by treatment with PTH may be considered
for women at high risk of femoral neck and other
fractures. Antiresorptive therapy given after treat-
ment with teriparatide maintains or increases the
gains in BMD. Further research in this area is nec-
essary to establish efficacy and safety of different
regimens.
Recent advances in the understanding of bone
pathophysiology at a cellular and molecular level
have allowed for development of novel treatments
for osteoporosis, such as denosumab described
above and already in clinical use. A number of
other novel antiresorptive compounds, including
cathepsin K inhibitors, are being investigated in
postmenopausal osteoporosis. Odanacatib given
for 24 months in a phase II trial increased the lum-
bar spine BMD by 5.5%. A phase III trial of over
16,000 postmenopausal women with osteoporosis
is expected to be completed by July 2012. Results
are also pending on the phase II trial of another
cathepsin K inhibitor, ONO-5334. As inhibition of
cathepsin K does not affect osteoclast viability,
theoretically osteoclast–osteoblast communication
should be preserved allowing for uninterrupted new
bone formation. It remains to be seen whether this
concept translates into an advantageous clinical ef-
fect over the classic antiresorptives.
Development of anabolic therapies has gained
momentum as well. Calcilytic drugs are antagonists
of the calcium sensing receptor in the parathyroid
gland and their action mimics hypocalcaemia, caus-
ing a short pulse of PTH secretion (resembling the
anabolic action of PTH peptides given by daily in-
jections). Results of two phase II clinical trials on
the most advanced oral compound in this class, MK-
5442, in postmenopausal osteoporosis are expected
in 2012.
Understanding of the pathophysiology of two
rare conditions characterized by high bone mass,
van Buchem’s disease and sclerosteosis, both due
to inactivating mutations of the gene encoding scle-
rostin (endogenous inhibitor of the Wnt-signalling
There is a need for more
research... to understand the
underlying mechanisms of bone
loss leading to osteoporosis,
so that novel treatments
can be developed
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GYNAECOLOGYGYNAECOLOGY I Peer revIewed
pathway in osteoblasts), has lead to the develop-
ment of anti-sclerostin antibodies. In a phase I
trial, a single 3 mg/kg subcutaneous dose of the
anti-sclerostin antibody AMG 785 increased bone
formation markers after 21 days by 60–100% with-
out affecting markers of bone resorption. Results
of a phase II trial in postmenopausal women with
low BMD comparing the effect of AMG 785, alen-
dronate, and teriparatide are anticipated in August
2012.
CONCLUSIONS
In the ageing population, osteoporosis is a growing
health problem and an increasing economic burden.
Efforts to attain and maintain peak bone mass for
as long as possible seem a logical approach and
include a healthy lifestyle, nutritious and balanced
diet with optimal calcium and vitamin D intake
and physical exercise with skeletal mechanical
loading. In addition, a plethora of pharmacologi-
cal treatments is available for women with or at
risk of osteoporosis or fragility fractures and can
be targeted to the individual. Thus, HRT may be
considered for women with early menopause and
postmenopausal women until the age of 60 unless
there are contraindications. SERMs may suit young-
er postmenopausal women at greater risk for verte-
bral fractures than hip fractures and/or intolerant
of bisphosphonates. Bisphosphonates are recom-
mended as first-line therapy; however, there have
been concerns with regard to long-term safety, and
their use is generally not recommended for longer
than 10 years. For older patients intolerant of bis-
phosphonates, strontium ranelate is a good choice.
Denosumab is a safe option in patients intolerant of
or with contraindications to bisphosphonates and
improves compliance. Anabolic therapy with PTH
peptides is currently reserved for severe osteopo-
rosis. A number of novel treatments, eg, cathepsin
K inhibitors, calcilytic drugs, and anti-sclerostin
antibodies, are currently being assessed in clinical
trials. There is a need for more research in order
to understand the underlying mechanisms of bone
loss leading to osteoporosis, so that novel treat-
ments can be developed with an emphasis not only
on suppression of bone resorption, which may lead
to unwanted consequences long term, but on bone
preservation and improvement of bone quality.
FURTHER READING
Baron R, Ferrari S, Russell RG. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone 2011;48:677–692.
Bolognese MA. SERMs and SERMs with estrogen for postmeno-pausal osteoporosis. Rev Endocr Metab Disord 2010;11:253–259.
Bowring CE, Francis RM. National Osteoporosis Society’s Position statement on hormone replacement therapy in the prevention and treatment of osteoporosis. Menopause Int 2011;17:63–65.
Favus MJ. Bisphosphonates for osteoporosis. N Engl J Med 2010;363:2027–2035.
Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treat-ment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96:1911–1930.
National Institute for Health and Clinical Excellence (NICE). Alendro-nate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in post-menopausal women, www.nice.org.uk/guidance/TA160; 2011.
National Institute for Health and Clinical Excellence (NICE). Alendro-nate, etidronate, risedronate, raloxifene and strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women, www.nice.org.uk/guidance/TA161; 2011.
National Institute for Health and Clinical Excellence (NICE). Deno-sumab for the prevention of osteoporotic fractures in postmeno-pausal women, www.nice.org.uk/guidance/TA204; 2010.
Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet 2011;377:1276–1287.
Rosen CJ, ed. Primer on the metabolic bone diseases and disorders of mineral metabolism. Washington: American Society for Bone and Mineral Research, 2008.
About the AuthorAnna Daroszewska is a Clinical Senior Lecturer and Honorary Consul-tant Rheumatologist at the Molecular Medicine Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edin-burgh, UK.
JPOG_SepOct_2013_Final_COMBINE.indd 194 10/4/13 9:18 AM
Perinatal Case Management—Caring for Mothers as They Care
for BabiesCh’ng Ying Chia, MA (Applied Social Studies); Jemie Biwen Wang, Bachelor of Psychology (Hons);
Helen Chen, MBBS, M Med (Psych), Dip. Psychotherapy
OBSTETRICS I Peer revIewed
JPOG SEP/OCT 2013 • 195
INTRODUCTION
Chronic kidney disease (CKD) is defined as abnormalities in serum biochemistry, urinary
constituents (blood and/or protein), or renal structure that are present for 3 months or
more. The National Kidney Foundation K/DOQI classification of CKD divides CKD into
five stages, dependent on the estimated glomerular filtration rate (eGFR) (Table 1).
CKD is rare in pregnant patients, affecting 0.15% of pregnancies, and most affect-
ed patients have early stages of CKD (stages 1–3a; eGFR > 45 mL/min). Pregnancy may
be the first time that blood pressure and urine analysis are performed for some women;
hypertension, proteinuria, or haematuria detected at booking may uncover previously
undiagnosed CKD. The development of hypertension and urinary dipstick abnormalities
later in pregnancy may be a manifestation of CKD but more commonly represents pre-
eclampsia. Chronic pyelonephritis is the commonest known aetiology of CKD in pregnant
women (Figure 1).
RENAL PHYSIOLOGY IN NORMAL PREGNANCY
During normal pregnancy, the maternal cardiovascular system undergoes important
changes. Blood volume and red cell mass increase by up to 50%, systemic vascular
resistance falls, and cardiac output increases by up to 30%. These cardiovascular adap-
patients with mild renal dysfunction (serum creati-
nine < 125 µmol/L) and 60–80% with severe impair-
ment (serum creatinine > 180 µmol/L), compared
with approximately 5% in the general population.
These estimations vary between studies as a result
of heterogeneity between study cohorts and varia-
tions in diagnostic criteria used. CKD is commonly
associated with proteinuria and hypertension prior
to conception, and the diagnosis of ‘superimposed
pre-eclampsia’ relies on arbitrary increases in these
parameters with or without additional clinical fea-
tures of pre-eclampsia (Box 1).
Renal function: decline in renal function dur-
ing pregnancy occurs rarely in patients with mild
renal impairment at baseline (serum creatinine <
125 µmol/L) and often reflects an episode of ob-
Box 1. National High Blood Pressure Education Program Report on High Blood Pressure in Pregnancy criteria for the diagnosis of superimposed pre-eclampsia
• Blood pressure > 160/110 mm Hg• Blood control suddenly worsening after a period of good control• Development of proteinuria > 2,000 mg/d or abrupt worsening of
proteinuria• Serum creatinine increasing to > 110 mmol/L
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struction, pyelonephritis, or pre-eclampsia. In such
cases, return to baseline renal function almost al-
ways occurs within 3 months post partum.
In contrast, women with moderate CKD (se-
rum creatinine > 125 µmol/L) have a 25% risk of
permanently losing 25% of their kidney function as
a result of pregnancy, increasing to a 50% risk in
those with baseline creatinine > 180 µmol/L. Fur-
thermore, women with a preconception serum cre-
atinine > 180 µmol/L have a one in three chance
of requiring dialysis during pregnancy or within 6
months of delivery.
Aetiology of CKD: the underlying aetiology
of CKD has little impact on maternal outcome in-
dependent of renal function and blood pressure
control.
There is an increased risk of asymptomatic
bacteriuria progressing to overt infection and pyelo-
nephritis during pregnancy. Patients with recurrent
UTI or vesicoureteric reflux are at particular risk
and should be screened for bacteriuria by dipstick
analysis and urine culture. Asymptomatic bacteriu-
ria should be actively treated to reduce the risk of
potentially serious sepsis and reduce the incidence
of preterm delivery.
Lupus nephritis often enters a phase of qui-
escence during pregnancy as a result of increased
endogenous corticosteroid production. Consequent-
ly, flares can often occur in the puerperium when
increased vigilance is recommended. If lupus flares
do occur during pregnancy, they can be difficult to
distinguish from pre-eclampsia – hypertension, pro-
teinuria and decline in renal function, often with
thrombocytopenia. The presence of invisible hae-
maturia, depressed serum complement levels, a
rise in anti-double-stranded DNA titre, and cutane-
ous manifestations of SLE support a diagnosis of a
lupus flare and should be treated promptly. Renal
biopsy may be required if renal function declines
quickly, or if nephrotic syndrome develops, in order
to determine the most appropriate treatment for
the renal disease. Patients with SLE and antiphos-
pholipid antibodies are at greatly increased risk of
thromboembolic disease and pre-eclampsia.
Hypertension: chronic hypertension is com-
mon in patients with CKD. Control may become
more difficult during pregnancy owing to cardiovas-
cular adaptations in the second and third trimesters
and the unsuitability of some antihypertensives
during pregnancy, even in the absence of pre-ec-
lampsia. Most notably, angiotensin-converting en-
zyme inhibitors and angiotensin receptor blockers
are commonly prescribed for patients with proteinu-
ric CKD owing to their effectiveness and renopro-
tective properties; however, they are associated
with severe congenital abnormalities and should be
avoided during pregnancy (see below).
There are contradictory reports of the impact
of blood pressure during pregnancy on progression
of maternal renal disease; however, contemporary
prospective data suggest that baseline diastolic
blood pressure > 75 mm Hg or use of antihyperten-
sive agents is predictive of accelerated decline in
renal function post partum. Severe hypertension
(> 160/100 mm Hg) in the third trimester requires
treatment to reduce the risk of intracerebral haem-
orrhage in labour.
Proteinuria: increased urine protein excre-
tion is predictive of progressive renal dysfunction in
general nephrology where proteinuria per se is be-
lieved to be nephrotoxic. During normal pregnancy,
where urinary protein excretion can double, the im-
pact of proteinuria on kidney function is less clear,
certainly in the short to medium term.
In patients with eGFR < 40 mL/min before con-
ception, proteinuria > 1 g/d is associated with an
increased rate of renal decline post partum com-
pared with those with less proteinuria. No similar
effect was seen in patients with preserved renal
function.
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Mothers who develop nephrotic syndrome
during pregnancy are at increased risk of venous
thromboembolism. Loss of antithrombotic serum
components in the urine leads to increased throm-
botic tendency, and strong consideration should be
given to the use of prophylactic anticoagulation
with low-molecular-weight heparin (LMWH) (see
below).
In the absence of nephrotic syndrome or renal
dysfunction, proteinuria does not appear to have
a prominent independent effect on maternal out-
comes during pregnancy; however, there is emerg-
ing evidence that baseline proteinuria may predict
the risk of loss of renal function or dialysis post
partum.
ManagementPreconception counselling: ideally, all patients
with CKD should be offered counselling prior to
conception in order to evaluate the risks of pro-
ceeding with pregnancy and the likely outcomes.
Medications known to be harmful to the developing
fetus can be discontinued or substituted for safer
alternatives (see Tables 3 and 4 below).
Patients with active lupus nephritis or vasculi-
tis and those with poorly controlled blood pressure
should be advised to wait until these are optimized
before trying to conceive. Similarly, patients with
significant renal dysfunction (serum creatinine >
180 µmol/L) may not accept the risks associated
with proceeding with pregnancy and may be bet-
ter advised to wait until they have received a renal
transplant (see below).
In the majority of cases, patients need not be
discouraged from trying to conceive as long as the
potential risks are understood and the pregnancy is
closely monitored.
Investigations – pre-existing CKD: if pre-
conception results are unavailable, serum creati-
nine and either urine PCR/ACR or 24-hour urine col-
lection should be performed early in pregnancy to
determine baseline renal function and urine protein
excretion.
Patients should have the following recorded at
every subsequent visit:
• blood pressure
• urine dipstick
• urine PCR or ACR, and/or urine culture, if dip-
stick positive
Depending on the level of renal function at
baseline, the following should be measured every
6–8 weeks during pregnancy:
• serum creatinine and urea
• haemoglobin
More frequent measurement is required if
renal function is abnormal or deteriorating. Serum
ferritin, folate, and vitamin B12 should be measured
if anaemia is identified; serum albumin, calcium,
and vitamin D are indicated in women with heavy
proteinuria (PCR > 100 mg/mmol) or advanced renal
dysfunction (creatinine > 180 µmol/L).
Women with a history of recurrent UTI or struc-
tural abnormalities should submit a urine sample
for culture every month irrespective of symptoms to
identify asymptomatic bacteriuria.
A renal ultrasound is required during preg-
nancy if
• there is a sudden decline in renal function
• there are signs or symptoms suggestive of ob-
struction or renal stone disease
As above, mild pelvicalyceal dilatation is com-
monly identified during normal pregnancy. Func-
tional ureteric obstruction should only be suspected
if there is progressive dilatation on serial renal ul-
trasound scans, suggestive signs and symptoms or
obstruction, or worsening renal function.
Investigations – suspected new diagnosis
of CKD: renal disease might be discovered during
pregnancy and should be suspected in women with
hypertension, proteinuria, or haematuria identified
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OBSTETRICS I Peer revIewed
at booking or in early pregnancy.
A renal ultrasound is helpful to characterize
the aetiology and chronicity of CKD. Large kidneys
on ultrasound may reflect polycystic kidney dis-
ease, diabetic nephropathy, or chronic obstruction.
Focal scarring of kidneys may reflect a congenital
abnormality of the kidney and urinary tract in the
mother, most commonly vesicoureteric reflux. Small
kidneys may be the result of any chronic process,
and further diagnosis may be difficult.
Immunological investigations should be re-
quested if there is suspicion of intrinsic renal dis-
of intrinsic renal disease may be confirmed by renal
biopsy and can be performed during pregnancy, but
should be reserved for
• unexplained decline in kidney function in CKD
or acute kidney injury
• newly diagnosed nephrotic syndrome
• features suggestive of systemic disease or
vasculitis
A renal biopsy is not indicated to investigate
stable CKD, non-nephrotic range proteinuria, or
pre-eclampsia, and not after 32 weeks’ gestation
when the pregnancy should be brought to an end
prior to renal investigation.
Blood pressure control (Tables 3 and 4):
methyldopa, labetalol, nifedipine, and hydralazine
are the most frequently used agents to treat hy-
pertension in pregnancy. All appear to be safe and
well tolerated in pregnancy. Methyldopa should be
avoided in patients with depression.
Angiotensin-converting enzyme inhibitors and
angiotensin receptor blockers should be avoided
throughout pregnancy as they are associated with
congenital malformations and fetal urinary tract
agenesis. Women for whom there is a strong indi-
cation for these agents (heavy proteinuria, diabetic
nephropathy, or heart disease) may be advised to
continue therapy until conception is confirmed, but
a discussion regarding the potential risks should be
held as part of preconception counselling. Labetalol
appears safe, but other beta-blockers have been as-
sociated with IUGR. Diuretics can exacerbate intra-
vascular volume depletion in hypertensive disorders
of pregnancy and lead to IUGR.
For patients with CKD, it is well recognized
that control of hypertension is essential to abrogate
decline in renal function. Consensus guidelines de-
rived from the RCOG Study Group on renal disease
and pregnancy recommend that a target blood pres-
sure of 140/90 mm Hg is maintained during preg-
nancy. Data to support blood pressure treatment
targets for patients with CKD during pregnancy are
lacking, however.
Table 2. Immunological investigation of suspected intrinsic renal disease
Test Comments
Anti-nuclear antibodies (ANA) Associated with connective tissue diseases and SLE. Antibodies against double-stranded DNA (anti-dsDNA) and extractable nuclear antigens (ENA) should be performed if positive
Anti-neutrophil cytoplasmic antibodies (ANCA)
Associated with small vessel vasculi-tis (Churg-Strauss disease, granulo-matosis with polyangiitis, and micro-scopic polyangiitis)
Complement components C3 and C4
Decreased levels are found in active SLE, post-infectious glomerulone-phritis, mesangiocapillary glo-merulonephritis, subacute bacterial endocarditis, cryoglobulinaemia, and heavy chain-deposition disease
Other tests Rheumatoid factor, cryoglobulins, and C3 nephritic factor measurement may be indicated
SLE = systemic lupus erythematosus.
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Pre-eclampsia prophylaxis: CKD is iden-
tified as a ‘high-risk’ group for developing pre-
eclampsia by the National Institute for Health and
Clinical Excellence. Published data support the in-
creased incidence of the condition from severe to
mild CKD. In high-risk patients, aspirin (75 mg/d)
reduces the incidence of pre-eclampsia by approxi-
mately 25%. Although not licenced for this indica-
tion, it is recommended that aspirin prophylaxis is
offered to all women with CKD during pregnancy.
Venous thromboembolism prophylaxis:
pregnancy is a prothrombotic state, and this is ex-
acerbated by heavy proteinuria. Consensus opinion
recommends that patients with nephrotic syndrome
should receive prophylactic LMWH during preg-
nancy and until 6 weeks post partum. There is less
evidence to support prophylaxis for women with
heavy proteinuria but no nephrotic syndrome, or
more modest proteinuria. Nevertheless, many prac-
titioners encourage the use of LMWH throughout
pregnancy for women with a PCR > 100 mg/mmol,
particularly if women are obese or have other risk
factors for venous thromboembolism. Advice on
thromboprophylaxis in pregnancy is published by
the RCOG. LMWH should be continued for at least 6
weeks following delivery.
UTI prophylaxis (Tables 3 and 4): confirmed
asymptomatic bacteriuria and symptomatic UTI dur-
ing pregnancy should be treated with antibiotics to
reduce the risk of ascending infection and preterm
delivery. If more than one episode of bacteriuria is
confirmed during pregnancy, prophylactic antibiot-
ics should be prescribed. The choice of antibiotic is
determined by stage of pregnancy, sensitivities of
the cultured organisms, and local practice. Cepha-
losporins and penicillins are safe and well tolerated
throughout pregnancy. Gentamicin may be used for
severe pyelonephritis with appropriate monitoring.
Trimethoprim is a folate antagonist and should be
avoided in the first trimester. Nitrofurantoin is as-
About the AuthorsMatt Hall is a Consultant in Renal Medicine at Nottingham Transplant and Renal Unit, Nottingham City Hospital, Nottingham, UK. Nigel J Brunskill is Professor of Renal Medicine at the John Walls Renal Unit, Leicester General Hospital, Leicester, UK.
JPOG_SepOct_2013_Final_COMBINE.indd 205 10/4/13 9:18 AM
JPOG SEP/OCT 2013 • 206
IN PRACTICEIN PRACTICE I Peer revIewed
Figure 1. Blistering lesions on the patient’s arm (a, top) and leg (b, bottom).
Dermatology ClinicSudden Onset of Blistering Lesions in a Young BoyGayle Fischer, MB BS, MD, FACD
(Answers on p. 211)
What is the most likely diagnosis of these blistering lesions?
CASE HISTORY
a
b
IN PRACTICEIN PRACTICE i Peer reviewed
A 12-year-old boy presents with sudden onset of blistering lesions on his arms and
legs (Figure 1), occurring a few days after he developed a typical cold sore on his upper lip.
JPOG SEP/OCT 2013 • 206
JPOG_SepOct_2013_Final_COMBINE.indd 206 10/4/13 9:18 AM
Perinatal Case Management—Caring for Mothers as They Care
for BabiesCh’ng Ying Chia, MA (Applied Social Studies); Jemie Biwen Wang, Bachelor of Psychology (Hons);
Helen Chen, MBBS, M Med (Psych), Dip. Psychotherapy
JPOG SEP/OCT 2013 • 207
Carbetocin in the Prevention of Postpartum Haemorrhage:
An Asian PerspectiveShilla Mariah Yussof, MB BCh BAO (Hons) (Dublin);
Horng Yen Wee, MB BCh BAO (Dublin), BA (Dublin), FAMS (Singapore), MRCOG (UK)
INTRODUCTION
Postpartum haemorrhage (PPH) is one of the leading causes of maternal morbidity and
mortality. While the rate of PPH varies widely among different countries, it accounts for
approximately 30% of maternal deaths in Asia.1 The prevalence of PPH in South-eastern
Asia was estimated to be 4.88%, the highest within Asia, which has an average PPH
rate of 2.55%.2
The main cause of PPH is uterine atony. Active management of the third stage of la-
bour, which consists of early cord clamping, controlled cord traction, and the prophylac-
tic administration of a uterotonic agent, has been widely used worldwide to reduce PPH.
Of these measures, uterotonic agent is the only one supported by extensive evidence.3
The World Health Organization currently recommends active management of the
third stage of labour with oxytocin to prevent PPH.4 However, the half-life of this drug is
rather short (4–10 minutes), and it has to be administered continuously via intravenous
infusion to achieve sustained uterotonic activity.5–7 Its dose and duration vary widely
across institutions.8–11
Another widely used uterotonic agent is syntometrine, a derivative of oxytocin and
ergometrine. It is superior to oxytocin in risk reduction of mild PPH (500–1,000 mL).12
However, syntometrine is limited by its gastrointestinal and cardiovascular side effects,
which include maternal vomiting, hypertension, and pain requiring analgesia owing to
its ergot alkaloid component.13 The use of ergot alkaloids is also contraindicated in
women with pre-existing hypertension, pre-eclampsia, and cardiac conditions, and in
those with a history of migraine or Raynaud phenomenon. Ergometrine is also very un-
stable and has to be kept refrigerated and shielded from light, which limits its use in
rural areas.
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CARBETOCIN – PHARMACOLOGIC PROPERTIES
Carbetocin is an oxytocin agonist. With pharma-
cologic properties similar to natural oxytocin, the
drug binds to the smooth muscle receptors of the
uterus, causing rhythmic contractions and increas-
ing the frequency of contractions as well as uterine
tone.14,15 Administered either intravenously or in-
tramuscularly as a single dose of 100 µg, carbetocin
has a half-life of about 40 minutes; 4–10 times
longer than that of oxytocin.16 Contraction of the
uterus can be achieved within 2 minutes following
injection, persisting for an average of 120 minutes
following intramuscular injection and an average of
60 minutes with intravenous injection.17 The main
advantage of carbetocin over oxytocin is its longer
duration of action, allowing a single intramuscular
injection instead of an intravenous infusion. As
such, carbetocin is a promising alternative utero-
tonic agent for the prevention of PPH.
CARBETOCIN IN VAGINAL DELIVERIES
A number of studies have evaluated the efficacy of
carbetocin in vaginal deliveries. Asian data from a
study by Leung et al in Hong Kong compared car-
betocin and syntometrine in the management of
the third stage of labour in 300 women undergoing
vaginal delivery.18 The authors found that intramus-
cular carbetocin was as effective as intramuscular
syntometrine in preventing primary PPH but was
less likely to induce hypertension after delivery.18
There was no difference in the drop of haemoglo-
bin concentration within the first 48 hours between
the two groups.18 The incidence of additional oxy-
tocic injections, PPH, and retained placenta were
also similar.18 However, the use of carbetocin was
associated with a significantly lower incidence of
nausea, vomiting, and hypertension after delivery.18
Another study by Ngan et al in Macau com-
pared 100 µg carbetocin and a combination of 5 IU
of oxytocin and 0.2 mg of ergometrine in the control
of postpartum blood loss in 118 women following
vaginal delivery.19 They found that carbetocin was
associated with significantly less blood loss (mean,
163 mL less) and haematocrit drop, and a statisti-
cally significant reduction in the risk of PPH.19
Nirmala et al in Malaysia compared the use
of carbetocin and syntometrine following vaginal
delivery in 120 women with risk factors for PPH.20
No significant differences in terms of requirement
for additional oxytocic agents, time interval to well-
additional uterotonics was lower in the carbetocin
group (RR, 0.62; 95% CI, 0.44–0.88; four trials, 1,173
women).22 There was no statistically significant dif-
ference in the need for blood transfusion between
the carbetocin and syntometrine group.22 Similar to
vaginal deliveries, there was also a reduced need
for uterine massage when comparing carbetocin
and oxytocin (RR, 0.54; 95% CI, 0.37–0.79; two tri-
als, 739 women).22
CARBETOCIN SAFETY AND TOLERABILITY
The recent Cochrane review by Su et al also com-
pared the adverse effects of different uterotonic
agents.22 The risk of experiencing headache, chills,
abdominal pain, dizziness, tremor, nausea, vomit-
ing, back pain, pruritus, feeling of warmth, metallic
taste, flushing, sweating, shortness of breath, and
premature ventricular contractions were similar be-
tween the carbetocin and oxytocin groups for both
vaginal and caesarean deliveries. Although women
who underwent vaginal deliveries experienced few-
er headaches, nausea, and vomiting when treated
with carbetocin compared with oxytocin, the differ-
ence was not statistically significant. When com-
pared with syntometrine in vaginal delivery, the risk
of nausea (RR, 0.24; 95% CI, 0.15–0.40) and vomit-
ing (RR, 0.21; 95% CI, 0.11–0.39) was significantly
lower in the women treated with carbetocin.22
Women who received carbetocin were also less
likely to have hypertension at 30 minutes (RR, 0.07;
95% CI, 0.01–0.49; two trials, 570 women) and at
60 minutes (RR, 0.07; 95% CI, 0.01–0.54; two trials,
540 women) after vaginal delivery.22 See Table 1 for
a summary of oxytocic drugs currently available.
COST-EFFECTIVENESS OF CARBETOCIN
Many factors, such as cultural differences, govern-
ment policy, availability of trained medical staff,
storage space, and cost-effectiveness, may con-
tribute to differences in the management of PPH
and, ultimately, the choice of uterotonic agents. Al-
though there is currently limited data on the cost-
effectiveness of individual uterotonic agents, one
study from Mexico compared the cost-effectiveness
of prophylactic carbetocin with oxytocin following
caesarean delivery.23 The authors compared the in-
cidence of uterine atony in patients receiving car-
betocin vs oxytocin (8% vs 19%; P < 0.0001) and,
with additional financial data from the Mexican
Institute of Social Security, were able to calculate
Table 1. Summary of oxytocic drugs currently available26-28
Carbetocin (Duratocin)
Oxytocin (Syntocinon)
Oxytocin/ergometrine (Syntometrine)
Active ingredient
Carbetocin 100 µg in 1-mL ampoule
Oxytocin 5 IU or 10 IU in 1-mL ampoule
Oxytocin 5 IU + 0.5 mg ergometrine maleate in 1-mL ampoule
Dosage IV bolus: 100 µg
IV infusion: 5 IUIM: 5–10 IU
IM: maximum three ampoules within 24 h (interval of 2 h)
Onset of action
Within 2 min IV: < 1 minIM: 2–4 min
~2.5 min
Duration of action
~1 h IV: less than IMIM: 30–60 min
~3 h
Adverse reaction
Nausea and vomiting, abdominal pain, hypo-tension
Headache, hypotension, tachycardia/bradycardia
Nausea and vomiting, hypertension, cardiac arrhythmias
IM = intramuscular; IV = intravenous.
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OBSTETRICS I Peer revIewed
the mean cost-effectiveness ratio using incremental
cost-effectiveness ratio analysis.23 The mean cost
per patient treated was lower for the carbetocin
group (US$3,525 vs US$4,054; P < 0.0001), suggest-
ing that carbetocin was more cost-effective.23
CURRENT USE OF CARBETOCIN
Carbetocin has been approved for use in the pre-
vention of uterine atony after delivery by caesarean
section with spinal or epidural anaesthesia in 23
countries, including China, Hong Kong, Malaysia,
and Singapore. The Royal College of Obstetricians
and Gynaecologists states that carbetocin is as ef-
fective as oxytocin infusion for the prevention of
PPH in caesarean section and syntometrine in vagi-
nal delivery.24 However, the drug is currently not
recommended for routine use owing to the limited
data to support its cost-effectiveness. The Society
of Obstetricians and Gynaecologists of Canada rec-
ommends the use of carbetocin for the prevention
of PPH instead of continuous oxytocin infusion in
elective caesarean section and for women deliver-
ing vaginally with one risk factor for PPH.25
CONCLUSION
Postpartum haemorrhage is one of the most com-
mon causes of maternal morbidity and mortality
worldwide. Prophylactic administration of a utero-
tonic agent plays an important role in the preven-
tion of PPH. While there are already numerous ef-
fective agents available on the market, each agent
has its own advantages and drawbacks. While both
oxytocin and ergometrine are effective in prevent-
ing PPH, oxytocin is limited by its short duration of
action, whereas syntometrine is associated with
multiple side effects. Carbetocin is a long-acting
oxytocin analogue that combines the safety and
tolerability of oxytocin with sustained uterotonic
activity. So far, data from several studies, includ-
ing meta-analyses, have shown that carbetocin is
effective and safe in both caesarean and vaginal
delivery, with a better side effect profile. These
promising findings suggest that carbetocin may be
suitable as the drug of choice for primary preven-
tion of PPH.
Further studies on the cost effectiveness of
carbetocin, compared with other uterotonic agents,
and the use of carbetocin as a therapeutic agent for
PPH are useful areas to be explored.
About the AuthorsDr Yussof is Medical Officer in the Department of Obstetrics
and Gynaecology at KK Women’s and Children’s Hospital. Dr
Wee is Senior Consultant, and Obstetrician and Gynaecolo-
gist at Novena Medical Centre; and Visiting Consultant in the
Department of Obstetrics and Gynaecology at KK Women’s and
Children’s Hospital, Singapore.
Acknowledgement
This paper was made possible through a collaboration between KK Women’s and Children’s Hospital (KKH) and the Journal of Paediatrics, Obstetrics and Gynaecology. KKH is the largest medical facility in Singapore which provides specialized care for women, babies and children.
REFERENCES
A complete list of references can be obtained upon request to the editor.
1. Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PFA. WHO analysis of causes of maternal death: a systematic review. Lancet 2006;367:1066–1074.2. Carroli G, Cuesta C, Abalos E, Gulmezoglu AM. Epidemiology of postpartum haemorrhage: a systematic review. Best Pract Res Clin Obstet
Gynaecol 2008;22:999–1012.3. Aflaifel N, Weeks AD. Active management of the third stage of labour. BMJ 2012;345:e4546.4. World Health Organization. WHO guide-lines for the management of postpartum haemorrhage and retained placenta. Avail-able at: http://whqlibdoc.who.int/publications
/2009/9789241598514_eng.pdf. Accessed November 23, 2012.5. Ryden G, Sjoholm I. Half-life of oxytocin in blood of pregnant and non-pregnant women. Acta Endocrinol (Copenh) 1969;61:425–431.6. Fabian M, Forsling M, Jones J. The clearance and antidiuretic potency of neurohypophysial
hormones in man, and their plasma binding and stability. J Physiol 1969;204:653–668.
JPOG_SepOct_2013_Final_COMBINE.indd 210 10/4/13 9:18 AM
IN PRACTICE
JPOG SEP/OCT 2013 • 211
IN PractIce I Peer revIewed
Dermatology ClinicSudden Onset of Blistering Lesions in a Young BoyGayle Fischer, MBBS, MD, FACD
Answer:
ERYTHEMA MULTIFORME
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
The diagnosis in this case is erythema mul-
tiforme. Careful observation of these blis-
ters show that they have the morphology of
‘target lesions’. Although not every lesion
demonstrates this, most have a red areola,
then an area of grey with a red centre. True
target lesions are highly characteristic of
erythema multiforme.
The most common condition confused
with erythema multiforme is urticaria,
which may be ‘targetoid’, as shown in Fig-
IN PRACTICE i Peer reviewed
ure 2, but careful observation reveals that
these lesions are in fact simply annular.
Differentiating erythema multiforme from
urticaria is straightforward. The lesions in
urticaria never blister and always migrate
if observed over several hours. Erythema
multiforme lesions are fixed and last up
to 2 weeks. However, both conditions are
often acute in onset.
Other causes of blistering rashes in-
clude bullous impetigo, other viral exan-
themata, and tinea.
CLINICAL SPECTRUM AND CAUSES
Erythema multiforme has a wide clinical
spectrum ranging from a benign blister-
ing rash involving only the arms and legs
to a widespread life-threatening erup-
tion causing severe erosions of all mu-
cosal surface including the conjunctivae.
Many cases of erythema multiforme
are the result of a recent herpes simplex
infection such as a cold sore; however,
infections with Mycoplasma pneumoniae
may also result in severe erythema mul-
tiforme. Less often, drug eruptions may
result in the same type of rash.
When caused by herpes simplex
infection, erythema multiforme often re-
curs with each attack. This can be highly
disruptive as the rash lasts for about 2
weeks.
Figure 2. ‘Targetoid’ urticaria
JPOG SEP/OCT 2013 • 211
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JPOG SEP/OCT 2013 • 212
IN PRACTICEIN PRACTICE I Peer revIewedIN PRACTICE i Peer reviewed
Medicine Today June 2013;14(6):60–61. Reprinted with
permission
About the AuthorAssociate Professor Fischer is Associate Professor of Dermatology at Sydney Medical School – Northern, University of Sydney, Royal North Shore Hospital, Sydney, NSW, Australia.
Figure 3. Severe mucosal erosions of erythema multiforme.
JPOG SEP/OCT 2013 • 212
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Continuing Medical Education
JPOG SEP/OCT 2013 • 213
Screening for Group B Streptococcus in PregnancyKY Leung, MBBS, MD, FRCOG, FHKAM(O&G); Teresa WL Ma, MBBS, FRCOG, FHKAM (O&G); KKW To, MBBS, MRCP, FRCPath, FHKAM (Pathology); KY Wong, MBBS, MRCP, FHKAM (Paediatrics);
Thomas KT Li, MBChB(HK), DRCOG, MRCOG, DCG(HKCOG), FHKAM(O&G); CW Law, MBBS, MRCP, FHKCPaed, FHKAM (Paediatrics); Sarah Morag McGhee, BA, BSc, PhD Glas, FFPH (RCP) UK
GBS culture remains the reference standard for the detection of GBS colonization in pregnant women.
INTRODUCTION
Group B Streptococcus (GBS) is the com-
monest cause of severe early-onset neo-
natal infection, which is associated with
a high rate of morbidity and mortality
(5–10%).1–3 About half of GBS meningitis
will be complicated by neurodevelopment
impairment. Because the early-onset dis-
ease develops shortly and rapidly after
birth, there has been little improvement in
the disease treatment, and the focus thus
lies in disease prevention.
GBS colonization in the maternal
gastrointestinal and/or genital tracts is a
prerequisite for early-onset GBS (EOGBS)
disease. It is well documented that intra-
partum antibiotics prophylaxis (IAP) given
to high-risk women can reduce the GBS
colonization rate of newborns (odds ratio
[OR], 0.1) and the incidence of EOGBS dis-
ease (OR, 0.17), providing that there has
been at least 2 hours of exposure to the
prophylactic antibiotics during labour.4
However, which screening method to use
to identify high-risk women is controver-
sial. The clinical risk strategy, which is
used in the UK, was recommended by the
Royal College of Obstetricians and Gynae-
cologists,5 while the universal swab-based
strategy, which is used in the US and some
European countries,6 was recommended
in the Centers for Disease Control and
Prevention (CDC) guidelines in 2002 and
2010.7 Because of the lack of local data,
a 1-year pilot study on universal prenatal
swab-based screening was conducted in a
public hospital in Hong Kong to study the
cost-effectiveness. The conventional labo-
ratory test for GBS is culture. Recent re-
search has focused on the improvement of
microbiological techniques to detect GBS
colonization and infection.
The aim of this review article is to
discuss the current screening methods for
GBS in pregnancy, the updated CDC guide-
lines, the improvement in laboratory tech-
niques, and a pilot study in Hong Kong.
5 SKP
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JPOG SEP/OCT 2013 • 214
CLINICAL RISK FACTORS
The clinical risk factors for EOGBS disease
are well known and are listed in Table 1.8,9
Under the risk-based strategy, IAP is given
to a woman without taking a swab if she
has one or more of the risk factors.
If a woman gives a history of maternal
GBS colonization in her previous pregnancy
but without neonatal disease, prenatal
GBS screening will be required in her cur-
rent pregnancy as the recurrence risk is
more than one-third.10 If the GBS status is
unknown during term labour in the current
pregnancy, IAP will be given.10
However, this risk-based strategy can-
not identify a subset of pregnant women
who do not have any risk factors but are
colonized with GBS at delivery. Besides, the
risk-based approach may inappropriately
expose 65–85% of women with risk factors
who are GBS-negative to antibiotics.11
UNIVERSAL SWAB-BASED STRATEGY
Current American and Canadian guide-
lines recommend routine vaginal/rectal
swab for GBS screening of women at
35–37 weeks of gestation (Table 2).7,12 If
the vaginal/rectal swab or urine cultures
show the presence of GBS, or if the wom-
an has given birth to an infant with inva-
sive GBS disease, IAP will be given to the
mother.7,12 If the GBS status is unknown,
risk factors will be used to determine the
administration of IAP.7 If the GBS screen-
ing is negative, the risk of EOGBS disease
will be low even if the woman has one of
the risk factors.13
If the vaginal/rectal swab shows the
presence of GBS, antenatal antibiotics
treatment cannot prevent EOGBS disease
because per oral antibiotic treatment does
not eliminate vaginal or rectal coloniza-
tion.2 On the other hand, treatment of
urinary tract infection or asymptomatic
bacteriuria with GBS during pregnancy is
indicated.14
However, universal swab-based
strategy may not be accepted by some
women because giving IAP in screen-pos-
itive cases will affect their autonomy and
the feasibility of home birth. Side effects
of IAP include anaphylaxis (1 in 10,000) or
rarely death (1:100,000). Besides, increas-
ing use of IAP can lead to an increase in
Gram-negative or drug-resistant early-
onset neonatal infection.15–17 Furthermore,
there will still be affected infants who
lack the typical intrapartum risk factors for
GBS infection, are born to mothers with a
negative GBS screen, or represent missed
opportunities for prevention.18 Health-care
providers should remain alert for signs of
sepsis in any newborn infant.
UNIVERSAL SCREENING OR NOT?
Whether to implement universal swab-
based strategy or not depends on the local
incidence of EOGBS disease, the preva-
lence of clinical risk factors in EOGBS dis-
ease, and the current obstetric practice. In
the US, universal swab-based strategy has
Table 1. Clinical risk factors for early-onset group B Streptococcus (GBS) disease
A previous delivery of a newborn with GBS diseaseAntenatal GBS bacteriuriaMembrane rupture of 18 hours or moreGestation < 37 weeksIntrapartum fever
Table 2. Universal swab-based screening
1. Routine vaginal/rectal swab for GBS screening in women at 35–37 weeks of gestation.
2. Give intrapartum antibiotics a) if the vaginal/rectal swab or urine cultures show the presence of GBS, or b) if the woman has given birth to an infant with invasive GBS disease, or c) if the GBS status is unknown, and a risk factor (as in Table 1) is present.
GBS = group B Streptococcus.
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JPOG SEP/OCT 2013 • 215
been adopted because of the high preva-
lence of EOGBS (1.8 per 1,000 births) and
low prevalence (38%) of clinical risk factors
in EOGBS disease. This swab-based strat-
egy can prevent 75% of EOGBS disease by
giving IAP to 31% of pregnant women.11
On the other hand, the clinical risk-
based strategy has been recommended in
the UK because of the low prevalence of
EOGBS disease (0.5 per 1,000 births) even
in the absence of systematic screening
or widespread IAP and high prevalence
(60–70%) of clinical risk factors in EOGBS
disease.5 This risk-based strategy can pre-
vent 67% of EOGBS by giving IAP to 17%
of pregnant women.11 Universal swab-
based strategy was found to be not cost-
effective in the UK.19
WHICH SITE?
GBS colonization in the maternal gastroin-
testinal and/or genital tracts is a prereq-
uisite for EOGBS disease. The colonization
can be permanent, intermittent or transient.
The colonization rate varies from 10% to
30%.20–22 Perinatal colonization rate is
around 50%, but only 1% becomes infected.
To increase the detection rate of GBS
colonization, swabs are taken from both
the lower vagina (vaginal introitus) and
the rectum (through the anal sphincter) in-
stead of from one site alone.23 The use of
two separate swabs is preferred over the
use of one swab for both sites because of
hygienic problem. To save laboratory cost,
these two swabs can be stored in one
transport medium as there is no need to
differentiate between these two sites for
screen-positive cases. A speculum is not
needed for taking lower vagina swabs.
Taking rectal swabs may cause dis-
comfort or pain. An alternative is to take
perineal swabs which may be preferred
by women. A recent study showed that
agreement was high (96%) between the
vaginal–rectal and the vaginal–perianal
collection methods.24 However, data are
still limited.
It is unclear whether it is cost-effec-
tive to add a routine urine test for asymp-
tomatic bacteriuria on top of vaginal–rec-
tal swabs at 35–37 weeks’ gestation.7
BY WHOM?
The vaginal–rectal swabs are usually
taken by a health-care provider. After hav-
ing been given appropriate instructions,
pregnant women can collect their own
vaginal–rectal screening specimens and
give similar GBS yield.25 However, they
may prefer a health professional to col-
lect their swabs.26 Less-educated women
may be more reluctant to collect their own
samples.25
PROCESSING
The swabs will be placed into an appropri-
ate non-nutritive transport medium which
can help sustain the viability of GBS in
settings where immediate laboratory pro-
cessing is not possible.27 If processing is
delayed, refrigeration (at 4ºC) will be used
for storage. Processing the swabs within
24 hours of collection is recommended.28
Alternatively, the swabs can be placed
into the enrichment broth immediately af-
ter collection.
The use of selective broth media
can facilitate GBS isolation by preventing
the overgrowth of other commensal bac-
teria in vagina/rectum.29 Selective broth
medium, such as Todd-Hewitt broth sup-
plemented with nalidixic acid and either
gentamicin or colistin, is inoculated and
incubated at 35–37ºC in ambient air or
5% CO2. The broth is then subcultured to
a blood agar plate. The latter is inspected
for GBS after incubation for 18–24 hours.
If GBS is not identified, re-incubation and
re-inspection will be required at 48 hours.
WHEN TO TAKE THE SWABS?
A recent systematic review in 2010 con-
firms the recommendations to screen for
GBS at 35–37 weeks’ gestation.30 The
negative predictive value of GBS cultures
Table 3. Rapid test for group B Streptococcus
1. Fluorescence in situ hybridization2. Latex agglutination test3. Optical immunoassays and enzyme immunoassays4. DNA probes5. Nucleic acid amplification tests
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JPOG SEP/OCT 2013 • 216
performed within 5 weeks before deliv-
ery is very high (95–98%) but declines
beyond 5 weeks. GBS colonization early
in pregnancy is not predictive of EOGBS
disease because the coloniza tion can be
transient.31 It will be appropriate to take a
swab for GBS screening at 35–37 weeks.
However, there are two disadvan-
tages. First, women who deliver before
35 weeks of gestation are not screened
for GBS, but preterm newborns are at
high risk of developing EOGBS disease.32
Second, up to 67% of infants with EOGBS
were delivered by mothers who were neg-
ative on prenatal GBS screening.18 About
6% of GBS carriers remaining undetected
in antenatal cultures.30 GBS colonization
can be intermittent during pregnancy.
A change in the GBS colonization status
from screening to delivery can occur in 9%
of women.33 Consequently, under- or over-
treatment with IAP may be resulted.
Although the results of intrapartum
swabs can reflect the GBS status more
accurately than those of antepartum
swabs,34 the culture method may not pro-
vide a timely result to guide IAP.
CULTURE OR RAPID TEST?
GBS culture remains the reference stand-
ard for the detection of GBS colonization,
but it usually takes 24–72 hours to get the
results. Therefore, culture-based testing
is suitable for antepartum but not intra-
partum screening.
Ideally, the use of a highly sensitive
and specific test with rapid turnaround
time can assess intrapartum GBS coloni-
zation and hence guide IAP. Studies have
shown that the rapid tests (Table 3), in-
cluding fluorescence in situ hybridiza-
tion, latex agglutination test, optical im-
munoassays and enzyme immunoassays,
were not sensitive and specific enough
to replace the established culture meth-
od.35–41 Recently, molecular testing meth-
ods have been developed, including DNA
probes42 and nucleic acid amplification
tests (NAAT) such as polymerase chain
reaction (PCR).43 The performance of com-
mercially available NAAT on non-enriched
samples was variable and not adequate in
comparison with culture. While the sensi-
tivity of NAAT for GBS can be as high as
92.5–100.0% with use of an enrichment
step, the latter increases the turnaround
time.7,42 A rapid PCR test can detect non-
viable or low-count bacteria44 and is not
affected by the presence of blood, meco-
nium, or amniotic fluid.33 The turnaround
time of this rapid real-time PCR test can
be within 1 hour.45 More data are needed.
However, there are concerns on the
real-world turnaround time, lack of anti-
microbial susceptibility, availability of 24-
hour service, staffing requirements, and
costs. Universal screening using a rapid
test was not cost-effective, based on its
current sensitivity, specificity and cost.41
A rapid test may be useful for women at
term with unknown GBS status and with-
out risk factors. On the other hand, the
current evidence does not support their
use in replace ment of antenatal culture
or risk-based assessment of women with
It is recommended that a swab for GBS screening be taken at 35–37 weeks’ gestation.
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Continuing Medical Education
unknown GBS status during intra partum.
THE EFFECTS OF UPDATED CDC GUIDELINES7 ON OBSTETRIC PRACTICE
Bacteriuria
To ensure proper testing, ‘pregnancy’
should be specified when sending urine
samples to a laboratory. The latter should
report GBS in urine culture specimens
when present at concentrations of ≥ 104
colony-forming units/mL in pure culture
or mixed with a second microorgan ism.
EOGBS is associated with maternal GBS
bacteriuria (generally >105 colony-forming
units/mL of urine).46 Few data are available
on the risk with low (< 104) colony-count
GBS bacteriuria.46
Antibiotic Susceptibility
To ensure laboratory testing for antimicro-
bial susceptibility to clindamycin, ‘penicil-
lin-allergic’ history, if any, should be speci-
fied on antenatal swabs for GBS screening.
Intra Partum
NAAT can be used to detect GBS in women
with unknown GBS status and without any
risk factors during intra partum. However,
NAAT testing is optional, and its availabil-
ity is limited.
Threatened Preterm Labour
If a woman is admitted with signs and
symptoms of labour before 37 weeks’ ges-
tation, GBS screening should be performed
unless it was performed within 5 weeks.
IAP should be given for unknown GBS
status or a positive GBS screen within 5
weeks, and then discontinued subsequent-
ly if the woman is not in true labour or if
the GBS culture is negative. GBS screening
should be repeated at 35–37 weeks’ gesta-
tion.
Preterm Prelabour Rupture of Mem-
branes
If a woman is admitted with leaking before
37 weeks’ gestation, GBS screening should
be performed unless it was performed
within 5 weeks. If antibiotics are given to
prolong latency for preterm prelabour rup-
ture of membranes, the antibiotics should
also be able to cover GBS adequately.
Otherwise, an additional GBS prophylaxis
should be given for 48 hours unless a GBS
screen performed within the preceding 5
weeks was negative. GBS testing results
should not affect the duration of antibiot-
ics which are given to prolong latency.
UNIVERSAL PRENATAL SCREENING FOR GBS IN HONG KONG
In the past, all the public hospitals in Hong
Kong used the clinical risk-based strategy
to prevent EOGBS disease, and the inci-
dence of EOGBS was around 0.7–1.1 per
1,000 births. A working group including ob-
stetricians, paediatricians, and microbiol-
ogists was formed to study the prevention
strategy in 2008.
Pilot Study
There are racial or ethnic differences in
EOGBS disease. Because of the lack of
local data, a 1-year pilot study was con-
ducted in Queen Mary Hospital and Tsan
Yuk Hospital to determine the cost-effec-
tiveness of prenatal universal screening
for GBS. During the study period from April
2009 to March 2010, all pregnant women
seeking antenatal care were invited to
participate in this study. GBS screening
was performed according to the 2002 CDC
guidelines.47 All the swab specimens were
sent to the microbiology laboratory of
Queen Mary Hospital for testing for GBS.
IAP was given to screen-positive women.
Newborn infants born to mothers with GBS
colonization were managed according to a
protocol.
Maternal GBS Colonization Rate
During the pilot project which involved
3,908 pregnant women, 90% or 3,542 were
eligible for screening at 35–37 weeks’ ges-
tation. After explanation and counseling
on GBS screening by a midwife, 82% of
these eligible women accepted the screen-
ing. The total number of women who un-
derwent GBS screening was 2,890. The
main reasons for declining GBS screen-
ing included (1) unwillingness to undergo
screening (35.4%), (2) screening done pri-
vately (24.7%), (3) screening deemed un-
necessary (20.4%), (4) planned elective
Caesarean section (10.4%), and (5) plan to
deliver in a private or other hospital (8.2%).
We noticed a low screen-positive rate
(4.2%) in the first month of screening. After
reviewing the procedures of swab taking,
transport medium and laboratory testing,
the screen-positive rate increased to around
9.5% in subsequent months. The overall in-
cidence of maternal GBS colonization was
9.6%. This was consistent with the results
of another local study that the prevalence
JPOG-SepOct_2013_CME_ID_Final_ScreeningforGroup BStreptococcusinPregnancy.indd 217 10/4/13 11:32 AM
JPOG SEP/OCT 2013 • 218
of GBS on booking was 10.4%.22
Like another local study,22 the GBS
colonization rate was significantly higher
in health-care professionals (19.4%) than
in housewives (7.5%) (P = 0.004). The GBS
colonization rate was also higher in women
with a parity of 3 or above (27.3%) than
women with a parity below 3 (9.9%) (P <
0.001). However, either a health-care pro-
fessional or a woman with a parity of 3 or
above was not a good screening marker as
they constituted only a small proportion of
the pregnant women. Surprisingly, a risk
factor was present in only 12.9% of women
with GBS colonization. There was no major
maternal complications related to GBS.
Babies
During the pilot project, a total of 1,770
swabs (including gastric aspirate, ear, and
blood) were taken from the babies. There
were three cases of EOGBS disease pre-
sented with septicaemia. One of them de-
veloped meningitis as well. In two of them,
the mothers declined screening while the
screening result was negative in the re-
maining one. This result was compatible
with the 4% false-negative rate which
was reported in the literature.18 There was
no neonatal mortality related to GBS.
LOGISTIC PROBLEMS
There were no major logistic difficulties.
Around 8% of women did not return at 35–
37 weeks’ gestation for GBS screening.
Tracing the GBS reports from our electron-
ic medical system was preferred over pa-
per records, which might not be available
during the intrapartum period. The compli-
ance to the protocol was, in general, good
except for one screen-positive case in
which IAP was not given. Fortunately, the
neonate was not infected. There were no
adverse events or complaints by patients.
COST-EFFECTIVENESS ANALYSIS
The cost-effectiveness analysis was per-
formed by the Department of Community
Medicine using a prediction model. This
modelling study has shown that, based
on the best evidence we have available at
present, the swab-based strategy in Hong
Kong would likely cost more but probably
avoid more cases of EOGBS than the cur-
rent clinical risk factor-based strategy.
This finding is consistent with a study in
the US that universal screening was pre-
dicted to prevent more EOGBS disease,
but at a larger cost than the risk-factor
strategy (75% vs 54%; US$12,000 vs
US$3,000).11
The incremental cost-effectiveness
ratio (ICER) was HK$255,367 (about
US$32,000) per life-year gained. The ICER
was most sensitive to the rates of mater-
nal colonization, vertical transmission,
mortality, and disability. The effectiveness
of IAP and the rate of receiving IAP were
less important. Varying the number of days
in hospital and the proportion of days in
the neonatal intensive care unit for EOGBS
cases did not have an important impact
on the cost-effectiveness of the strate-
gies. The cost-effectiveness acceptability
curves show that using the World Health
Organization benchmark for value of a life-
year (one to two times per capita gross do-
mestic product), over 80% of simulations
found that the swab-based strategy was
more cost-effective than the current clini-
cal risk factor-based strategy.
In the UK, a cost-effectiveness study
has shown that culture-based testing of
women with no risk factors or rupture of
membranes ≥ 18 hours with treatment
for all preterm and high-risk term women
would be the most cost-effective strat-
egy.19 GBS screening in high-risk women
would not be cost-effective, as even those
with negative results would be better off
treated to reduce the risk of EOGBS dis-
ease.
CONCLUSION
Whether to implement universal swab-
based strategy or clinical risk-based strat-
egy depends on the local incidence of
EOGBS disease, the prevalence of clinical
risk factors in EOGBS disease, and the cur-
rent obstetric practice. Universal swab-
based strategy and clinical risk-based
strategy differ in the proportion of women
being given IAP, and cost-effectiveness.
It seems that the universal swab-based
strategy would likely cost more but prob-
ably avoid more cases of EOGBS disease
than the clinical risk factor-based strat-
egy. However, universal prenatal screen-
ing cannot prevent all affected infants be-
cause of a false-negative result, the lack
of the typical intrapartum risk factors for
GBS infection, or missed opportunities for
screening. Improved management of pre-
term deliveries and improved communica-
tion, collection, processing and reporting
of culture results may prevent additional
JPOG-SepOct_2013_CME_ID_Final_ScreeningforGroup BStreptococcusinPregnancy.indd 218 10/4/13 11:32 AM
Continuing Medical Education
JPOG SEP/OCT 2013 • 219
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cases of EOGBS disease.7,48 Ideally, a
highly sensitive and specific (≥ 90%) but
low-complexity test with a rapid turna-
round time (< 30 minutes) can be used to
determine intrapartum GBS status, as well
as mutations likely to confer resistance to
clindamycin and/or erythromycin. A rapid
test may be useful for women at term with
unknown GBS status and without risk fac-
tors. However, using a rapid test for uni-
versal screening was not cost-effective
based on its current sensitivity, specificity
and cost.41 Further studies are required.
About the AuthorsDr Leung is Chief of Service and Consultant in the Department of Obstetrics and Gynaecology, and Dr Ma is Consultant in the Department of Obstetrics and Gynaeco-logy, Queen Elizabeth Hospital. Dr To is Clinical Assistant
Professor in the Research Centre of Infection and Immu-
nology, Department of Microbiology, The University of
Hong Kong. Dr Wong is Consultant in the Department of
Paediatrics and Adolescent Medicine, and Dr Li is Associ-
ate Consultant and Honorary Clinical Assistant Professor
in the Department of Obstetrics and Gynaecology, Queen
Mary Hospital. Dr Law is Consultant in the Department
of Paediatrics, Queen Elizabeth Hospital. Dr McGhee is
Professor in the Department of Community Medicine,
School of Public Health, The University of Hong Kong,
Hong Kong.
JPOG-SepOct_2013_CME_ID_Final_ScreeningforGroup BStreptococcusinPregnancy.indd 219 10/4/13 11:32 AM
Program pendidikan kedokteran berkelanjutan ini dipersembahkan oleh MIMS, bekerjasama dengan Ikatan Dokter Indonesia.
Setelah membaca artikel ‘Screening for Group B Streptococcus in Pregnancy’, jawab pertanyaan berikut kemudian kirimkan dengan menggunakan formulir jawaban yang sudah disediakan ke CME Journal of Paediatrics, Obstetrics & Gynaecology, untuk mendapatkan 5 SKP.
Artikel CME:
Screening for Group B Streptococcus in Pregnancy
Jawab pertanyaan di bawah ini dengan Benar atau Salah
5 SKP
1. Maternal temperature of 38.8ºC during the intra partum is a risk factor for early-onset group B Streptococcus (GBS) disease.
2. Administration of intrapartum antibiotic prophylaxis for GBS is indicated in a woman who goes into labour at 38 weeks’ gestation with unknown GBS status and gives a history of maternal GBS colonization in her previous pregnancy but without neonatal disease.
3. If the vaginal/rectal swab shows the presence of GBS, antenatal antibiotics treatment will be required to eradicate GBS.
4. For GBS screening, swabs are taken from both the high vagina and the anus.
5. Delayed processing of the swabs for more than 24 hours does not affect the laboratory detection of GBS.
6. It is recommended to take swabs for GBS screening at 35–37 weeks’ gestation.
7. The performance of a rapid test for GBS on non-enriched swab samples is as good as the culture method.
8. If a woman is admitted with painful uterine contractions at 35 weeks’ gestation and unknown GBS status, GBS screening should be performed and intrapartum antibiotic prophylaxis for GBS given.
9. GBS colonization rate was significantly higher in health-care professionals than in housewives in Hong Kong.
10. In the UK, culture-based testing of women with no risk factors while being given intrapartum antibiotics for GBS for all preterm and high-risk term women is the most cost-effective strategy.
CME Questions CME Questions
JPOG SEP/OCT 2013 • 220
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