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ISSN 2411-0183
VOL. 44 NO. 3



How can Your
Microbiologist Help
you Manage
Paediatric Infection?

Management of
Urinary Incontinence
in Frail Elderly Women

Human Papillomavirus
and Cervical Cancer
MIMS JPOG 2018 VOL. 44 NO. 3 i

2018 VOL. 44 NO. 3

Editorial Board
Board Director, Paediatrics
34th Annual Meeting of the European Society of
Professor Pik-To Cheung
Associate Professor, Department of Paediatrics and Adolescent Medicine Human Reproduction and Embryology (ESHRE),
The University of Hong Kong, Hong Kong
July 1-4, Barcelona, Spain
Board Director, Obstetrics and Gynaecology
Professor Pak-Chung Ho
Director, Centre of Reproductive Medicine 89
The University of Hong Kong - Shenzhen Hospital, China
• Slow-release insemination ups pregnancy rate for
young infertile women
Professor Biran Affandi Professor Seng-Hock Quak
• GnRH agonist + hCG improves oocyte retrieval in IVF
University of Indonesia, Indonesia National University of Singapore, patients
Professor Hextan
Yuen-Sheung Ngan Adjunct Associate Professor
The University of Hong Kong, Hong Kong Tan Ah Moy
KK Women’s and Children’s Hospital,
Professor Kenneth Kwek
KK Women’s and Children’s Hospital,
Dr. Catherine Lynn Silao
University of the Philippines Manila,
Professor Kok Hian Tan Philippines
KK Women’s and Children’s Hospital,
Dwiana Ocviyanti, MD, PhD
University of Indonesia, Indonesia
Professor Dato’
Dr. Ravindran Jegasothy
Dr. Karen Kar-Loen Chan • Kids eat more veggies when
The University of Hong Kong,
Dean Faculty of Medicine, Hong Kong plates have those images
MAHSA University, Malaysia
Dr. Kwok-Yin Leung • Alcohol intake during
Associate Professor Daisy Chan The University of Hong Kong,
Singapore General Hospital, Singapore Hong Kong breastfeeding affects cognition
Associate Professor Raymond Dr. Mary Anne Chiong in babies
Hang Wun Li University of the Philippines Manila,
The University of Hong Kong, Hong Kong Philippines

Adjunct Associate Professor Dr. Wing-Cheong Leung

Ng Kee Chong
Kwong Wah Hospital, Hong Kong, 91
Hong Kong
Division of Medicine & Academic Clinical
Program (Paediatrics), c/o KK Women’s and • HPV testing could detect cervical precancers earlier
Children’s Hospital, Singapore than cytology

• Prenatal depression increases
over time
MIMS JPOG 2018 VOL. 44 NO. 3 iii

2018 VOL. 44 NO. 3

CEO Yasunobu Sakai
Managing Editor Elvira Manzano
Medical Editor Elaine Soliven
Designer Sam Shum
Production Tetsuya Hamaki, Agnes Chieng, Raymond Choo
Circulation Christine Chok Hypertension in Pregnancy
Accounting Manager Minty Kwan
Advertising Coordinator Pannica Goh
Hypertensive disorders of pregnancy
remain a common complication of
Published by: pregnancy and a major cause of
MIMS (Hong Kong) Limited
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mortality worldwide. Hypertensive
disorders range from mild gestational
hypertension to early onset pre-
eclampsia which remains a leading cause of maternal death
Enquiries and Correspondence worldwide. Due to their unpredictable nature and potential poor
China Philippines
outcomes, patients with hypertensive disorders of pregnancy
Yang Xuan Rowena Belgica warrant cautious care including consultant obstetric, neonatal,
Tel: (86 21) 6157 3888 Tel: (63 2) 886 0333
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Hong Kong Singapore outcomes.
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How can Your Microbiologist Help you
Email: Manage Paediatric Infection?
Malaysia In this review, we will focus on current
Tiffany Collar, Sumitra Pakry,
Sharon Ong, Wong Wen Dee diagnostic methods for common
Tel: (60 3) 7623 8000 paediatric microbiology consultations,
with a focus on newer molecular
technology to reduce laboratory
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iv MIMS JPOG 2018 VOL. 44 NO. 3

2018 VOL. 44 NO. 3

REVIEW ARTICLE MIMS JPOG welcomes papers in the

following categories:
Review Articles
Comprehensive reviews providing the latest clinical information
115 on all aspects of the management of medical conditions affecting
children and women.
Management of Urinary Incontinence in
Frail Elderly Women Case Studies
Urinary incontinence (UI) is defined by Interesting cases seen in general practice and their management.
the International Continence Society
as any involuntary leakage of urine. It
Pictorial Medicine
Vignettes of illustrated cases with clinical photographs.
is a common clinical problem, and its
incidence increases with age. It is a For more information, please refer to the Instructions for Authors
particular problem in the frail elderly, who on our website, or contact:
can sometimes pose a diagnostic and The Editor
therapeutic challenge by virtue of their complexity. UI is a major cause MIMS Pte Ltd
of disability and dependency, and adversely affects the psychological 438A Alexandra Road
Alexandra Technopark
and physical health of the older person. However, treatment can lead
to significant improvements.
Singapore 119967
Gabrielle Prud’homme, Leanne Alexander, Susan Orme Tel: (65) 6290 7400
Fax: (65) 6290 7401

Human Papillomavirus and Cervical
Cancer 2 SKP

Cervical cancer is the fourth most common cancer in women in

the world, and there were about 528,000 new patients and 266,000
deaths in 2012. This article aims to review the causal relationship
between human papillomavirus (HPV) and cervical cancer and
discuss existing methods that prevent HPV from leading to cervical
Ka Yu Tse, Philip Pun Ching Ip, Karen Kar Loen Chan

The Cover:
Hypertension in Pregnancy
©2018 MIMS Pte Ltd

Peggy Tio, Designer


34th Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE),
July 1-4, Barcelona, Spain – Elaine Soliven reports

Slow-release insemination with IUI (16.9 percent vs 7.2 percent, RR, Compared with women given hCG
ups pregnancy rate for 2.33; p=0.032). only, those in the dual trigger group had
young infertile women “We are aware that the crossover de- significantly more oocytes retrieved (12.9
sign might be seen as a limitation of this vs 10.6; p=0.02).
Young infertile women who undergo in- study. Some authors reject the utilization Women treated with dual trigger vs
trauterine slow-release insemination (SRI) of this study design in infertility trials. How- hCG also had a significantly higher rate
may achieve a higher rate of pregnancy, ever, others claim this [as] an efficient and of oocyte recovery (number of oocytes
according to a study presented at ESHRE pragmatic design, particularly as only one in each follicle, 96.1 percent vs 76.6 per-
2018. cycle of each treatment is given to each cent; p=0.001 [above 10 mm] and 145.1
“SRI [theorized] that if persistent woman,” Marschalek said. percent vs 121.8 percent; p=0.03 [above
low concentration of sperm might pro- “[Nevertheless,] we think that this 15 mm]).
long the period of potential fertilization, is an interesting finding; the extent to A majority, but not all of the oocytes
thereby it mimics the physiological which advanced male or female age were mature, said study lead author
sperm transportation into the fallopian influences pregnancy rates after SRI Dr Jigal Haas from the IVF unit at TRIO
tubes because it is a slow release of needs to be addressed, and we want Fertility Clinic in Toronto, Ontario,
sperm,” said study lead author Dr Julian to perform further studies on that,” said Canada.
Marschalek from the Division of Gynae- Marschalek. Compared with those in the hCG
cological Endocrinology and Reproduc- only group, women in the dual trigger
Dr Julian Marschalek, et al, European Society of Human Re-
tive Medicine at the Medical University of production and Embryology (ESHRE) 2018, July 1-4, Barce- group had significantly more metaphase
lona, Spain [abstract O-118].
Vienna, Austria. II oocytes (10.1 vs 8.6; p=0.04), zygotes
This randomized crossover study in- (7.9 vs 6.3; p=0.04), embryos (6.6 vs
volved 182 women with infertility (median 5.7; p=0.03), and blastocysts (3.7 vs 3.1;
age 33 years) who were randomized to re- GnRH agonist + hCG improves p=0.02), as well as top-quality blasto-
ceive either standard intrauterine insemi- oocyte retrieval in IVF patients cysts (2.5 vs 1.8; p=0.02).
nation (IUI, n=96) or SRI (n=86) as their A higher rate of cumulative pregnan-
first cycle of treatment, of whom 7 and 11 Dual triggering with a gonadotropin-re- cy was observed in women who had dual
became pregnant, respectively. The 102 leasing hormone (GnRH) agonist and hu- trigger vs hCG treatment (64 percent vs
women who did not achieve pregnancy man chorionic gonadotropin (hCG) may 57 percent), though the difference was
were crossed over to the other method as increase the number of oocytes among not statistically significant due to small
their second cycle of treatment (IUI, n=44 women undergoing in vitro fertilization sample size.
and SRI, n=58). [ESHRE, abstract O-118] (IVF), according to a study presented at “We think that the increase in the
There were no significant differences ESHRE 2018. number of mature oocytes may poten-
with regard to cause of infertility, male pa- This single-centre, prospective dou- tially improve the outcome of the IVF
rameters, or reproductive medications, in- ble-blind trial consisted of 160 women cycle,” said Haas, recommending a
cluding clomiphene, gonadotrophin, and (mean age 36 years, mean BMI 24 kg/ larger study assessing pregnancy out-
progesterone, between groups. m2) on their first to third IVF cycle at- comes in women given the dual trigger
While the rate of pregnancy did tempts. Participants were given hCG combination.
not statistically differ between women alone (10,000 IU and placebo, n=80) or “We believe that by hCG, we get
who received SRI and IUI (13.2 percent hCG plus a GnRH agonist (dual trigger great results, but by the dual trigger, we
vs 10.0 percent, relative risk [RR], 1.31; group; 10,000 IU and 0.5 mg, n=80) 36 can get better results,” Haas noted.
p=0.202), a subgroup analysis of wom- hours prior to oocyte retrieval. The base-
Dr Jigal Haas, et al, European Society of Human Reproduc-
en aged <35 years showed a significant- line and stimulation cycle characteris- tion and Embryology (ESHRE) 2018, July 1-4, Barcelona,
Spain [abstract O-208].
ly higher overall pregnancy rate among tics were similar between the treatment
women who underwent SRI compared groups. [ESHRE 2018, abstract O-208]

P more (4.04 grams) vs baseline, but caveats and a study of a much larger
neither of those increases were statis- scale is warranted in the future.
tically significant. Melnick EM, Li M. Association of plate design with consump-

Paediatrics “This approach of using nudge

tion of fruits and vegetables among preschool children. JAMA
Pediatr 2018;doi:10.1001/jamapediatrics.2018.1915.
methods to change what people eat is re-
Kids eat more veggies when ally important and there has been a lot of
plates have those images research on it in the general population,
but there is little on how that affects kids,” Alcohol intake during
Preschool children consumed more veg- Li said. “I think the exposure kids have breastfeeding affects
etables when their plates had images of to food is really impactful in their adult cognition in babies
fruits and vegetables, according to a lon- behaviour in the long term.”
gitudinal study. However, this effect was The study included 235 children Children whose mums consumed alco-
not observed for fruit consumption, offer- from Colorado evenly split between hol when breastfeeding them were more
ing important insights for those manag- boys and girls. All used white plates at likely to experience dose-dependent
ing paediatric nutrition. baseline and were shifted to segment- reductions in abstract reasoning at age
6–7 years, a study has shown. The effect
waned by age 8–11 years.
Researchers said alcohol passes
quickly through the breast milk and re-
duces milk production. The practice of
pumping and dumping breast milk after
alcohol consumption does not decrease
ethanol concentration in breast milk be-
cause for as long as alcohol is present
in the maternal blood, ethanol in breast
milk will remain high.
Researchers from the Macquarie
University in Sydney, Australia analysed
data from the Growing Up in Australia:
The Longitudinal Study of Australian
Children, which included 5,107 babies
who were assessed every 2 years. Multi-
variable linear regression analyses were
used to determine the link between al-
Children who used plates with ed plates with images 4 weeks later. cohol use and smoking by breastfeed-
images took 13.82 grams more veg- The researchers gave introduction ing mothers and babies’ scores on three
etables daily compared to when they about the pictures of fruits and vegeta- measures (Matrix Reasoning, Peabody
used plain white plates (p<0.001), bles on their plates. In both instances, Picture Vocabulary Test–Third Edition,
said Drs Emily Melnick and Meng Li, the menus were the same each day. and Who Am I?) over time.
both from the Department of Health The strongest effect was seen in the Breastfed infants whose mothers con-
and Behavioural Sciences at the Uni- intervention group on the second day sumed alcohol were more likely to have
versity of Colorado Denver in Denver, when fruit was omitted from the menu reduced Matrix Reasoning scores at age
Colorado, US. This led them to con- and included cucumbers and carrots 6–7 years (B coefficient [B], -0.11, 95 per-
sume 7.54 grams more vegetables instead. cent confidence interval [CI], -0.18 to -0.04;
(p=0.001). These children also took The authors admitted that the sam- p=0.01). This association was not found in
more fruit (3.66 grams) and consumed ple size being small was one of the study women who had never breastfed (p=0.87).

“Alcohol exposure through breast cluded 19,009 Canadian women aged

milk was responsible for the findings. G 25–65 years who were randomized
What is more difficult to ascertain and to Pap liquid-based cytology (control
quantify, however, are the potential ef- Gynaecology group, n=9,457) or primary HPV test-
fects of other environmental and genetic ing (intervention group, n=9,552).
risks that can lead to these results,” said HPV testing could detect The primary outcome was the rate
Dr Lauren Jansson from the Johns Hop- cervical precancers earlier of CIN3+ at 48 months. Secondary
kins University in Baltimore, Maryland, than cytology endpoints included the 48-month rate
US, in a commentary. “The finding is not of CIN2+, the threshold for colposcopy
surprising when we consider the poten- Women who received primary human referral, and the effect of primary HPV
tial pharmacokinetic basis for it and the papillomavirus (HPV) test alone were testing on colposcopy.
known harmful effects of alcohol on the less likely to develop grade 3 or worse At 48 months, the rate of CIN3+
developing brain.” cervical intraepithelial neoplasia (CIN3+) was significantly lower in the interven-
at 48 months vs those who had Pap cy- tion group than in the control group (2.3
tology screen, a study has shown. vs. 5.5 per 1,000; risk ratio [RR], 0.42),
The 2-year risk of CIN2+ neo- with an absolute difference of 3.2 fewer
plasia was also reduced with the HPV cases per 1,000. Overall, both methods
test compared with Pap smear alone. detected about the same number of
“These suggest that primary HPV test- cases by 48 months.
ing detects cervical neoplasia earlier The greatest benefit was in HPV
and more accurately than cytology,” negative women at baseline; HPV in-
said Dr Ogilvie from the Universi- cidence rate was 1.4 per 1,000 by 48
ty of British Columbia in Vancouver, months vs 5.4 per 1,000 in the control
Canada. group. This translates to an RR of 0.25
The Human Papilloma Virus for or an absolute reduction of 4 cases per
Cervical Cancers Screening study in- 1,000 women.

She added that alcohol concentra-

tions in breast milk resemble those in
maternal blood within 30–60 minutes of
ingestion — about <5–6 percent of the
weight-adjusted maternal dose — and
newborns metabolize alcohol at approxi-
mately half the rate of adults. No link was
found for smoking during breastfeeding.
The researchers admitted that they
didn’t record the quantity of alcohol con-
sumed by the mothers nor the timing
of alcohol intake, which make for study
Gibson L and Porter M. Drinking or Smoking While
Breastfeeding and Later Cognition in Children. Pediatrics
2018;142(2):e20174266; Jansson LM. Maternal Alcohol Use
During Lactation and Child Development. Pediatrics 2018;

The intervention group was 61 per-

cent more likely to have a CIN2+ result
by 12 months (RR, 1.61), but 53 percent
less likely to have it at 48 months (RR,
“By 48 months, significantly fewer
CIN2+ cases were detected overall and
across all age groups in the intervention
group compared with the control group,”
the researchers said. At 48 months, the
CIN2+ rate was 5 per 1,000 vs 10.6 per
1,000 – a 53 percent reduced risk (RR,
0.47) and an absolute reduction of 5.6
cases per 1,000.
Again, the benefit accrued early
and mostly in women who were neg-
ative by HPV or cytology at baseline.
Among these, the CIN2+ risk for the
intervention, compared with the con-
trol group, was 64 percent lower (RR,
0.36), and the absolute difference in
incidence was 6.38 per 1,000. At the
end of the study, cumulative colposco- Researchers sought to compare women than in their mothers’ generation
py referral rates were similar between the prevalence of depression during (relative risk [RR], 1.51). Results didn’t
groups. pregnancy in young mothers today change when the analyses were restrict-
“The similarity in colposcopy rates and their mothers’ generation. Partic- ed to the 66 mother-child pairs. Mater-
shows that fears about overdiagnosis with ipants included the original mothers, nal prenatal depression was associated
HPV testing are unfounded,” said Ogilvie. who were recruited when they were with daughters’ prenatal depression
pregnant, and their female children, or (RR, 3.33).
Ogilvie GS et al. Effect of Screening With Primary Cervical
HPV Testing vs Cytology Testing on High-grade Cervical In- female partners of male children, who The finding persists even after ad-
traepithelial Neoplasia at 48 Months: The HPV FOCAL Rand-
became pregnant. Both groups were justing for factors that differ across gen-
omized Clinical Trial. JAMA 2018;320:43-52.
of the same age range (19–24 years). erations and in analyses restricted to
The first generation of pregnancies mother-child pairs.
occurred in 1990–1992 (n=2,390), As prenatal depression has major

O the second in 2012–2016 (n=1,80).

Both groups completed the Edin-
implications for service providers and
public health efforts, more research to
burgh Postnatal Depression Scale identify potential causes are needed,
Obstetrics (EPDS) – a 10-item self-report meas- said the study authors. The findings also
ure of depression – at 18 weeks of highlight the need for increased support
Prenatal depression pregnancy. to young pregnant women to minimize
increases over time Of pregnant women in the first the far-reaching effects of depression.
generation, 17 percent had high EPDS
Pearson RM, et al. Prevalence of Prenatal Depression Symp-
The prevalence of prenatal depression is scores (≥13) compared with 25 percent toms Among 2 Generations of Pregnant Mothers – The Avon
Longitudinal Study of Parents and Children. JAMA Network
higher today than in the 90s, according in the second generation. Having high Open 2018;doi:10.1001/jamanetworkopen.2018.0725.
to the Avon Longitudinal Study of Par- EPDS scores was more common in the
ents and Children study. second generation of young pregnant

Hypertension in Pregnancy
Roisin Ryan MB BCh BAO; Fergus McCarthy PhD MSc Dip MRCOG MRCPI

Hypertensive disorders of pregnancy remain a common complication of pregnancy

and a major cause of maternal and perinatal morbidity and mortality worldwide.
Hypertensive disorders range from mild gestational hypertension to early onset
pre-eclampsia which remains a leading cause of maternal death worldwide.
Although there have been major advances in understanding the pathophysiology
of the disease in recent years, interventions to screen for and prevent hypertensive
disorders of pregnancy have had disappointing results. Due to their unpredictable
nature and potential poor outcomes, patients with hypertensive disorders of
pregnancy warrant cautious care including consultant obstetric, neonatal, and
anaesthetic involvement to optimise both maternal and foetal outcomes.

INTRODUCTION classifies hypertension in pregnancy as

Hypertensive disorders of pregnancy are follows: chronic hypertension, gestational
frequently encountered complications of hypertension, pre-eclampsia de novo, or
pregnancy and have a number of possible superimposed on chronic hypertension;
aetiologies. The International Society for or white coat hypertension. In the United
the Study of Hypertension in Pregnancy Kingdom, the number of maternal deaths

Table 1. Risk Factors for Pre-eclampsia sure (BP) is 160/96 mm Hg. The woman informs
you that she wishes to have another child as she
is now in a new relationship. She also tells you that
Risk factor Unadjusted relative risk
she has heard about a test that she can take which
(95% confidence interval)
will tell you if she will get pre-eclampsia in this
Age ≥40 years, primiparous 1.68 (1.23–2.29)
pregnancy again and would like more information.
Age ≥40 years, multiparous 1.96 (1.34–2.87)
Family history 2.90 (1.70–4.93)
Risk factors and recurrence
Nulliparity 2.91 (1.28–6.61) This patient has multiple risk factors for recur-
Multiple pregnancy 2.93 (2.04–4.21) rence of pre-eclampsia. These include increased
Pre-existing diabetes 3.56 (2.54–4.99) maternal age, poorly controlled chronic hyper-
Pre-pregnancy body mass index ≥35 4.29 (3.52–5.49) tension, previous early onset pre-eclampsia (<34
Previous pre-eclampsia 7.19 (5.85–8.83) weeks’ gestation), raised BMI, family history of
Antiphospholipid syndrome 9.72 (4.34–21.75) pre-eclampsia, and new partner. Women with
severe pre-eclampsia, have an increased risk of
recurrence in their next pregnancy (about 1 in 6
[16%] pregnancies), but the disorder is generally
from hypertension in pregnancy has fallen steadily less severe and manifests 2–3 weeks later than in
over the past few decades, as well as the asso- the first pregnancy. This risk increases to about 1
ciated complication rates. However, hypertensive in 4 (25%) pregnancies if the pre-eclampsia was
disorders remain a major cause of maternal and complicated by severe pre-eclampsia, HELLP
perinatal morbidity and mortality and are respon- syndrome, or eclampsia and led to birth before 34
sible for 14% of total maternal deaths worldwide. weeks’ gestation. The risk of recurrence is about 1
Interventions to prevent hypertensive disor- in 2 (55%) pregnancies if the pre-eclampsia led to
ders in pregnancy, including pre-eclampsia, in the birth before 28 weeks’ gestation. Considering her
general antenatal population have been disap- increased age and poorly controlled BP, this risk
pointing, and the mainstay of treatment involves may be higher. Her risk of HELLP syndrome recur-
close antenatal supervision of mother and foetus ring is approximately 3–4%. Other risk factors for
and timely delivery to prevent deterioration of the pre-eclampsia are presented in Table 1.
condition and subsequent morbidity and mortality.
CASE 1: RISK AND RECURRENCE OF The patient should be counselled to avoid
PRE-ECLAMPSIA pregnancy until her BP is optimally controlled.
A patient is referred to you for pre-pregnancy coun- Given her age, this should be done in a time-
selling. She is 40 years old, smokes 20 cigarettes ly, efficient, and safe manner. A careful histo-
a day, and has been taking treatment (enalapril ry should be taken, and contact made with her
20 mg once daily) for hypertension for the past general practitioner to ensure all causes of sec-
2 years. This woman had one previous pregnan- ondary hypertension have been excluded and
cy 6 years ago which was complicated by severe the patient has been appropriately investigated
pre-eclampsia and HELLP (haemolysis, elevated (Table 2). Once a diagnosis of essential hyperten-
liver enzymes, and low platelets) syndrome result- sion is made, BP should be optimally managed.
ing in delivery by emergency caesarean section at As the women wishes to conceive, you may con-
27 weeks’ gestation. Her mother and two sisters all sider switching her to an alternative agent (see
had pregnancies complicated by pre-eclampsia. later section on management of hypertension)
On examination, her BMI is 38 and her blood pres- as enalapril, an angiotensin converting enzyme

Table 2. Causes of Secondary Chronic Hypertension and Key Diagnostic Tests

Idiopathic Essential hypertension Key diagnostic test/clinical clues

Vascular disorders Renovascular hypertension Renal ultrasound

Aortic coarctation Hypertension in upper limbs/diminished or delayed femoral pulses;

Endocrine disorders Diabetes mellitus Adrenergic symptoms (tremor, pallor, tachycardia, palpitations) and symptoms
of hypoglycaemia (fatigue, lethargy, headaches, drowsiness, coma); Glucose
tolerance test
Hyperthyroidism Anxiety, weakness, tremor, palpitations, heat intolerance, increased perspiration;
Thyroid function tests
Hypothyroidism Weight gain, lethargy; Thyroid function tests
Phaeochromocytoma Headache, palpitations, sweating: Measurement of 24-hour urine fractionated
catecholamines and metanephrines
Acromegaly Macrognathia, enlargement of hands and feet; Measurement of serum insulin-
like growth factor-1
Cushing’s syndrome Cushingoid facies, central obesity, proximal muscle weakness, and ecchymoses;
Initially measurement of ACTH
Primary hyperaldosteronism Hypokalaemia, metabolic alkalosis; measurement of plasma renin and
aldosterone concentrations
Renal disorders Renal failure resulting from:
Diabetic nephropathy
Reflux nephropathy History of urinary tract infections
Chronic glomerulonephritis
Nephritic and nephrotic Nephrotic syndrome: heavy proteinuria (>3.5 g/day). Nephritic syndrome:
syndrome variable degrees of proteinuria with the presence of red cells and/or white
blood cells
Polycystic kidney Family history
Connective tissue Systemic lupus erythematosus Malar rash, photosensitivity, discoid rash, oral ulcers, arthritis; raised protein
disorders creatinine ratio, presence of Anti-dsDNA, Anti-Sm, and/or ANA
Systemic sclerosis Skin thickening; anti-topoisomerase I (anti-Scl-70), anti-centromere, and anti-
RNA polymerase III antibodies
Polyarteritis nodosa General symptoms such as fatigue, weight loss, weakness, fever, arthralgia,
or skin lesions. Systemic signs such as hypertension, renal insufficiency, or
neurologic dysfunction
Rheumatoid disease Inflamed painful joints; rheumatoid factor

(ACE) inhibitor is contraindicated in pregnancy smoking cessation, and pre-conceptual folic acid
due to teratogenesis (increased risk of cardio- should also be given.
vascular and neurological malformations if used
in the first trimester). As the patient is high risk Prediction of pre-eclampsia
for recurrence of pre-eclampsia, low-dose aspirin In terms of prediction, women can be catego-
should be commenced once conception occurs. rised as high risk (as this woman is) and low
General obstetric advice such as weight loss, risk. She should be reassured that she will be

followed closely during pregnancy to monitor Chronic hypertension

for signs of pre-eclampsia, but that there is Chronic hypertension is defined as hypertension
no test which reliably predicts pre-eclampsia. preceding pregnancy. BP falls in the first and
A combination of maternal risk factors, Pla- second trimesters. Therefore, women, such as
cental Growth Factor, and uterine artery Dop- in this case, with high BP before the 20th week
pler may identify women who would benefit of pregnancy, are assumed to have pre-existing
from treatment with aspirin to prevent pre- or essential hypertension. As many women of
term pre-eclampsia as shown recently in the reproductive age present for BP measurement
ASPRE study, but this screening approach for the first time when pregnant, chronic hyper-
has not yet been universally accepted or tension is often revealed in the first half of preg-
implemented. nancy. Approximately 90–95% of cases of chron-
ic hypertension are considered to be essential.
CASE 2: CHRONIC HYPERTENSION/ Secondary causes which account for approx-
PREGNANCY-INDUCED HYPERTENSION imately 5–10% are listed in Table 2. In women
A 35-year-old woman attends your antenatal clin- presenting with hypertension in the first half of
ic at 12 weeks’ gestation in her first pregnancy. pregnancy, it is important to look for an under-
She has a BMI of 22 and is a non-smoker. Her lying cause. These investigations should at least
BP is 150/95 mmHg. She is non-proteinuric and include:
asymptomatic. • 
Urine analysis and protein creatinine ratio
(looking for blood, protein, or glucose and
Diagnosis of hypertension quantification of the degree of proteinuria)
in pregnancy • Urea and electrolytes
Pre-eclampsia is associated with significant ma- • Renal tract ultrasound
ternal and perinatal morbidity and mortality. As Women with underlying renal disease, par-
such, it is imperative that every effort is made ticularly with raised pre-pregnancy creatinine,
to accurately classify women with hypertension are at significantly increased risk of poor preg-
in pregnancy as having chronic hypertension, nancy outcome and require multidisciplinary
non-proteinuric PIH, or pre-eclampsia as the ae- care.
tiology and management of the three conditions
is very different. Gestational hypertension
Gestational hypertension is a rise in the BP
Measurement of blood pressure in the absence of proteinuria after 20 weeks’
BP should be measured with the woman rested gestation. True non-proteinuric pregnancy in-
and seated at a 45-degree angle with the arm at duced hypertension does not appear to be
the level of the heart. It is imperative that an ap- associated with an increase in maternal or foe-
propriately sized cuff is used. To avoid incorrect tal morbidity. However, the risk of progression
measurement of BP, if the mid-arm circumfer- from gestational hypertension to pre-eclamp-
ence is greater than 33 cm, a large cuff should sia is approximately 20–30%, and therefore
be used. Korotkoff phase 1 is used to measure vigilance is required. This rate increases to
systolic BP and Korotkoff 5 is appropriate for approximately 50% when gestational hyper-
measurement of diastolic BP, as it is most con- tension develops before 32 weeks’ gestation.
sistent in pregnancy. The method used to re- As a result of this risk of progression to pre-ec-
cord BP should be consistent and documented, lampsia, weekly urinalysis and BP checks are
and a machine validated for use in pregnancy generally recommended in women with gesta-
such as Microlife® should be used. tional hypertension.

Box 1. Management of Hypertension in Pregnancy

• Screening
š Women should be screened for signs of hypertension using BP checks and urinalysis monthly until 30 weeks’ gestation, fortnightly from
30 weeks’ gestation and weekly from 36 weeks’ gestation.
š If elevated BP ± proteinuria, refer for admission or monitoring in antenatal day unit.
• Maternal assessment
š Repeat (at least 4 hourly) BP measurement.
š Quantitative measurement of protein in urine. (Pre-eclampsia = >0.3 g protein 24-hour urine collection).
š Platelet count, serum uric acid concentration, and tests of liver function (alanine and aspartate aminotransferase levels). Coagulation
screen if altered liver function.
• Antihypertensive therapy
š Consider admission, monitor closely, and treat if blood pressure is persistently above 160/100 mm Hg. Aim for target diastolic BP 85
mm Hg.
• Anticonvulsant therapy
š If convulsions occur, use magnesium sulphate, intravenously or intramuscularly.
š In cases of severe pre-eclampsia, consider prophylactic magnesium sulphate.
• Foetal management
š Give prophylactic steroids if the duration of gestation is less than 34 weeks’ gestation.
š Perform an ultrasound assessment of foetal weight on initial presentation and repeat fortnightly.
š Doppler ultrasonographic assessment of umbilical blood-flow velocity if evidence of growth restriction.
š Regular cardiotocography (CTG/non-stress tests).
š Ultrasonography at least twice a week for liquor volume.
š Multidisciplinary approach regarding timing and mode of delivery.
• Post-partum care
š Continued close monitoring of the mother by experienced carers.
š If on magnesium therapy, continue for at least 24-hour post-partum until stable.
š Careful fluid balance (total 80 mls/hour intake) and early use of diuretics if pulmonary oedema secondary to fluid overload is
š Decrease dose of antihypertensive agents as indicated. Avoid sudden cessation immediately post-partum as rebound hypertension
• Follow-up
š Long-term follow-up to make sure that the BP falls (within 6 weeks post-partum), and suitable referral if it does not.
š Discussion about the illness and the significance for the future.
š Recommend pre-conceptual counselling for future pregnancies.

Treatment of hypertension to either “less tight” control (aiming for diastolic

in pregnancy (Box 1) BP of 100 mm Hg) or “tight” control (aiming for
The use of antihypertensive drugs in hyperten- diastolic BP of 85 mm Hg) of their hypertension.
sive women without renal impairment is con- The trial demonstrated that women in “less tight”
sidered by some to be beneficial in preventing compared with “tight” control groups had similar
sudden increases in BP, cerebral haemorrhage, rates of adverse perinatal (31.4% vs 30.7%) and
or hypertensive encephalopathy. The Control of maternal outcomes (3.7% vs 2.0%), despite high-
Hypertension in Pregnancy Study (CHIPS) was er mean diastolic BP by 4.6 mm Hg. However, se-
a randomised controlled trial in which women vere hypertension (≥160/110 mm Hg) developed
with hypertension in pregnancy were randomised more frequently in “less tight” vs “tight” control

pathetic discharge that increases the periph-

eral vascular resistance via α-adrenoceptors.
Blocking the ß-adrenoceptors alone cannot
prevent this compensatory response, but the
addition of an α-adrenoceptor blocker can. It
is this action that renders labetalol suitable for
gaining quick control of the BP. Labetalol, like
all ß-adrenoceptors, is contraindicated in wom-
en with a history of asthma.
• Nifedipine is a calcium channel blocker used
in the treatment of chronic hypertension in
pregnancy. Data suggest that it is safe, but cu-
mulative evidence is not as extensive as with
older drugs such as labetalol and methyldo-
pa. The principal side effect is headache,
which can be severe, may last for several days
after commencing treatment and may return
after increasing the dose. Use of the long-act-
ing once-daily preparation improves compli-
ance. Nifedipine is a potent antihypertensive
A systolic BP greater than 160 mm Hg should be considered a medical emergency
agent but should not be given sublingually as
and quick effective treatment is advocated to prevent haemorrhagic stroke.
it may cause a precipitate fall in BP, which can
lead to foetal distress. The concomitant use of
(40.6% vs. 27.5%). As a result, tight control of BP nifedipine and magnesium sulphate must be
is advocated to prevent potential adverse mater- with caution due to potential risk of serious ad-
nal outcomes. verse maternal effects such as hypotension.
Both CMACE and NICE Clinical Guidelines α-Methyldopa (a centrally acting α-adrenergic
on Hypertension in Pregnancy recommend that all agonist that inhibits vasoconstricting impulses
pregnant women with a systolic BP of 150 mm Hg from the medulla oblongata) has traditionally
or more require antihypertensive treatment. Consid- been the most commonly used agent for the
eration should also be given to initialising treatment control of BP during pregnancy, particularly in
at lower pressures if the overall clinical picture sug- those with chronic hypertension. Its safety has
gests rapid deterioration and/or where the develop- been well established both in pregnancy and
ment of severe hypertension can be anticipated. in the long-term follow-up of the infants. One
A systolic BP greater than 160 mm Hg should of the most frequent side effects is sedation,
be considered a medical emergency and quick ef- which can be profound. This is often poorly tol-
fective treatment is advocated to prevent haemor- erated and leads to unpredictable compliance.
rhagic stroke. However, α-methyldopa remains the preferred
Antihypertensive agents which may be used agent of the National High Blood Pressure Ed-
in pregnancy include: ucation Programme.
• Labetalol; a combined ß-adrenoceptor block- ACE inhibitors and angiotensin receptor
er that also blocks α-adrenoceptors. Ordinary blockers (ARBs) and diuretics should be avoided
ß-adrenoceptor blockers are unsuitable for pro- in pregnancy. Diuretics may reduce uteroplacental
ducing a quick antihypertensive effect because perfusion. Second- and third-trimester exposure to
a quick fall in BP triggers a compensatory sym- ACE inhibitors appears to be fetotoxic, producing

foetal hypocalvaria, and renal defects. The cause renal insufficiency (creatinine <90 μmol/L),
of these defects seems to be related to foetal hy- liver involvement (elevated liver transaminas-
potension and reduced renal blood flow. Anuria as- es of at least twice upper value of normal),
sociated with oligohydramnios can produce foetal neurological complications, and haematologi-
limb contractures, craniofacial deformations, and cal complications (eg, thrombocytopenia with
pulmonary hypoplasia. Intrauterine growth restric- platelet count below 150 x 109/L).
tion, prematurity, persistence of a patent ductus • Uteroplacental dysfunction; foetal growth re-
arteriosus, severe neonatal hypotension, neonatal striction.
anuria, and neonatal or foetal death have all been Pre-eclampsia is a potentially life-threatening
observed with use of these drugs, and they should hypertensive disorder of pregnancy characterized
therefore be discontinued pre-conceptually or as by vascular dysfunction and systemic inflamma-
early in the first trimester as possible. tion involving the brain, liver, and kidneys of the
Angiotensin receptor blockers are newer mother. In developed countries, the incidence of
agents that have not been formally studied in pre-eclampsia has risen in the United States of
pregnancy, they are probably best avoided given America, but maternal mortality from pre-eclamp-
their common pathway with ACE inhibitors. sia has decreased significantly in the UK in recent
decades at a rate of 0.13 per 100,000 maternities
CASE 3: MANAGEMENT OF in the 2017 MBRACCE report.
PRE-ECLAMPSIA It usually occurs during the second half of
A woman attends the emergency room complain- pregnancy and complicates approximately 5% of
ing of headaches and epigastric pain. She is at 34 first time pregnancies and 2–3% of pregnancies
weeks’ gestation in her first pregnancy. Her blood overall.
pressure was mildly elevated (140/90 mm Hg) at her
28- and 31-week antenatal visits during this preg- Pathophysiology of pre-eclampsia
nancy, but she was asymptomatic, did not have Pre-eclampsia results from impaired trophoblast
proteinuria, her liver function tests were normal, and differentiation and invasion in early pregnancy re-
her BP settled on repeated measurements. On ex- sulting in the failure of trophoblast cells to destroy
amination she has 3+ protein on urine dipstick and the muscularis layer of the spiral arterioles result-
her BP on four occasions over a 2-hour period rang- ing in the development of a poorly perfused pla-
es from 160–172/90–102 mm Hg. She complains of centa and stimulation of a systemic inflammatory
reduced foetal movements and reports some response. However, this reduced placental perfu-
unprovoked bleeding from her vagina. sion alone is not sufficient to cause the maternal
syndrome of pre-eclampsia, and it is thought that
Pre-eclampsia this process requires the influence of additional
Pre-eclampsia is defined by the International So- maternal factors including genetic make-up and
ciety for the Study of Hypertension in Pregnancy environmental factors (such as obesity and diet),
as gestational hypertension of at least 140/90 mm which together results in widespread endothelial
Hg on two separate occasions measured at least dysfunction and hypertension.
4 hours apart accompanied by one or more of the
following: Management of pre-eclampsia
• Significant proteinuria of at least 300 mg in a Ideally women at high risk of pre-eclampsia
24-hour collection of urine or protein creati- should be reviewed pre-conceptually and advised
nine ratio of ≥30 mg/mmoL on a spot urine or to take 75 mg of aspirin daily from 12 weeks’ ges-
at least 1 g/L (2+ on urine dipstick). tation until delivery. Table 1 highlights risk factors
Other maternal organ dysfunction including for the development of pre-eclampsia.

Table 3. Investigations and Monitoring of Pre-eclampsia

Laboratory tests Full blood count Elevated haematocrit, thrombocytopenia

Uric acid Sensitive, but only of clinical importance if levels are extremely high or increasing
Urea and electrolytes
Liver function tests Alanine transaminase (ALT), aspartate transaminase (AST) will be elevated in
Coagulation screen Prothrombin time (PT), activated partial thromboplastin time (APTT), prolonged in
HELLP. Only required if platelet count is abnormal
Urinalysis 1+ = 0.3 g/L, 2+ = 1 g/L, and 3+ = 3 g/L
24-hour urine collection >0.3 g protein excretion
Protein creatinine ratio 30 mg/mmoL correlates with 0.3 g in the 24-hour collection
Ultrasound Foetal weight Perform at time of diagnosis and 4 weekly thereafter, subject to clinical
Serial growth scans condition
Amniotic fluid index
Umbilical artery
Doppler velocimetry

Investigations and monitoring of the suspect- come including progression to pre-eclampsia.

ed pre-eclamptic patient are listed in Table 3. The Furthermore, no differences were observed
pre-eclampsia integrated estimate of risk (PIERS) in neonatal outcomes or caesarean section
multivariable risk model uses gestational age, rates.
chest pain or dyspnoea, oxygen saturation, plate- Patients with pregnancy induced hyperten-
let level, creatinine, and aspartate transaminase. It sion may be monitored through a combination of
aims to predict the risk of adverse maternal out- general practitioners and hospital day care units.
comes in the first 48 hours of hospital admissions. Severe pre-eclampsia necessitates inpatient care
The pharmacological treatment of pre-ec- with a close monitoring of the symptoms, signs,
lampsia focuses on controlling maternal hyper- and biochemical parameters. “Severe” pre-ec-
tension. No drugs in current clinical use benefi- lampsia is difficult to define, however, the follow-
cially affect the human placenta. As a result, ing features generally indicate the development of
management involves treatment of maternal severe pre-eclampsia.
hypertension and close antenatal supervision • Eclampsia
of the mother and foetus with timely delivery to • Severe hypertension eg, a systolic BP over
prevent deterioration of the mother and foetus. 160 mm Hg with at least 2+ proteinuria
Pre-eclampsia can occasionally be managed • 
Moderate hypertension associated with any
conservatively. Maternal and foetal monitoring of severe headache with visual disturbance,
should continue until foetal maturity has been epigastric pain, signs of clonus, liver tender-
achieved, at which stage the cervix is assessed ness, platelet count falling to below 100 x
with Bishops scoring and, if favourable, induc- 109/L, creatinine >100 mmol/L, and alanine
tion of labour is carried out. As a result of the aminotransferase rising to above 50 IU/L
HYPITAT trial, delivery is generally advocated In extreme prematurity, transfer to hospi-
by 37 weeks’ gestation. This is associated with tal with adequate neonatal facilities (with steroid
a significant reduction in adverse maternal out- administration to enhance lung maturity) is indi-

cated. Severe pre-eclampsia presenting prior to Box 2. Key Points in the Management of the Severe Pre-eclamptic Patient
foetal viability is an indication for termination of
pregnancy due to the risk of maternal death. • Insert an indwelling catheter and measure hourly urine output until stable.
The optimum time of delivery is of crucial • Record blood pressure and pulse every 15 minutes until stable and then half
importance and remains a balance between hourly.
the risks of major complications to the mother
• Oxygen saturation should be measured continuously and charted with the
and intrauterine growth restriction in the foetus BP. If saturation falls below 95% then medical review is essential to rule out
against the risks of delivery and prematurity to pulmonary oedema and other complications.
the foetus. The mode of delivery is a balance • Strict fluid balance should be recorded with detailed input and output
between caesarean section and vaginal delivery. measurements.
Caesarean section is a better option for rapid
• Respiratory rate should be measured hourly. A reducing respiratory rate may
deteriorating maternal and foetal condition, or indicate magnesium toxicity.
alternatively for those remote from term with an
• Temperature should be measured four hourly.
unfavourable cervix. Epidural analgesia may be
When present, central venous pressure and arterial lines should be
beneficial by preventing the increase of catecho-
measured continuously and charted with the BP.
lamine release, in order to prevent further eleva-
tions of BP during uterine contractions. It may • Neurological assessment should be performed hourly using either the Alert,
Voice, Pain, Unresponsive system, or Glasgow Coma Scale.
also allow a more controlled second stage.
Oral antihypertensive are discussed above. • Foetal wellbeing should be monitored using a cardiotocography.
In severe pre-eclampsia, there are two antihyper- • 
Blood tests should be repeated at least every 12 hours whilst on the
tensive regimens to choose from: magnesium sulphate protocol. In the event of complications, such as
• Labetalol (200 mg) can be given orally prior haemorrhage or abnormal or deteriorating haematological, and/or biochemical
parameters, more frequent blood tests should be taken eg, every 4–8 hours.
to or in the absence of intravenous access,
and if there is no response within 30 minutes,
a second oral dose can be given. If there is
no initial response to oral therapy or if it is In pre-eclampsia, magnesium sulphate is in-
not tolerated, a bolus of 50 mg given intra- dicated as the first-line anticonvulsant. Formal clin-
venously over at least 5 minutes can be ad- ical review should occur every 4 hours, observing
ministrated, repeated to a maximum of 200 for side effects (motor paralysis, absent reflexes,
mg, at 10 minutes intervals. Following this, respiratory depression, and cardiac arrhythmia).
or as treatment for moderate hypertension, a The antidote is 10 mL of 10% calcium gluconate
labetalol infusion can be commenced (5 mg/ given slowly intravenously. About 97% of the mag-
mL at 4 mL/hour via a syringe pump, the infu- nesium sulphate is excreted in the urine. Oligu-
sion rate being doubled every 30 minutes to a ria (<80 mL/24 hours) can thus lead to toxicity.
maximum of 32 mL [160 mg]/hour until the BP Therefore, in the presence of oliguria, magne-
has dropped and stabilised at an acceptable sium sulphate should be reduced or withheld. If
level). Labetalol is contraindicated in women magnesium is not excreted, levels should not fall.
with asthma and should be used with caution Box 2 highlights key management steps in the
in cardiac disease. treatment of patients with severe pre-eclampsia.
• Hydralazine is given by bolus infusion (10–20
mg over 10–20 minutes measuring the BP CASE 4: MANAGEMENT OF
every 5 minutes). This may be followed by an ECLAMPSIA
infusion (40 mg hydralazine in 40 mL normal You receive an urgent call to attend the emergen-
saline, which should run at 1–5 mL/hour [1–5 cy room. A patient has just arrived unbooked.
mg/hour]). Her husband tells you she is roughly 7 months

Box 3. Diagnostic Criteria Used for Eclampsia the past day. He reports that she started shaking
1 hour ago and became unresponsive. On ex-
• Any woman with convulsion(s) during pregnancy or in the first 10 days of amination, BP is 200/140 mm Hg and the patient
post-partum, together with at least two of the following features within 24 is rigid, with a Glasgow Coma Scale score of 5.
hours of the convulsion(s).
• Hypertension (a booking diastolic pressure of <90 mm Hg, a maximum
diastolic of ≥90 mm Hg, and a diastolic increment of ≥25 mm Hg).
Eclampsia refers to the occurrence of one or
• Proteinuria (at least + protein in a random urine sample or ≥0.3 g in a 24-hour
more generalized convulsions and/or coma
in the setting of pre-eclampsia and in the ab-
• Thrombocytopenia (platelet count of less than 100 x 109/L).
sence of other neurological conditions. The UK
• Raised plasma alanine aminotransferase concentration (≥42 IU/L) or an Obstetric Surveillance System (UKOSS) report
increased plasma aspartate aminotransferase concentration (≥42 IU/L).
gives an estimated incidence of 27.5 cases per
100,000 maternities with a case fatality rate es-
timated to be 3.1%. This was almost a halving
of the incidence of eclampsia since 1992. Ec-
Practice Points lampsia is associated with significant maternal
morbidity, in particular cerebrovascular events
• Automated BP devices may underestimate the BP in pregnancy and (2.3%) which are now the major cause of death
therefore caution should be exercised in their use. If used, machines (previously this was pulmonary oedema). The
validated for use in pregnancy should be utilised.
benefit of magnesium sulphate in the prevention
An appropriately sized BP cuff should be used. If the mid-arm
of eclampsia has been well demonstrated and
circumference is >33 cm, a large cuff should be used.
magnesium sulphate has been shown to halve
Labetalol remains the antihypertensive of choice. Methyldopa and
nifedipine may be used as second- or third-line agents. the risk of eclampsia among women with pre-ec-
lampsia. Box 3 indicates the diagnostic criteria
• Systolic BPs over 150 mm Hg should be treated.
for eclampsia. Cerebral haemorrhage has been
• Anaesthetists should anticipate an additional rise in BP at intubation
in women with severe pre-eclampsia who are undergoing caesarean reported to be the most common cause of death
section under general anaesthesia and take measures to avoid a speed in patients with eclampsia and stroke is known
that compromises maternal wellbeing, even when there are concerns
to be the most common cause of death (45%) in
about foetal wellbeing.
women with HELLP syndrome.
• If the platelet count is <20 x 109/L, a platelet transfusion is recommended
prior to caesarean section or vaginal delivery.
The management of this woman will focus
initially on resuscitation, and assessment of foetal
• A patient with pre-eclampsia should be fluid restricted to ≤80 mls total
fluid/hour until a natural diuresis occurs following delivery. viability. A multidisciplinary team will be required,
with anaesthetic, perinatal, haematological, and
• Syntometrine should not be given for the active management of the third
stage if the mother is hypertensive, or her blood pressure has not been consultant obstetric input. An ABC approach
checked. should be followed in this case, followed by load-
• Postpartum, women should be counselled appropriately regarding their ing with magnesium sulphate, a magnesium sul-
risk of recurrence of pre-eclampsia, as well as their increased risk of
phate infusion, stabilisation, and delivery.
developing cardiovascular and renal disease.


A patient presents for post-natal follow-up. She
pregnant in her first pregnancy. She has just ar- tells you that she was delivered at 34 weeks’ ges-
rived in the United Kingdom and is seeking asy- tation, 8 weeks ago for severe pre-eclampsia. She
lum from Congo. Her husband tells you she has required magnesium sulphate for 24 hours follow-
been unwell over the past 3 days and has com- ing delivery but did not have a seizure. She was
plained of epigastric pain and blurred vision for discharged on 200 mg labetalol twice daily.

Post-partum management of development of cardiovascular disease, renal

hypertension in pregnancy disease, and cardiovascular risk factors for sev-
BP rises progressively over the first five post-na- eral years following pregnancy and regular BP
tal days, peaking on days three to six after deliv- checks with their general practitioner should be
ery. Research has focused on the antenatal com- recommended.
plications, for both mother and baby, and the
risks and benefits of administering antihyperten- CONCLUSION
sive therapy prior to delivery. There is very little Hypertensive disorders are one of the common-
information on how best to manage post-partum est complications of pregnancy and may be
hypertension, regardless of type or severity, to associated with significant maternal and foetal
optimize maternal safety and minimize hospital morbidity and mortality. Although the aetiology
stay. Women with post-partum hypertension may of these disorders is becoming increasingly bet-
also experience longer hospital stays and pos- ter understood, interventions to prevent hyper-
sibly, heightened anxiety about their recovery. tensive disorders of pregnancy have had poor
NICE recommendations for post-natal care of results. The mainstay of treatment remains the
women with hypertension in pregnancy include use of antihypertensive medications, the use of
stopping methyldopa within 2 days of birth and magnesium sulphate in the prevention of ec-
asking the woman about severe headache and lampsia, and multidisciplinary input to ensure a
epigastric pain every time BP is measured. In timely delivery.
cases of mild or moderate pre-eclampsia plate-
let count, transaminases and serum creatinine FURTHER READING
1. Abalos E, Duley L, Steyn DW. Antihypertensive drug therapy for mild
should be measured 48–72 hours after birth or to moderate hypertension during pregnancy. Cochrane Database Syst
Rev, 2007; CD002252.
step-down. These do not need to be repeated if 2. Hypertension in pregnancy. The management of hypertensive disor-
ders during pregnancy. August 2010. National Institute for Health and
results are normal. In most cases of gestational Clinical Excellence,
3. Knight M. Eclampsia in the United Kingdom 2005. BJOG 2007;
hypertension and pre-eclampsia, there is a rapid 114:1072–8.
4. Koopmans CM, Bijlenga D, Groen H, et al. Hypitat study group. Induc-
and complete resolution within 6 weeks of de- tion of labour versus expectant monitoring for gestational hypertension
or mild pre-eclampsia after 36 weeks’ gestation (HYPITAT): a multicen-
livery of the foetus. Patients requiring antihyper- tre, open-label randomised controlled trial. Lancet 2009 Sep 19; 374:
tensive agents should be weaned off slowly and 5. Magee LA, vonDadelszen P, Rey E, et al. Less-tight versus tight control
of hypertension in pregnancy. N Engl J Med 2015 Jan 29; 372: 407–17.
medications should not be stopped suddenly as 6. Milne F, Redman C, Walker J, et al. The pre-eclampsia community
guideline (PRECOG): how to screen for and detect onset of pre-ec-
there may often be a rebound hypertension. lampsia in the community. BMJ 2005 Mar 12; 330: 576–80.
7. Rolnik DL, Wright D, Poon LC, et al. Aspirin versus placebo in pregnan-
cies at high risk for preterm preeclampsia. N Engl J Med 2017 Aug 17;
377: 613–22. Epub 2017 Jun
Long-term risks 28. PMID: 28657417.
8. The classification, diagnosis and management of the hypertensive dis-
Pre-eclampsia also carries implications in adult orders of pregnancy: a revised statement from the ISSHP Pregnancy
Hypertension. Int J Women’s Cardiovasc Health 2014; 4: 97–104. avail-
life, with offspring of affected pre-eclamptic preg- able at: 08/Revised-state-
nancies demonstrating poor growth in childhood, 9. von Dadelszen P, Payne B, Li J, et al. PIERS Study Group. Prediction of
adverse maternal outcomes in pre-eclampsia: development and valida-
and an increased risk of hypertension, heart dis- tion of the fullPIERS model. Lancet 2011 Jan 15; 377: 219–27.

ease, and diabetes. Women with pre-eclampsia © 2018 Elsevier Ltd. All rights reserved. Initially published in Obstetrics,
Gynaecology and Reproductive Medicine 2018;28(5):141–147.
have a 3.7 times higher risk of later hypertension,
a 2.2 times increased risk of coronary heart dis- About the authors
Roisin Ryan is a master’s student at the London School of Hygiene and
ease, and a 1.8 times higher risk of stroke. Tropical Medicine and a trainee in Obstetrics and Gynaecology, Ireland.
All women who have had pre-eclamp- Conflict of interest: none declared.

sia should be offered a medical review at the Fergus McCarthy is a Senior Lecturer at The Irish Centre for Fetal and Ne-
onatal Translational Research, University College Cork, Consultant in Ob-
postnatal review (6–8 weeks) after the birth. stetrics and Gynaecology, Maternal Fetal Medicine Subspecialist at Cork
University Maternity Hospital, Cork, Ireland, and Honorary Clinical Lectur-
Women who have had pre-eclampsia should
er, Department of Women and Children’s Health, School of Life Course
be educated regarding their increased risk of Sciences, King’s College London, UK. Conflict of interest: none declared.

How can Your Microbiologist

Help you Manage Paediatric
Ciara O’Connor B. Ed MB MRCPI MRCPUK MD FRCPath; Richard J Drew MB FRCPI FRCPath DipHIC MD PGDip PID (Oxon)

The presentation of a child to hospital with an acute illness is distressing for the child
and his/her parents or carers. The clinical aim of the admitting paediatric team is to
identify the cause of the illness, to treat it effectively, and to discharge the child home
quickly and safely. Multidisciplinary care between the paediatric and the clinical mi-
crobiology team, who oversee and support the laboratory work of skilled scientists,
is essential to manage paediatric infection. In this review, we will focus on current
diagnostic methods for common paediatric microbiology consultations, with a focus
on newer molecular technology to reduce laboratory turnaround time and discuss
the emergence of multidrug resistant organisms that are impacting on antimicrobial
prescribing practices. We will also highlight useful infection prevention and control
advice that will be beneficial to the on-call paediatrician.

INTRODUCTION that either colonise that site or can read-

In approaching any child with a potential- ily gain access to the site to cause infec-
ly infectious illness, it is worth considering tion, and what are the optimal specimens
the following: (1) what is the likely source to send and can molecular technology
of infection, what are the usual organisms such polymerase chain reaction (PCR)

Table 1. Classification of Common Organisms Causing Paediatric Diseases

Organisms detected via Gram stain

Typical shape of the organism when Gram stained and viewed under the microscope
Coccus Bacillus Coccobacillus Vibrio
(sphere shaped) (rod shaped) (variable (curved rod/
appearance) comma-shaped)
Gram-positive Staphylococcus spp. Nocardia spp.
Streptococcus spp.a Bacillus spp.
Enterococcus spp. Clostridium spp.
Micrococcus spp. Listeria spp.
Corynebacteria spp.
Gram-negative Kingella spp. Pseudomonas spp. Haemophilus influenzae Vibrio spp.
Neisseria spp. Bordatella spp.
Moraxella spp. Legionella spp.
Stenotrophomonas spp.
Pasteurella spp.
Capnocytophagus spp.
Bacteroides spp.
Fusobacterium spp.
Acinetobacter spp.
Shigella spp.
Campylobacter spp.
Helicobacter pylori
Salmonella spp.
Citrobacter spp.
Enterobacter spp.
Klebsiella spp.
Escherichia coli
Organisms not detected using Gram stain method. If suspect infection due to microorganisms listed below, contact the clinical microbiology
team to discuss local methods of diagnostic testing performed. Samples may be referred to a reference laboratory.
Spirochaetes Treponema spp.
Leptospira spp.
Borrelia spp.
Non-culturable as no cell wall Mycoplasma spp.
Obligate intracellular pathogens Rickettsia spp.
Chlamydia spp.
Coxiella spp.
Special staining process Mycobacteria spp.
performed to detect presence of
acid fast bacilli (AFB)
Streptococcus spp. can be classified by their appearance on blood agar after overnight incubation. A greenish appearance on the blood agar plate signifies the presence of
α-haemolytic Streptococcus spp., usually S. pneumoniae or a member of the viridans group, which encapsulates a broad range of Streptococci including S. oralis, S. sanguis,
S. mutans, and S. mitis, which are commensals of the oral cavity and upper respiratory tract. A clear zone of complete haemolysis on the blood agar plate around visible
colonies after an overnight incubation demonstrates the presence of ß-haemolytic Streptococcus spp., which includes Groups A, B, C, G Streptococci.

Table 2. Topical Antimicrobials carers. Occasionally, conjunctivitis may occur in

association with infection of the cornea (keratocon-
junctivitis) or eyelid (blepharoconjunctivitis). The
Antimicrobial name Organisms covered (in the absence of resistance
mechanisms) most common causes of bacterial conjunctivitis are
Topical antiviral Staphylococcus aureus, Streptococcus pneumo-
Aciclovir Herpes simplex virus niae, and Haemophilus influenzae, while the most
Varicella zoster virus common causes of viral conjunctivitis are adenovi-
Topical antibacterials ruses, herpes simplex virus (HSV)-1/-2, and varicel-
Chloramphenicol a
Most Gram-positive organisms la zoster virus (VZV). Neisseria gonorrhoea, Haemo-
Most Gram-negative organisms but no cover for philus parainfluenzae, and Group B Streptococcus
Pseudomonas spp. (GBS) can cause infection in the neonatal period.
Fusidic acid Staphylococcus aureus When conjunctivitis is suspected, eye swabs should
Also has streptococcal activity
be sent for culture and/or viral PCR analysis. Orbital
Most frequently prescribed topical antimicrobial for superficial eye infections as the majority cellulitis is an infection of the orbital tissue that can
are caused by Staphylococcus aureus.
occur secondary to trauma, surgery, or following
the spread of infection from the paranasal sinuses.
The most common causes of orbital cellulitis are S.
be utilised; (2) does the child have any past micro- aureus, anaerobes, and various streptococci. Eye
biology results and/or is the child colonised with swabs are of limited value in the investigation of or-
a multidrug resistant organism (MDRO) that may bital cellulitis. Intra-operative aspirates from infect-
limit prescribing practices; (3) is the child poten- ed tissues should be sent to the laboratory. Table
tially harbouring a transmissible organism and if so 2 shows the spectrum of cover of commonly pre-
what infection prevention and control precautions scribed topical ophthalmic antimicrobials.
do I need to implement pending confirmation; (4)
is prophylaxis needed for parents/carers or staff The brain and spine
who have come into contact with this child; and (5) Encephalitis is an inflammatory process in the
is a vaccination or vaccination booster required. brain accompanied by cerebral dysfunction man-
ifesting as an altered level of consciousness. Sei-
INTERPRETING PRELIMINARY zures are common. Encephalitis is predominantly
MICROBIOLOGY RESULTS caused by viruses including VZV, Ebstein Barr virus
Paediatric trainees are often phoned with prelim- (EBV), cytomegalovirus (CMV), HSV-1/-2, and en-
inary results from the microbiology laboratory teroviruses. Meningitis is defined as inflammation
describing a Gram stain result. Table 1 is a refer- of the meninges. From neonates to babies up to
ence guide for the common organisms that cause 2 months of age, GBS, Escherichia coli, Listeria
paediatric infections, divided into Gram-positive monocytogenes, and N. meningitidis are com-
and Gram-negative organisms and those that are monly isolated. In older children, viral meningitis
identified by alternative methods. is more common than bacterial meningitis. Other
bacterial causes of meningitis include S. pneumo-
COMMON PAEDIATRIC niae, N. meningitidis, and H. influenzae type b (Hib),
MICROBIOLOGY CONSULTATIONS in unvaccinated children. In taking the child’s his-
tory, it is essential to discuss potential risk factors
The eye for meningitis including the previous diagnosis of
Conjunctivitis is an inflammation of the conjunc- a cerebral tumour, the presence of cerebrospinal
tiva of either one or both eyes and is frequently fluid (CSF) shunts or cochlear implants, whether
described as “red or sticky eyes” by parents or the child has a meningomyelocele or other spinal

congenital malformations, and preceding infec- Otitis media is defined by the coexistence of fluid in
tions of contiguous sites such as the orbit, para- the middle ear and signs and symptoms of acute
nasal sinuses, middle ear cavity, or recent trauma illness. It occurs when oropharyngeal flora ascends
such as a basilar skull fracture. Chronic meningitis the eustachian tube. Typical causative organisms
is defined by the continued signs and symptoms of include S. pneumoniae, H. influenzae, and Morax-
meningitis for greater than 4 weeks with abnormal ella catarrhalis. Superficial external ear swabs are
CSF findings, most commonly caused by Myco- not helpful in the investigation of otitis media unless
bacterium tuberculosis. Rare non-infectious caus- there is perforation of the ear drum as ordinary res-
es of meningitis include sarcoid meningitis, post ident or commensal flora will be cultured. Deeper
intravenous immunoglobulin (IVIG) administration, swabs of pus or exudate from the affected ear are
or treatment with co-trimoxazole or non-steroidal the most useful laboratory specimens. If a fungal
anti-inflammatories (NSAIDs). infection is suspected, scrapings of material from
The diagnosis of meningitis is established by the ear canal are needed for laboratory culture.
the examination of CSF. It is essential to write on
the request form if a CSF shunt (ventriculo-atrial or The throat
ventriculo-peritoneal) and/or extra ventricular drain Pharyngitis or inflammation of the pharynx is usu-
(EVD) are in situ. CSF should be collected into ally caused by viral pathogens. Typical bacterial
three or more containers numbered consecutive- pathogens include Group A streptococci (GAS),
ly. No more than 2 hours should elapse between also known as S. pyogenes, various Corynebac-
CSF collection and laboratory microscopy and cul- terium spp., and occasionally Fusobacterium nec-
ture as cells can disintegrate rapidly. Never place rophorum. Epiglottitis is an inflammation of the
a CSF sample in any hospital refrigerator until mi- epiglottis characteristically associated with stridor.
croscopy and culture have been performed. Lab- Throat swabs should never be taken if there is any
oratory examination of CSF includes a complete concern for epiglottitis as doing so may precipitate
cell count, differential leucocyte count, and exam- an acute airway obstruction. Blood cultures should
ination of a Gram stained smear and culture. Nor- be sent. Where there is strong suspicion for GAS
mal CSF values are detailed in Table 3. In-house infection, an antistreptolysin O titre (ASOT) should
testing of CSF using multiplex PCR panels, with be checked by drawing a blood sample. Tonsillitis
the capability to identify bacteria, viruses and fungi is frequently viral in aetiology. Peritonsillar abscess
simultaneously, such as the FilmArray® Meningitis/ or quinsy is a rare bacterial complication of tonsil-
Encephalitis (Biomérieux, France), are increasing- litis where a unilateral collection of pus develops
ly utilised. Blood cultures, pharyngeal swabs and between the capsule of the palatine tonsil and the
stool specimens should also be sent when menin- superior constrictor muscle. It is usually associat-
gitis and/or encephalitis are suspected. ed with infection by S. anginosus group, GAS, and
F. necrophorum and F. nucleatum. Intra-operative
The ear pus should be sent for culture in the laboratory.
Otitis externa is defined as infection of the exter- Laryngitis or inflammation of the larynx (voice box)
nal auditory canal. Acute localised otitis externa typically presents with hoarseness and is general-
is usually caused by S. aureus. Acute diffuse otitis ly viral in aetiology. When taking throat swabs, al-
externa, also known as “swimmer’s ear”, is associ- ways avoid the tongue and uvula and aim to swab
ated with anaerobes, S. aureus, and Pseudomonas the tonsillar area and/or posterior pharynx.
aeruginosa. Chronic otitis externa can cause by fun-
gi such Candida or Aspergillus species. Malignant The lower respiratory tract
otitis externa is an invasive form of necrotising oti- The term lower respiratory tract infection (LRTI)
tis externa almost always caused by P. aeruginosa. encompasses a wide spectrum of clinical pres-

Table 3. Normal CSF Values

Opening pressure Normal opening pressure is 10–20 mm Hg. When measuring opening pressure, the child must be laid on his/her
side and should not be placed sitting upright.
Bacterial meningitis Elevated
Viral meningitis Usually normal
Fungal meningitis Variable
Tuberculous meningitis Variable
Erythrocytes No red blood cells should be present in normal CSFa
Leucocytesb,c Neonates Infants Children
(less 28 days of life) (1 to 12 months old) (older than 1 year)
0–30 cells x 106/L 0–15 cells x 106/L 0–5 cells x 106/L
Protein Neonates Infants Children
(less 28 days of life) (29-56 days of life) (2 months to 18 years old)
0.65–1.5 g/L 0.5–0.9 g/L 0.05–0.35 g/L
Glucose d
Neonates Infants Infants Children
(less 28 days of life) (29-58 days of life) (2-12 months old) (older than 1 year)
1.94–5.55 mmol/L 1.55–5.55 mmol/L 1.94–5.0 g/L 2.22–4.44 g/L

The presence of red blood cells (RBCs) in the CSF can result from an intracerebral or subarachnoid haemorrhage (SAH) or from a “traumatic” lumbar puncture (LP), in which
peripheral blood contaminates the CSF. A traumatic tap occurs in approximately 20% of LPs performed. Peripheral blood in the CSF after a “traumatic tap” will result in an
artificial increase in white blood cells (WBCs) by one WBC for every 500–1,000 RBCs in the CSF. This correction factor is accurate as long as the peripheral WBC count is not
extremely high or low. Examine the RBC count from sequential LP samples labelled 1, 2, and 3. Uniform bloodstaining of all samples suggests previous haemorrhage into the
subarachnoid space. Reducing red blood cell counts in sequential CSF samples, with the lowest count in sample 3, suggests bleeding induced by the LP procedure; a “trau-
matic tap”. Remember normal CSF is crystal clear. Xanthochromia is a more reliable predictor of haemorrhage and is present in greater than 90% of patients within 12 hours of
SAH onset. It is a yellow, orange, or pink discoloration of the CSF, caused by the lysis of RBCs resulting in haemoglobin breakdown to oxyhaemoglobin, methaemoglobin, and
bilirubin. Discoloration begins after RBCs have been in spinal fluid for about 2 hours and remains for 2–4 weeks.
A leucocyte or WBC: RBC ratio of 1.500–1:1000 is not indicative of infection. CSF obtained more than 12 hours after a CT or MRI brain confirmed intracranial haemorrhage may
show raised WCC counts of up to 500 x 106/L as a consequence of the normal physiological inflammatory response.
The CSF polymorph: Lymphocyte ratio is an unreliable with regard to whether meningitis is bacterial, viral, or mycobacterial in origin. This is particularly important in inter-
preting neonatal CSF results or when total leucocyte counts are less than 1000 x 106/L. In viral meningitis, there is a typically a lymphocytic predominance in the CSF, but in the
early course of the disease both neutrophils and lymphocytes can be found. Tuberculous meningitis can be associated with a neutrophil rather than a lymphocytic infiltrate
early in infection. It is important to remember that neutropenic patients may not produce any polymorph or neutrophil response in the CSF and lumbar puncture results should
be correlated with the clinical situation.
CSF glucose is normally two thirds of the serum glucose, measured during the preceding 2–4 hours before an LP is performed; can be higher in neonates. This ratio decreases
with increasing serum glucose levels. Bacterial meningitis can cause lowered CSF glucose levels. Glucose levels are usually normal in viral infections. Normal glucose levels
however do not rule out infection, because up to 50% of patients who have bacterial meningitis will have normal CSF glucose levels. A range of non-infectious inflammatory
conditions, SAH, and hypoglycaemia also cause hypoglycorrhachia (low glucose level in CSF).

Adapted from Public Health England, UK Standards for Microbiological Investigations: Investigation of Cerebrospinal Fluid (issue date 31.05.2017). Always check with local
laboratory with regard to cut-off values for CSF analysis. Always rule out any contraindications to performing an acute lumbar puncture before proceeding and if in doubt,
seek senior advice.

entations including pneumonia (inflammation ent greater than 48-hour post-hospitalisation).

of the lung parenchyma), bronchiolitis (infection S. pneumoniae accounts for 60% of all cases of
of the small airways), lung abscess (where lung community acquired pneumonia (CAP). In-house
parenchyma is replaced by pus-filled cavities), multiplex PCR assays, such as the FilmArray®
and empyema (where pus occupies the pleural Respiratory Panel (Bio-mérieux, France), for the
space). When documenting in the child’s medical detection of a wide range of bacteria and virus-
notes, the term ‘LRTI’ should be avoided and the es using nasopharyngeal aspirates or swabs are
anatomical site of the suspected infection clear- now widely used. The sensitivity of expectorated
ly specified. The aetiology of pneumonia and its sputum culture is poor for many pathogens due
management varies as to whether it had been to contamination with commensal oropharyngeal
acquired in the community or nosocomial (pres- flora and saliva. Early-morning sputum samples

are preferred as they contain pooled overnight se- ly contaminated with the child’s own faecal flora.
cretions. Bronchoalveolar lavage (BAL) samples The probability of a UTI is increased by the isola-
have greater sensitivity and specificity compared tion of the same organism from two specimens.
to expectorated sputum. Pertussis, also referred Generally, a pure growth of between 107–108 cfu/L
to as “whooping cough” is a high infectious res- (104–105 cfu/mL) is indicative of a UTI. E. coli is the
piratory disease caused by the Gram-negative most common organism associated with UTI ac-
organism Bordatella pertussis. Laboratory confir- counting for nearly 70% of all isolates cultured. It
mation of clinically suspected pertussis is made is worth remembering that the National Institute for
via culture or more commonly DNA detection on Health and Care Excellence (NICE) guidelines on
molecular assays using nasopharyngeal aspi- the management of UTIs in infants, children, and
rates or nasopharyngeal swabs/pernasal swabs. young people (under 16 years), published in 2013
PCR is increasingly utilised for the diagnosis of and updated 2017, classifies all non-E. coli UTIs as
pertussis as it has better sensitivity compared with “atypical infections” and additional investigations
culture-based methods. As with all PCR methods, are warranted. Microscopy for the presence of red
culture is still necessary in order to perform sus- cells, white cells, casts, cellular components, and
ceptibility testing, so it is beneficial to send sam- bacteria is performed in the laboratory. Chromog-
ples for culture and PCR testing simultaneously. enic agar plates, which allow the rapid identifica-
tion of bacteria present after overnight incubation,
The gastrointestinal tract based on a defined colour scheme of colonial
Peritonitis is inflammation of the peritoneum, growth, are increasing in popularity and help to
which is the serous membrane lining the abdom- guide empiric treatment pending final culture
inal cavity and the abdominal viscera. Primary results.
bacterial peritonitis, without evidence of intra-ab-
dominal organ perforation, is rare accounting for The skin and soft tissues
less than 1% if all cases of bacterial peritonitis. The key to a rapid diagnosis of skin and soft tis-
It can be seen occasionally in children with ne- sue infection is a thorough history. When the skin
phrotic syndrome. Secondary bacterial peritonitis is broken and infection ensues, it is important to
arises following gastrointestinal leakage within know if there is a history of underlying skin disorder
the peritoneal cavity following perforation of vis- such as psoriasis, eczema, or recurrent furuncles/
cera or abdominal trauma. In paediatrics, second- carbuncles, whether there was preceding trauma
ary bacterial peritonitis commonly complicates (indoor or outdoor), burn, bite (human, animal, in-
the perforation of an acute gangrenous appendix. sect), recent swimming pool/freshwater/saltwater
Samples of pus collected into sterile containers exposure, recent foreign travel, recent surgical pro-
are preferred to swab of pus. cedure/wounds, and parental/carer occupation as
healthcare worker exposure can increase the risk
The urinary tract of colonisation with methicillin-resistant S. aureus
There is a wide spectrum of urinary tract infections (MRSA). The majority of skin/soft tissue infections
(UTIs) but the two most common presentations are due to S. aureus and the beta-haemolytic strep-
in paediatrics are cystitis (bladder infection) and tococci groups A, C, G, and B.
acute or chronic pyelonephritis (infection of the
kidney and renal pelvis). Confirmation of a UTI in The bones and joints
a child is dependent on the quality of the speci- Osteomyelitis is infection resulting in inflammation
men. Mid-stream urine (MSU) samples and clean- of bone. Common causative organisms include S.
catch urine specimens are preferred. Bag and pad aureus, coagulase negative staphylococci (CoNS)
urine sampling is discouraged as these are easi- and Enterococcus species. Osteomyelitis asso-

Table 4. Commonly Prescribed Beta-Lactam Antimicrobials and Their Potential Spectrum of Cover – Not all Susceptible
Organisms are Listed

Always discuss with your local laboratory regarding resistance patterns, review past microbiology results if available and follow
empiric antimicrobial guidelines in your hospital. Susceptibility of an organism to an antimicrobial does not infer that it is the best
treatment option; always consider the anatomical site of infection.

Antimicrobial(s) Route Clinical use Commonly reported

side effectsc
Gram-positive cover Gram-negative cover

Penicillin-based Benzylpenicillin lVa Streptococcus pneumoniae Neisseria meningitidis Allergic reactions in <10%
antimicrobialse (penicillin G), Beta-haemolytic streptococci (not covered by penicillin V) exposed eg, urticaria,
(A, B, C, G) maculopapular rash
(especially with glandular
Phenoxymethyl- POb fever). Angioedema and
penicillin anaphylaxis rare (0.004
(penicillin V) –0.4%)
GI – diarrhoea, nausea,
Amoxicillin, lV, PO vomiting (2–5%)
Streptococcus pneumoniae
Escherichia coli Renal – interstitial
Ampicillin Beta-haemolytic streptococci
(only 30–60% cover) nephritis, haemorrhagic
(A, B, C, G)
Helicobacter pylori cystitis
Clostridium perfringens
(never as monotherapy Liver – elevated
Enterococcus faecalis
– usually triple therapy) transaminases. Highest
Listeria monocytogenes
risks with co-amoxiclav
(always IV treatment)
and flucloxacillin
CNS – encephalopathy or
Flucloxacillin lV, PO MSSA No cover for Gram-negatives
seizures can rarely occur
Beta-haemolytic streptococci
in renal failure or if very
(A, B, C, G)
high doses of penicillin
is used
Co-amoxiclav lV, PO Streptococcus pneumoniae Escherichia coli
Beta-haemolytic streptococci Klebsiella spp.
(A, B, C, G) Proteus spp.
Clostridium perfringens Anaerobes

Piperacillin lV Streptococcus pneumoniae Escherichia coli

-tazobactam Beta-haemolytic Klebsiella spp.
streptococci (A, B, C, G) Proteus spp.
MSSA Anaerobes
Clostridium perfringens Pseudomonas spp.d
Enterococcus faecalis

Aztreonam Aztreonam lV No cover for Gram-positives Escherichia coli

Klebsiella spp.
Proteus spp.
Pseudomonas spp.
(not all are sensitive)

ciated with water exposure increases the risk of upper respiratory tract infection (URTI). Radio-
infection with P. aeruginosa, sickle cell disease is logically obtained percutaneous bone biopsies
associated with Salmonella species and Kingella or intra-operative bone biopsies are the preferred
kingae can cause bone and joint infections after specimens for culture or molecular analysis. Septic

Table 4. Commonly Prescribed Beta-Lactam Antimicrobials and Their Potential Spectrum of Cover – Not all Susceptible
Organisms are Listed (continued )

Always discuss with your local laboratory regarding resistance patterns, review past microbiology results if available and follow
empiric antimicrobial guidelines in your hospital. Susceptibility of an organism to an antimicrobial does not infer that it is the best
treatment option; always consider the anatomical site of infection.

Antimicrobial(s) Clinical use Commonly reported side

Route effectsc
Gram-positive cover Gram-negative cover

Carbapenems Meropenem lV MSSA Moraxella catarrhalis GI – nausea, vomiting,

Streptococcus Neisseria meningitidis diarrhoea
pneumoniae Enterobacteriaceae Liver – elevated
Beta-haemolytic Acinetobacter spp. transaminases
streptococci (A, B, C, G) Pseudomonas Blood dyscrasias –
Viridans streptococci aeruginosa thrombocytopenia,
Listeria monocytogenes Anaerobes leucopenia
Haemophilus spp. CNS – increased risk of
seizure activity if
Ertapenem lV MSSA Haemophilus spp. concurrent
Streptococcus Anaerobes renal impairment.
pneumoniae Enterobacteriaceae Meropenem
also interacts with
Viridans streptococci (but not
sodium valproate
Beta-haemolytic Pseudomonas
Skin – rarely Stevens-
streptococci (A, B, C, G) aeruginosa Johnson syndrome
or Acinteobacter spp.) (SJS), toxic
epidermal necrolysis (TEN)


1st Generation 2nd Generation 3rd Generation 3rd Generation

eg, Cefalexin (PO only) eg, Cefuroxime eg, Ceftazidime eg, Ceftriaxone,
Enterococci (IV, available PO but poor (IV) cefotaxime (IV)
are inherently bioavailability in liquid format)
resistant to
cephalosporins Gram-positive Gram-negative Gram-positive Gram-negative Gram-negative Gram-positive Gram-negative
cover cover cover cover cover cover cover
Streptococcus Klebsiella spp. Streptococcus Proteus spp. Proteus spp. Streptococcus Escherichia
pneumoniae Escherichia pneumoniae Klebsiella spp. Klebsiella spp. pneumoniae coli
Group A, B coli Group A, B Escherichia coli Escherichia Group A, B Haemophilus
streptococci streptococci Haemophilus coli streptococci spp.
MSSA Viridans spp. Pseudomonas MSSA Neisseria
streptococci Moraxella spp. Spirochaetes meningitidis
MSSA catarrhalis Borrelia Neisseria
burgdorferi gonorrhoea
Proteus spp.
Klebsiella spp.

Abbrevition: MSSA = methicillin-sensitive Staphylococcus aureus

IV = intravenous route of administration.
PO = oral route of administration.
Side effect profile similar for penicillins and cephalosporins.
Meropenem, piperacillin-tazobactam. Pseudomonas species are usually susceptible to meropenem and piperacillin-tazobactam.
5% of patients with an allergy to penicillin-based antimicrobials will also be allergic to cephalosporins. Up to 10% of patients with an allergy to penicillin-based
antimicrobials will also be allergic to carbapenems.

Table 5. Managing Infectious Pathogens

Syndrome Diagnosis Does the child need to be isolated, and if so, for how
long should the child be isolated for?

Central nervous system Meningococcus Remove from isolation once the patient has had 24 hours
Pneumococcus of IV antibiotics
Haemophilus influenzae
Unidentified bacterial meningitis
Group B Streptococcus The child does not need to be isolated
Escherichia coli
Enterovirus For the duration of the admission, the child should
Parechovirus be isolated
VZV Isolate until all the lesions have been crusted over and
the patient is afebrile
HSV The child does not need to be isolated
HHV-6 Isolate until the patient is at least 48 hours afebrile
Respiratory Bronchiolitis Isolate until the patient is 48 hours asymptomatic
Bacterial pneumonia Remove from isolation once has had 24 hours of IV
Pertussis Isolate until 24 hours after the 5th (final) dose of
Viral pneumonia Isolate until the patient is 48 hours afebrile
TB Discuss with infectious diseases team and/or infection
Gastroenteritis Bacterial (Salmonella spp., Shigella spp., Discuss with infection control or microbiology
Campylobacter spp., Escherichia coli O157)
Viral (Rotavirus, Adenovirus) Isolate until the patient is 48 hours asymptomatic
Clostridium difficile
Infective gastroenteritis (? cause)
Systemic viral illness Parvovirus Maintain precautions for duration of hospitalisation
when chronic disease occurs in an immunocompromised
patient. For patients with transient aplastic crisis or
red-cell crisis, maintain precautions for 7 days
Measles Isolate until 4 days after onset of rash
Mumps Isolate until 9 days after onset of swelling
Enterovirus Discuss with infection control or microbiology
Varicella Isolate until all the lesions have crusted over
Group A Streptococcus Tonsillitis, pneumonia, or post-varicella infection Remove from isolation once the patient has had
24 hours of IV antibiotics
Resistant organisms MRSA Discuss with infection control
Human Herpesvirus Type 6.

Adapted from Siegel JD, Rhinehart E, Jackson M, Chiarello L, and the Healthcare Infection Control Practices Advisory Committee, 2007 Guideline for Isolation Precautions:
Preventing Transmission of Infectious Agents in Healthcare Settings. Updated February 2017. Available at:
Always refer to local guidelines and contact the infection prevention and control team if any queries.

arthritis is a pyogenic infection of a joint. Infection Following auramine staining, and regardless of
occurs via a haematogenous spread or directly whether AFB are detected or not, all specimens
from contiguous lesions. Any organism can be iso- are referred to the laboratory for mycobacterial cul-
late from aspirated joint fluid, but S. aureus is the ture for up to 8 weeks. Molecular techniques using
commonest. Skin wounds are the most likely por- real-time PCR have substantially changed the field
tals of entry of infection and again S. aureus is the of tuberculosis diagnosis and have been proven to
most common isolate. All types of sterile fluid can yield rapid results while being highly sensitive. The
be cultured. Broad range 16S (bacterial PCR) and GeneXpert® (Cepheid, USA) test is now one of the
18S PCR (fungal PCR) can be utilised in certain most widely used PCR assays worldwide, which
circumstances in the diagnosis of culture-negative can both diagnose TB and also test for resistance
bone and joint samples. To increase the diagnostic to the drug rifampicin, which forms part of the first-
yield from culture, it is recommended to perform a line drug treatment for TB.
joint aspirate off antimicrobials if possible, particu-
larly when chronic osteomyelitis is suspected. ANTIMICROBIAL RESISTANCE,
Possible mycobacterial infections AND STEWARDSHIP
Tuberculosis or (TB) is caused by members of the Multidrug resistant Gram-negative bacteria
M. tuberculosis complex (MTBC), most common- (MDRGNB) are defined as having three or more
ly M. tuberculosis, and M. bovis. Consideration antimicrobial resistance mechanisms affecting
should always be given to TB in any child with different classes of antimicrobials. Opportunistic
exposure to a TB endemic area, family members Gram-negative bacteria that present increasing re-
with confirmed TB, and any child living in socio- sistance issues include E. coli, Klebsiella spp., En-
economic circumstances associated with over- terobacter spp., Serratia spp., Citrobacter spp., P.
crowding, homelessness, and poverty. Nontuber- aeruginosa, and A. baumannii. MDRGNBs colonise
culous mycobacteria (NTM) are also increasingly the human gut asymptomatically, creating a reser-
encountered as a cause of disease. One of the voir for transfer to other body sites and to other
most common NTM species is M. marinum as- patients. Much concern has been raised over the
sociated with a localized skin lesion, commonly past decade regarding carbapenemase-produc-
referred to as a “fish tank” or “swimming pool” ing Enterobacteriaceae (CPE), also known as car-
granuloma, following contamination of an open bapenemase-resistant Enterobacteriaceae (CRE),
wound or an abrasion with water from fish tanks, which confer resistance to carbapenem antimicro-
swimming pools, and natural areas of fresh or salt bials, for example meropenem or ertapenem. The
water. Another NTM, M. abscessus, is now regard- acquisition of extended-spectrum beta-lactamase
ed as an infection to be considered in all patients (ESBL)-producing enzymes in Gram-negative or-
with cystic fibrosis, in the context of declining lung ganisms confers the ability to hydrolyse penicillins,
function and poor response to standard therapies. cephalosporins, and aztrenoam. Genes for ES-
Where there is clinical suspicion for mycobacterial BLs are also frequently encoded on transferable
infection, many specimens are suitable for testing plasmids, that encode resistance genes for other
including fluid from sterile body sites (CSF, pleu- classes of antimicrobials, such as beta-lactams,
ral fluid, ascites, joint fluid), skin or tissue biopsies, fluoroquinolones, aminoglycosides, and sulpho-
bone marrow, BAL washings, blood, sputum, and namides, and as a consequence, ESBL-produc-
gastric washings. The most important tool in the ing organisms are frequently resistant to multiple
diagnosis of tuberculosis is direct microscopic classes of antimicrobials. With regard to Gram-pos-
examination of appropriately stained specimens itive MDROs, the incidence of vancomycin-resist-
for acid-fast bacilli (AFB) using an auramine stain. ance Enterococci (VRE) and community-acquired

Practice Points to consider the need for prophylaxis for parents/

carers of the child. In the UK, local occupational
• In the management of paediatric infection, the guidance of a clinical health teams will usually support paediatricians
microbiologist can be helpful in identifying laboratory diagnostic methods and where necessary arrange prophylaxis for staff.
to expedite a child’s diagnosis and subsequently advising regarding
Neonatologists must be particularly aware of the
switching from empiric to directed antimicrobial therapy if indicated.
risk of GAS when invasive disease occurs in either
• A thorough history is essential to the aid the diagnosis of infection. mothers or their babies within 30 days of delivery.
• Preventing the onward transmission of infectious diseases is paramount These cases should be discussed on a case-by-
to protecting the safety of all hospital staff. case basis with a consultant staff.
• Always prescribe the most narrow-spectrum antimicrobial(s) possible to
reduce the risk of adverse events and the potential for the development of IS A “NON-ROUTINE” VACCINATION
antimicrobial resistance. NEEDED?
• The need for prophylaxis and vaccination is easily forgotten but is crucial Vaccination or booster vaccination for protection
to the safe management of some infectious presentations. against rabies (bat exposure, dog or cat bites)
and tetanus (environmental wound contamina-
tion) may occasionally be required. It is advisable
strains of methicillin-resistant S. aureus (CA-MRSA) to check local policies and to administer as soon
are increasing. MRSA is the only MDRO for which as possible.
a decolonisation regimen is available, affording the
potential to clear colonisation. VRE, CPE/CRE, and FURTHER READING
1. Public Health England, UK standards for microbiological investiga-
ESBLs are all associated with gut carriage, which tions. Available at:
may or may not spontaneously clear with the pas- - Investigation of Specimens for Screening for MRSA. Issue date 03.04.2014
- Investigation of Cerebrospinal Fluid. Issue date 31.05.2017
sage of time, but in practice, children with repeated - Investigation of specimens for Mycobacterium species. Issue date
antimicrobial and hospital exposure are unlikely to - Investigation of Ear Infections and Associated Specimens. Issue date
lose carriage of these MDROs. Table 4 demon- - Investigation of Bacterial Eye Infections. Issue date 04.05.2017
- Culture of specimens for Bordatella pertussis and Bordatella paraper-
strates the common organisms covered by each tussis. Issue date 10.11.2014
- Investigation of Throat Related Specimens. Issue date 15.04.2015
type of beta-lactam antimicrobial. - Investigation of Fluids from Normally Sterile Sites. Issue date
- Investigation of Viral Encephalitis. Issue date 16.04.2014
- Investigation of bronchoalveolar lavage, sputum and associated spec-
INFECTION PREVENTION AND imens. Issue date 24.08.2017
- Investigation of bone and soft tissue associated with osteomyelitis.
CONTROL ESSENTIALS FOR THE Issue date 14.12.2015
- Investigation of urine. Issue date 16.08.2017
PAEDIATRICIAN ON-CALL 2. Report of the Cystic Fibrosis Trust of the Mycobacterium abscessus
Infection Control Working Group. Cystic Fibrosis Trust. Mycobacterium
All paediatric staff have a vital part to play in the abscessus-Suggestions for infection prevention and control. (Interim
guidance – October 2013). Available at: https://www.
prevention of onward transmission of infection, uk/the-work-we-do/clinical-care/consensus-documents.
3. Sandford guide to antimicrobial therapy. 44th Edn. Virginia, USA: Antimi-
particularly outside of routine hours, when on-call, crobial Therapy Inc., 2014.
4. U.S Department of Health and Human Services. Centers for Disease Con-
staffing numbers are often low, and availability of trol and Prevention (CDC). Antibiotic resistance threats in the US 2013.
Available at:
beds can become an issue. The isolation times of 5. Wilson AP, Livermore DM, Otter JA, et al. Prevention and control of mul-
tidrug-resistant gram-negative bacteria: recommendations from a joint
common infectious paediatric pathogens are listed working party. J Hosp Infect 2016; 92(suppl 1): S1–44.
in Table 5. This should be seen as only a guideline
© 2018 Elsevier Ltd. All rights reserved. Initially published in Paediatrics and
and every child should be judged on a case-by- Child Health 2018;28(6):254–262.
case basis.
About the authors
Ciara O’Connor is a Clinical Microbiology Specialist Registrar in the Depart-
IS ANTIBIOTIC PROPHYLAXIS ment of Clinical Microbiology, Temple Street Children’s University Hospital,

NEEDED? Dublin 1, Ireland.

When the diagnosis of either meningococcal Richard J Drew is a Consultant Microbiologist in the Department of Clinical
Microbiology, Temple Street Children's University Hospital, Dublin 1 and in
meningitis or pertussis is made always remember the Department of Microbiology, Royal College of Surgeons in Ireland.

Management of Urinary
Incontinence in Frail
Elderly Women
Gabrielle Prud’homme BMBS; Leanne Alexander MBChB (Hons) BA (Hons) MRCP DGM; Susan Orme BMBS (Hons) BMedSci FRCP

Urinary incontinence (UI) is defined by the International Continence Society as

any involuntary leakage of urine. It is a common clinical problem, and its incidence
increases with age. It is a particular problem in the frail elderly, who can sometimes pose
a diagnostic and therapeutic challenge by virtue of their complexity. UI is a major cause
of disability and dependency, and adversely affects the psychological and physical
health of the older person. However, treatment can lead to significant improvements.

Estimations of UI prevalence vary according to the definitions used but is thought to
be around 15–30% in the ambulant community dwelling elderly, rising between 50 and
80% among those in long-term care.
Normal ageing is not a cause of urinary incontinence, although age-related chang-
es in lower urinary tract function can predispose older people to UI which is then exac-
erbated by comorbidities. UI is a major cause of disability and dependency, significantly
increasing the risk of care home placement and adversely affecting the psychological,
physical, and social wellbeing of older people. It also predisposes to carer negativity
and stress, which itself is a major factor in placement for institutional care.

Table 1. Conditions Contributing to Urinary Incontinence

Condition Type of incontinence Notes

Dementia Urge incontinence Causes UI by variety of mechanisms:
Functional incontinence a) Decreased motivation and initiative to go to the toilet
b) Social disinhibition
c) Decreased executive function
d) Immobility or gait disturbance
e) Severe autonomic failure (Lewy Body Dementia)
Stroke Urge incontinence Varying effects on bladder and bowel function, mobility and functional
Functional incontinence ability to toilet
Occasionally urinary retention UI post stroke often improves over time
Poor prognostic indicator for those in whom it persists
Parkinson’s Functional incontinence Also, autonomic failure in “Parkinson’s Plus” syndromes
disease Urge incontinence
Delirium Delirium can be associated with detrusor underactivity or bladder outflow
obstruction causing urinary retention (“cystocerebral syndrome”) as well
as infection causing UI.
Normal pressure Incontinence, gait, and cognitive deficits
hydrocephalus Potentially reversible with VP shunt
Anxiety and Can result from incontinence
depression Less motivation to stay continent
Can also cause mildly impaired cognition
Arthritis Functional incontinence
Urge incontinence
Diabetes Functional incontinence Polyuria in poorly controlled DM
Peripheral neuropathy
Autonomic neuropathy
Increased susceptibility to UTI
Peripheral oedema Nocturia Reabsorption of peripheral oedema causing increased circulating
(Heart failure, venous Nocturnal polyuria volume and increased nocturnal urine production.
insufficiency, Nocturnal enuresis Increased ANP levels secondary to myocardial stretch from increased
circulating volume may also contribute to increased nocturnal urine
Constipation and Combined faecal and urinary incontinence Outflow tract obstruction causing urge incontinence from detrusor
faecal impaction Urge incontinence overactivity. Straining can result in weakened pelvic floor muscles.
Urinary retention
COPD Stress incontinence Cough can exacerbate stress incontinence

The frail elderly has traditionally been under in the UK alone. Prevalence continues to increase
treated due to fears over the side effects of the med- as a consequence of an ageing population with re-
ications, under reporting of symptoms, and low ex- source implications for the NHS and social care.
pectations of treatment outcomes by both patients The true prevalence of UI is difficult to accurately
and doctors. However, significant improvements estimate as many sufferers never seek treatment
can be achieved with correct assessment and treat- due to embarrassment, lack of awareness of treat-
ment. The following forms a framework to aid the ment options, and the myth that UI is a normal con-
management of this challenging group of patients. sequence of ageing.
Estimations also vary widely according to
PREVALENCE the definition used, but a review of the literature
A 1993 MORI poll in the UK showed a lifetime prev- suggests a prevalence of 15–30% for community
alence of UI at all ages of 6.6% in men, and 14% dwelling older people. All studies report a higher
in women with approximately 3.9 million sufferers incidence of UI among care home residents in the

range of 50–80% because UI are associated with Box 1. Drugs that Cause or Exacerbate Urinary Incontinence
older age, frailty, cognitive impairment, and limited
mobility leading to a greater level of dependency. • Alcohol
All of these factors are more prevalent amongst • Alpha adrenergic agonists (eg, midodrine, pseudoephedrine)
those in long-term care. • Alpha blockers (eg, doxazosin, tamsulosin)

The severity of UI has been defined in various • ACE inhibitors (eg, ramipril, lisinopril)
• Caffeine
ways, but mostly according to the frequency of
• Cholinesterase inhibitors (eg, donepezil, rivastigmine)
urine loss. The general prevalence of severe urinary
• Diuretics (eg, bendrofluazide, furosemide, bumetanide)
incontinence (weekly or more) in all age groups is
• Anticholinergic drugs
thought to be between 3 and 7%. The Newcastle
• Oral oestrogen therapies (eg, HRT)
85+ cohort study in 2009 reported an overall inci-
• Opioids (eg, codeine, morphine, tramadol)
dence of severe UI in 21%, commoner in women.
• Sedatives and hypnotics (eg, benzodiazepines, zopiclone)

UI is associated with other comorbidities and can HOW IS CONTINENCE MAINTAINED?
contribute significantly towards declining functional Maintaining continence is a complex process, and
status and poor quality of life. It is also associated depends on:
with substantially increased risk of admission to 24- 1. An intact bladder, sphincter, and pelvic floor
hour care. Incontinence in this context may be func- function with normal innervation.
tional and treatment should be modified according- 2. An ability to communicate the need to go to the
ly. A list of some of the major conditions contributing toilet if immobile.
to UI can be found in Table 1. Appropriate treatment 3. Adequate cognition to know how to find the toi-
of the conditions listed is a necessary part of conti- let and to keep continence until on the toilet.
nence management in this patient group. 4. 
Sufficient mobility and manual dexterity to
The more common medications associated remove clothing.
with exacerbations of UI are listed in Box 1. In particu- 5. 
Ability to voluntarily initiate micturition at the
lar, diuretics increase the volume of urine produced. appropriate time.
Changing to a loop diuretic with a longer half-life The frontal cortex is responsible for voluntary
such as torasemide can make some improvement control of micturition with the sensation of a full
in incontinence associated with diuretic timing. bladder as well as external sphincter contraction
Medication review is therefore essential with and relaxation. The motor cortex controls bladder
particular reference to drugs that contribute towards motor function, as well as the ability to mobilize to
incomplete bladder emptying or cause constipation. the toilet, bypassing any environmental hazards
en route. All of these processes can be affected by
CONDITIONS CAUSED BY URINARY intercurrent illness.
UI is generally thought to be a predictor of adverse AGE-RELATED CHANGES AFFECTING
outcomes in older people. Those with UI have a THE URINARY TRACT
greater mortality, but generally also have more Multiple age-related changes occur in the lower uri-
significant comorbidities, which may partly explain nary tract as well as age-associated comorbidities
this association. There is no universally agreed that are linked with UI.
definition of frailty, but it is thought of as a multisys-
tem syndrome of impaired mobility, fatigue, mus- Bladder changes
cle strength, and balance. Common conditions Collagen deposition within the bladder wall results
caused by UI are listed in Table 2. in a reduction in functional bladder capacity and

Table 2. Conditions Caused by Urinary Incontinence Other changes

Ageing causes reduced pituitary production of an-
tidiuretic hormone (ADH) reducing urine-concen-
Condition Notes
trating ability. Nocturia is also more common due to
Depression Also reduced quality of life and social isolation.
and anxiety reversed diurnal urine production through increased
Falls and Falls and fractures can result from UI, especially production of atrial natriuretic peptide (ANP). This
fractures UUI and OAB. acts on the kidney to produce greater volumes of
Nocturia Nocturia can result in daytime sleepiness, and more dilute urine at night. Nocturnal urine production
have an adverse effect on cognition. It is associated can also be increased by peripheral oedema re-en-
with an increased falls risk between 10% and 21% tering the circulation at night whilst lying in bed.
with two or more voids per night, as well as an
Changes in the immune system related to age
increased fracture risk and nocturnal enuresis.
can lead to an increased likelihood of UTI. Practical
Pressure areas UI is an important feature in the development of
pressure areas, and slows their healing. Can also problems with maintaining anal and vulval hygiene
cause skin rashes and dermatitis. may also contribute.
Urinary tract UTI is associated with chronic urinary retention, as
infection well as indwelling catheters and condom drainage WHAT ARE THE SYMPTOMS AND
systems. SUBTYPES OF UI?

Overactive bladder
lower urinary flow rates through a reduction in blad- Overactive bladder (OAB) is defined as urgen-
der elasticity. Decreased innervation results in less cy that occurs with or without urge UI, usually with
cholinergic transmission and a reduced sensation frequency and nocturia and in the absence of other
of bladder filling so that the first sensation of need- pathology. OAB that occurs with urge UI is known as
ing to void is closer to the functional bladder ca- “OAB wet”. OAB that occurs without urge UI is known
pacity, giving less time to get to the toilet, and void as “OAB dry”. OAB is the most common cause of UI
appropriately. in the elderly. In the elderly, these are most common-
ly cerebrovascular or neurodegenerative in origin.
Residual volume Several studies have reported a link between larger
A residual volume of more than 100 mL is indic- numbers of white matter lesions and worsening ur-
ative of incomplete bladder emptying in younger gency urinary incontinence (UUI) symptoms.
person but in the elderly up to 200 mL can be con-
sidered normal. Very large residual volumes (>300 Stress incontinence
mL) are associated with increased risk of upper Stress urinary incontinence (SUI) is the com-
urinary tract dilation and renal impairment. plaint of involuntary leakage of small amounts of
urine on effort or exertion, sneezing, or coughing.
Urethral changes It is more common after the menopause.
Ageing results in increased collagen deposition
in the urethra and loss of circular smooth muscle Incontinence due to incomplete bladder
in the urethral sphincter. This results in decreased emptying
urethral closing pressure. Is usually secondary to an underactive bladder, or
a bladder outflow obstruction, and tends to cause
Vaginal changes a continuous loss of small amounts of urine. Caus-
Post-menopausal atrophy can cause loss of lactoba- es include spinal cord lesions (MS, cord compres-
cilli leading to colonization with pathogens such as sion), peripheral nerve lesions (eg, diabetic neu-
E. coli, enterococci, etc, as well as atrophic vaginitis. ropathies), and constipation. Constipation is the

most prevalent cause of this in hospital inpatients Box 2. History Taking

and long-term care settings.
Urinary symptoms
Mixed incontinence • Storage – any urgency, frequency, or nocturia symptoms
This is a combination of OAB and SUI symptoms. • What is the flow of urine like?
Treatment initially should be aimed at the predom- • Any urinary leakage, amount lost, and its precipitants
inant symptom. • Distress caused and current coping strategies
• Haematuria/UTI symptoms?
Functional incontinence
• Constipation symptoms? Is the patient taking any treatment for this?
Functional incontinence is a general term to de-
• Straining (can weaken pelvic floor muscles)
scribe the factors outside the lower urinary tract that
• Presence and frequency of any faecal incontinence
contribute to UI, including mobility, environmen-
Fluid intake
tal factors, medications, and other comorbidities. • Caffeine intake
There are a variety of ways to manage mobility and • Alcohol intake
continence that are discussed later in this article. • Volume and timing of drinks in comparison to symptoms
Nocturia • Previous urological/renal problems, haematuria, or recurrent UTI
The International Continence Society defines noc- • Previous pelvic surgery
turia as having to wake one or more times to void • Details of pregnancies, mode of delivery, and birth weight of children
urine at night. Nocturnal polyuria is defined as pro- • Other comorbidities contributing to UI
• Any cognitive impairment?
ducing more than 35% of total daily urine output
at night. Incidence increases with age and usually
• Sedatives and hypnotics
50% men and women over the age of 60 will have
• Antimuscarinics
nocturia. By the age of 80, the majority of women
• Diuretics and timing of diuretics
will have symptoms.
• Constipating medications (opiates, calcium channel blockers)
ASSESSMENT OF FRAIL OLDER • General functional status and ability to perform activities of daily living
INCONTINENCE • Access to toilets/continence aids
• Impact on quality of life – incontinence questionnaire (ICIQ)
History • Availability of carers around timing of symptoms
A comprehensive history is the most important
part of any assessment of a frail older patient and
should include a thorough assessment of function- recommend the use of bladder diaries over a
al ability and social circumstances in order to en- minimum of 3 days in order to initially assess
able comprehensive holistic management (Box 2). anyone with UI. Fluid intake, voiding times and
In patients with cognitive impairment, some history quantities, and episodes of urinary incontinence
should be elicited from the carer if possible. are recorded. This can be done either by the pa-
tient or a carer and is a useful tool in identifying
Examination the cause of the UI but it is not always possible to
See Box 3. achieve in the frail. In the setting of severe cog-
nitive or functional impairment, a modified diary
Investigation where the number of voids, episodes of UI and
Investigations should include baseline blood number of drinks consumed gives some useful
tests as well as a bladder diary. NICE guidelines information.

Box 3. Examination Factors such as the aetiology of incontinence,

mobility, comorbidities, anaesthetic risk, potential side
• Record BMI effects, and patient choice all need to be considered.
• Assess general mobility
• Test for cognitive impairment with AMT. If score <8/10, consider MMSE Conservative measures: Certain conservative
(score <27 is abnormal) measures apply to all aetiologies of UI and it is im-
• Abdominal examination and PR portant to give simple advice first.
• External genitalia Hygiene – Advise washing daily and after
• PV examination if indicated
every accident using unscented soap or baby
•  eurological exam – especially legs and for signs of unrecognized
N wipes paying attention to adequate drying. Advise
loose fitting clothes to reduce the risk of skin dam-
age from soiling.
Fluid, caffeine, and alcohol intake – Advise
Box 4. Reversible Causes of Urinary Incontinence drinking 2–3 pints of fluid a day. Less than this
can exacerbate irritable bladders and more will
• Constipation
increase the volume or urine production. Advise
• Metabolic disturbance (eg, hypercalcaemia, and hyperglycaemia)
avoiding caffeine (switch to decaffeinated tea and
• Urinary tract infection
coffee if possible) and excess alcohol as both have
• Delirium and acute confusional states
a diuretic effect and can exacerbate incontinence.
• Atrophic vaginitis
Weight loss – Obesity carries an increased risk
• Medications (see Box 1)
of SI and UUI, and in these cases weight reduction
• Restricted mobility
and education programmes can help especially in
those with a body mass index greater than 30 kg/m2.
Urinalysis and a post-void bladder scan are Smoking – Whilst stopping smoking has no
also indicated. direct effect on urinary incontinence, persistent
cough contributes to stress incontinence and stop-
Specialist investigation ping smoking may reduce this.
Urodynamics: Frail older women may be considered
more suitable for conservative management and so Reversible causes – See Box 4.
urodynamics may be unnecessary. A functional as-
sessment of walking and undressing will usually be Medication review – Medication review is
of more diagnostic value in this patient group. essential (Box 5).

Management Environmental interventions – Difficulty in

General measures and lifestyle modifications: accessing toilet facilities is potentially a major factor
The management of UI requires a multidisciplinary in incontinence in the frail. This is known as func-
approach. This is of particular importance in the frail. tional incontinence and usually coexists with other
National guidelines such as the NICE guidelines for forms of incontinence. In many, poor mobility may
the management of UI tend to focus on younger be a contributing factor but environment also plays
fitter patients, although recommendations are now a part. Occupational therapists assess functional
included for frailer adults. NICE clinical guidelines difficulties and problems with home environment.
on UI in neurological disease focus on incontinence They may be able to provide downstairs commodes
in patients with multiple sclerosis, Parkinson’s dis- and adjust lighting and flooring. Clothing that is
ease, dementia, and stroke which may be applica- elasticated or with Velcro fastening can be used to
ble to some of the frail elderly patients. aid rapid removal. It is important to consider such

factors in hospitals and care homes in addition to Box 5. Side Effects of Anticholinergic Medication
patients’ own residences because a change in a frail
person’s environment can exacerbate any UI. CNS
Containment devices – Many frail elderlies • Sedation
will require the use of devices to contain urine to • Cognitive impairment
preserve dignity when incontinent. A wide range • Delirium
of absorbent pads is available. Pads can be worn Gastrointestinal
• Dry mouth
next to the skin or as absorbent sheets for beds.
• Constipation
Body worn pads are superior to sheets as they are
less likely to wrinkle and cause pressure damage • Mydriasis (Glaucoma)
and less likely to affect pressure relieving mattress- • Impaired accommodation (blurred vision)
es. Such devices are not treatments in themselves CVS
but are used in addition to other therapies or as a • Arrhythmia
long-term management strategy in those with re- • Tachycardia
fractory symptoms despite treatment. The patient • Orthostatic intolerance
and carer preferences should be considered when
• Retention
choosing containment products.
Catheters – The indications for catheteriza-
tion include chronic urinary retention where medi- intervals between each void. It utilises scheduled
cal management has failed, and surgery is thought voiding when awake, and relaxation techniques
to be inappropriate, pressure sores, or wounds to suppress the sensation of urgency in the time
prone to urinary contamination. between voids. It can be very effective in those
The different methods of catheterization include with normal cognitive function.
intermittent catheterization (either by patient or car- Prompted voiding and scheduled toileting
er), long-term urethral catheterization, or suprapubic – In those with cognitive impairment who do not
catheter. Intermittent catheterization and suprapubic have the cognitive capacity to comply with behav-
catheterization have lower risks of urinary tract infec- ioural interventions, timed and prompted voiding
tion and also have less impact on sexual function. can reduce the risk of UI. Prompted voiding in-
It is important that in any patient requiring catheter- volves asking patients at regular intervals whether
ization that patients and carers are counselled re- they would like to go to the toilet. It is carer and
garding the indications, complications, and care. patient dependent and requires a moderate de-
gree of remaining cognition.
Specific measures Timed toileting is carer dependent and may
be more appropriate in those with severe cognitive
Stress incontinence (SI) impairment. Both techniques aim to reduce incon-
tinent episodes but do not affect bladder function
Conservative and they may increase the workload for carers.
Pelvic floor exercises and vaginal cones – They are only effective for daytime incontinence.
Both of these techniques though demonstrated to
be highly efficacious in younger women, but are Pharmacological therapy
likely to be less effective in certain groups of frail Serotonin and noradrenaline reuptake inhibi-
elderly as patients must have adequate higher tors (Duloxetine) – SNRIs have been shown in a
mental functions and sufficient motivation. recent Cochrane review to improve quality of life
Bladder training and habit retraining – in patients with UI, although it has little impact on
Bladder training aims to gradually increase the the numbers cured. The inhibition of serotonin and

Table 3. Drugs with Anticholinergic Side Effects action between these receptors contribute to the
symptoms of OAB.

Anti-emetics Hyoscine, cyclizine, prochlorperazine Type M1 is found the in hippocampus and

Antiparkinsonian Procyclidine, trihexyphenidyl forebrain and plays an important role in memory
medication and cognition.
Antispasmodic Oxybutynin, trospium, tolterodine, solifenacin It is the presence of muscarinic receptors in
Anti-arrhythmic Disopyramide, procainamide, quinidine other organs that causes the extensive side effects
Antihistamine Chlorpheniramine found with anticholinergic agents (Table 3). Use of
Antidepressants Amitriptyline, imipramine, doxepin, nortriptyline other drugs with anticholinergic properties (eg, tri-
Antipsychotics Chlorpromazine, dozapine, fluphenazine, thioridazine cyclic antidepressants, antipsychotics, ranitidine,
ACE inhibitors, and bronchodilators) is common
in the elderly and concomitant use increases the
noradrenaline reuptake specifically in the sacral risk of anticholinergic side effects. The side effect
spinal cord increases the tone of the sphincter profiles of available drugs govern choice of agent
through parasympathetic inhibition and improves in the frail. It is recommended that use of such
urethral closure. Side effects are significant. At drugs be reviewed early and frequently. NICE
present, duloxetine is recommended should pel- state that oxybutynin, an antimuscarinic, is con-
vic floor therapy be unsuccessful and the patient traindicated in the frail elderly. It is associated
prefer to avoid surgery. Whilst this is a common sit- with acute confusion in this patient group. Fes-
uation in the frail elderly, side effects of duloxetine oterodine has a good evidence base for use in
may limit its use in this group. NICE suggest it may the elderly as does solifenacin. They are generally
be considered as a second-line treatment for those well tolerated. Artificial saliva and osmotic laxative
unsuitable for surgery. can be prescribed at the outset of treatment to
Oestrogen therapy – Around the meno- counteract common side effects of dry mouth and
pause withdrawal of oestrogen may result in a constipation, therefore improving treatment com-
reduction of periurethral pressure. Theoretically pliance and success.
replacing this oestrogen locally will reduce SI. B3-adrenoceptor agonist – Mirabegron is a
There is some evidence that topical oestrogens novel drug in treatment of OAB. Beta-3 agonists
may improve incontinence for the duration of are a class of non-antimuscarinic medications
treatment, but the effect is modest and only small which use the sympathetic nerve pathway to
proportions of women benefit. NICE recommend stimulate beta-3 receptors in the bladder, caus-
its use in OAB patients who are post-menopau- ing smooth muscle relaxation. Use of drugs in
sal with vaginal atrophy. It also has a role in the this class offer targeted treatment for OAB as 97%
prevention of recurrent urinary tract infection and of the beta-adrenergic receptor subtypes within
local symptoms in women with atrophic vaginitis. the bladder are of beta-3. Beta-3 agonists do not
cause antagonism of M3 receptors and as such
Urge incontinence/overactive bladder has a reduced risk of urinary retention and oth-
Conservative measures: As above. er anticholinergic side effects, making it a viable
treatment option for patients who cannot tolerate
Pharmacological treatment these side effects or in whom the anticholinergics
Anticholinergic therapy – Anticholinergic are contraindicated or where there is concern
drugs used in UUI act on smooth muscle recep- over overall anticholinergic load. Anticholiner-
tors of which there are five types: M1–M5. Type gic medications should be used with caution in
M2 causes bladder relaxation during filling and M3 the elderly due to evidence suggesting that high
mediates bladder contraction, therefore the inter- cumulative doses of these medications can be

associated with increased risks of dementia and Practice Points

Alzheimer’s disease, making beta-3 agonists an
effective treatment choice in this patient group. • Urinary incontinence is not a normal feature of ageing.
The main contraindication is uncontrolled hyper- • A full history and examination including functional and cognitive status should
be performed as part of the assessment.
tension. Care should be taken if the patient is on
• The impact of medication on continence should always be considered.
Desmopressin – Desmopressin is an ana- • 
Physiologically young elderly patients should be considered for surgical
intervention if conservative management fails.
logue of vasopressin that reduces water excretion
• Timed toileting can be of use in managing UI even in the frail cognitively
from the kidneys. Taken at night, it may reduce impaired elderly.
symptoms in those with troublesome nocturia. • It is important to exclude and to treat constipation in the frail.
However, due to increasing evidence of hypon- • When considering treatment with an antimuscarinic total anticholinergic drug
atraemic electrolyte disturbance and interaction load should be considered.

with other medications, this should not be used • Refer to NICE clinical guideline 171 Urinary Incontinence in Women and NICE
clinical guideline 148 Urinary Incontinence in neurological disease for best
in the frail elderly unless all alternatives have been practice.
considered and treatment is supervised by dai-
ly U&E measurement in the first week. This is an
off-licence treatment and requires informed con- of OAB with anticholinergics compared with pla-
sent from the patient. cebo had statistically significant differences in
favour of antimuscarinic therapy. It provided evi-
Anticholinergics and cognitive impairment dence that antimuscarinics provide health-related
There has been concern that interaction of an- quality of life benefits to patients with OAB.
ticholinergic drugs with M1 receptors in the brain
can cause problems with attention, concentration, Surgical therapies: Details about specific surgical
memory, and visuospatial awareness. The most re- intervention are beyond the scope of this article,
cent NICE guidelines have stated that oxybutynin however it is important to consider the appropri-
is contraindicated in the frail elderly because of this ateness of surgery in the elderly. Experienced sur-
effect, this has long been known to clinicians. geons and anaesthetists should make any deci-
The concern that all antimuscarinics have sions regarding surgery.
this effect has been addressed in the literature Frailty has been shown to independently pre-
on OAB. Recently, the SOFIA trial studied the effi- dict postoperative complications, length of stay,
cacy, tolerability, and safety of fesoterodine, an and discharge to care homes. However, it is im-
anticholinergic, in 794 individuals over the age of portant not to discount such management purely
65, providing robust data in the elderly age group. on the basis of age, and “physiological age” is an
It was a prospective, randomized, double-blind, increasingly common concept in modern surgery
placebo-controlled multicentre trial that inves- within the ageing population.
tigated the effect of fesoterodine on the symp- In patients with prolapse, pessaries or surgery
toms of OAB and specifically examined cognitive can be considered. Prolapse does not tend to cause
function. The trial established that fesoterodine stress incontinence. However, anterior repair with
reduced OAB symptoms and that there was no urethral buttressing whilst no longer a recommend-
significant reduction in cognitive function demon- ed treatment for SUI in the younger population,
strated by monitoring of the MMSE. may be of value in the frail elderly with concomitant
There was a meta-analysis of the effects of SUI and anterior vaginal wall prolapse.
antimuscarinics on health-related quality of life, The use of pessaries in the frail elderly is often
which includes cognition, in OAB treatment by well tolerated and if effective may avoid the need for
Khuller, et al, 2006, which showed that treatment surgery.

Incontinence associated with CONCLUSION

incomplete bladder emptying Chronological age is no indicator of frailty. Treat-
Medication review is essential as anticholinergic ment options in the biologically young cognitively
medications can increase incomplete bladder intact female should not differ from those of the
emptying and should be avoided. Constipation chronologically young.
should be avoided. Specific treatment depends The frail older woman is disproportionate-
on the cause. ly more disadvantaged by UI. It can affect both
social and domiciliary functioning and negatively
URINARY INCONTINENCE AND impact on their relationship with their carers. The
COGNITIVE IMPAIRMENT supposition that the frail female will inevitably be
The incidence of dementia rises substantially after incontinent and that nothing can be done to alle-
the age of 75, and UI in the cognitively impaired viate her symptoms is a myth.
can range from 11% in an outpatient setting to 90% The importance of comprehensive medi-
in care homes. Dementia can cause UI by a variety cal and multidisciplinary assessment cannot be
of mechanisms ranging from decreased motiva- overemphasized. Goal setting that is realistic and
tion and initiative to go to the toilet, social disinhi- perhaps based on improvement rather than abso-
bition, decreased executive function, immobility or lute cure can be more appropriate in this group.
gait disturbance, or even severe autonomic failure. Assessment of functional status, carer availability,
In Alzheimer’s disease UI presents an average and cognition allows these goals to be tailored to
of 6.5 years after dementia onset. However, in Lewy the needs of the individual. Avoidance of consti-
Body Dementia UI presents sooner after dementia pation, appropriate medication review, promotion
onset (3.2 years) and in vascular dementia UI can of hygiene, and availability of appropriate aids
precede dementia onset by 5 years or more. and containment products can help frail older
Managing UI in the patient with cognitive im- women maintain social activity and to remain in
pairment presents a challenge. Patients are often their preferred environment.
difficult to assess as they may not be able to give
an accurate history and may not comply with ex- FURTHER READING
1. Abrams P, Cardozo L, Fall M. The standardisation of terminology of lower
amination or investigations. Patients with demen- urinary tract function: report from the Standardisation Sub-committee
of the International Continence Society. Neurourol Urodyn 2002; 21:
tia tend to have other major comorbidities and 167–78.
2. Chapple C, Khullar V, Gabriel Z, Dooley JA. The effects of antimuscarin-
may be on medications that cause UI. They are ic treatments in overactive bladder: a systematic review and meta-anal-
ysis. Eur Urol 2005; 48: 5–26.
more likely to be susceptible to the side effects 3. DuBeau C, Kuchel G, Johnson T, Palmer M, Wagg A. Incontinence in
the frail elderly: report from the 4th International Consultation on Inconti-
of drugs, particularly anticholinergics and may be nence. Neurourol Urodyn 2010; 29: 165–78.
4. Khullar V, Chappel C, Gabriel Z, Dooley JA. The effects of antimuscarin-
on other drugs that interact with medications for ics on health-related quality of life in overactive bladder: a systematic
review and meta-analysis. Urology (Impact Factor 2.42) 09/2006; 68(2
UI. Patients may be difficult to nurse, may pull out Suppl):38–48.
5. Staskin DR, Peters KM, MacDairmid S, Shore N, de Groat WC. Percu-
catheters, and pads putting significant strain on taneous tibial nerve stimulation: a clinically and cost-effective addition
to the overactive bladder algorithm of care. Curr Urol Rep 2012 Oct; 13:
carers. However, the benefits of any improvement 327–34.
6. Wagg A, Verdejo C, Molander U. Review of cognitive impairment with
in continence in this patient group cannot be un- antimuscarinic agents in elderly patients with overactive bladder. Int J
Clin Pract Aug 2010; 64: 1279–86.
Methods such as prompted and timed toilet- © 2017 Elsevier Ltd. All rights reserved. Initially published in Obstetrics, Gy-
naecology and Reproductive Medicine 2017;28(2):39–45.
ing are effective and avoiding constipation is im-
portant. A medication review is vital in these pa- About the authors
Gabrielle Prud’homme is a GP Registrar at Barnsley Hospital NHS Founda-
tients. Anticholinergic drugs can be considered but tion Trust, UK. Conflict of interest: none declared.

use with care (see Box 5 and Table 3). NICE clinical Leanne Alexander is a Speciality Doctor in Geriatric Medicine at Barnsley
Hospital NHS Foundation Trust, UK. Conflicts of interest: none declared.
guideline on Urinary incontinence in neurological
Susan Orme is a Consultant in Geriatric Medicine at Barnsley Hospital NHS
disease provides advise for patients with dementia. Foundation Trust Hospital, Barnsley, UK. Conflicts of interest: none declared.

Human Papillomavirus 2 SKP

and Cervical Cancer

Ka Yu Tse, MRCOG, Cert RCOG (Gyn Onc); Philip Pun Ching, Ip FRCPath, FHKCPath; Karen Kar Loen Chan, FRCOG, Cert RCOG (Gyn Onc)

Cervical cancer is the fourth most com-
mon cancer in women in the world, and
there were about 528,000 new patients
and 266,000 deaths in 2012. In Hong
Kong, its crude incidence rate dropped
from about 14 per 100,000 women
in late 1990s to around 10.5 in early
2010s, and is currently the 9th com-
monest female cancer. (Table 1a and
1b)1 This phenomenon may be attrib-
uted to the implementation of cervical
smear screening programme. Never-
theless, it remains as the 8–9th lead-
ing cause of female cancer death over
the last decade and the crude mortal-
ity rate rose from its trough at 3.0 per
100,000 women in 2003 to 4.0 in 2011.
From these results, it is obvious that
cervical cancer still poses a threat to
women’s health. This article aims to Cervical cancer is the fourth most common cancer in the world — with about 528,000
review the causal relationship between patients diagnosed in 2012.
human papillomavirus (HPV) and cervi-
cal cancer and discuss existing meth- it HPV type 16, which 61.1 percent of in the anogenital tract diseases.5 HPV
ods that prevent HPV from leading to the cervical cancer samples from their is present in about 90% of high-grade
cervical cancer. German cohort revealed this DNA. 3
cervical intraepithelial neoplasia (CIN)
One year later they found another and cervical cancer 6
(Figure 1) and
BIOLOGY OF HUMAN virus in their cervical cancer cell lines 70–80% are related to HPV-16 and 18.
PAPILLOMAVIRUS and biopsy samples and designated Other high-risk subtypes of HPV in-
Herpes simplex virus was once con- it as HPV 18.4 They also hypothesized clude 31, 33, 35, 39, 45, 51, 52, 56, 58,
sidered the culprit for cervical cancer. that the viral DNA might be integrated and 59 as classified by the International
Professor Zur Hausen first proposed into the host cell genome. After this Agency for Research on Cancer.7 They
the possible association of HPV with initial work, extensive research was are acquired sexually. Other routes of
genital cancer in 1970s.2 In 1983, his performed on this virus. More than 100 transmission, like vertical transmission
team identified new HPV DNA from HPV subtypes have now been identi- from mothers to infants, have also been
one cervical cancer biopsy and named fied and more than 40 are implicated described.

Table 1a. Incidence of Cervical Cancer in 1995–2011 in Hong Kong 1

Years New cases Rank in new female Crude incidence Age standardised Median age at
registered cancer rate* rate* diagnosis
1995 498 NA 16.2 14.8 NA
1996 445 NA 13.8 12.5 NA
1997 474 NA 14.6 12.4 NA
1998 491 4 14.9 11.6 53
1999 436 4 13 9.8 54
2000 444 5 13.1 10.7 53
2002 442 5 12.7 9.9 52.5
2003 408 5 11.6 8.9 50
2004 439 5 12.3 9.4 54
2006 459 5 12.8 9.4 54
2007 399 7 11 7.7 52
2010 400 10 10.7 7.3 NA
2011 391 9 10.4 7.2 53
NA – not applicable
*All rates are expressed as per 100,000 women.

HPV is a non-enveloped virus gene product which plays an impor- peak at ≥45 years in the Americas and
containing double-stranded circular tant role in apoptosis and cell growth Africa. In Hong Kong, the HPV preva-
DNA. The DNA sequence consists of arrest. On the other hand, E7 protein lence was estimated to be 6.7% with
early and late open reading frames, binds to and inactivates retinoblasto- a peak at 26–30 years followed by an-
encoding proteins E1–8 and L1–2, re- ma (Rb) protein which regulates cell other smaller peak at 46–55 years. 10
spectively. HPV usually targets at the cycle by controlling the transition at Young age, having ≥4 sexual partners
proliferating basal cells of the squa- G1/S phase. E4 protein may further and smoking were independent risk
mous epithelium. Once inside the cell, disrupt the cytoplasma cytokeratin factors for HPV infection on multivar-
the viral genome replicates migrating matrix mediating the release of HPV iate analyses. About half of the HPV
away from the basal layer to the upper particles. infection persists for 6–12 months,
epithelium. The episomal HPV DNA is A meta-analysis comprising of and high-risk HPV persists longer than
also integrated into the host genome 194 studies and more than one million low-risk HPV (9.3 vs 8.4 months). 11 Up
and the viral genome usually opens in women with normal cervical cytology to 70–100% of the HPV infection can
the E1–2 region. E2 is a repressor of showed that the global prevalence of be cleared in 2–5 years especially in
the E6–7 promoter, disruption of which HPV infection was 11.7% (confidence young women. 12 About 1.6% of high-
will result in unregulated expression of interval [CI], 11.6–11.7) and was up grade CIN would progress to cancer
E6 and E7. 8 E6 protein of those high- to 24.0% in Sub-Saharan Africa.9 The in 10 years if left untreated and the
risk HPV acts by binding to and thus prevalence was highest in women median time is 23.5 years (95% CI,
inactivating TP53 tumour suppressor younger than 25 years, with a second 20.8–26.6 years). 13

Table 1b. Mortality of Cervical Cancer in 1995–2011 in Hong Kong 1

Years Deaths Rank in female Crude mortality Age standardised Median age at
registered cancer deaths rate* rate* death
1995 159 NA 5.2 4.6 NA
1996 134 NA 4.2 3.5 NA
1997 144 NA 4.4 3.8 NA
1998 145 7 4.4 3.2 68
1999 159 7 4.8 3.5 64
2000 128 8 3.8 3 68
2002 121 9 3.5 2.6 68
2003 106 >10 3 2.1 69
2004 128 8 3.6 2.6 66
2006 133 9 3.7 2.4 66
2007 129 8 3.5 2.3 70
2010 146 9 3.9 2.4 NA
2011 151 8 4 2.5 63
NA – not applicable
*All rates are expressed as per 100,000 women.

HUMAN PAPILLOMAVIRUS The HPV testing was first ap- 75%.18-20 In a recent meta-analysis, the
TESTING proved by the US Food and Drug Ad- pooled sensitivity of HC2 in detecting
It has been shown that conventional ministration (FDA) in 1988 but was only CIN 2+ was higher than that of repeat-
cytology only has 76% sensitivity of de- used for follow-up of ASCUS (atypical ing cytology, with relative sensitivity of
tecting CIN 2 or worse (CIN 2+). 14
On squamous cells of undetermined sig- 1.27 (95% CI, 1.16–1.39; p<0.0001)
the other hand, some centres found that nificance) in 1999. The ASCUS/LSIL and 1.23 (95% CI, 1.06–1.4; p=0.007)
liquid-based cytology is not more sensi- (low-grade squamous intraepithelial for patients with ASCUS and LSIL, re-
tive or specific than conventional cytolo- lesion) Triage Study (ALTS) was one of spectively.21 However, while the spe-
gy, though it can reduce the rate of un- the earliest studies demonstrating an cificities between the two methods in
satisfactory smears as by conventional improved sensitivity of detection of CIN triaging patients with ASCUS were sim-
cytology and allow HPV testing in the 3 by triaging patients to colposcopy ilar, specificity of HC2 was significantly
same specimen. 15-16
In order to optimize based on testing high-risk HPV DNA by worse than that of repeating cytology
the performance of cervical screening Hybrid Capture 2 (HC2) and thin-layer in case of LSIL (relative specificity 0.66,
in detecting high-grade CIN and cancer, cytology results. 17
Subsequently, var- 95% CI, 0.58–0.75; p<0.0001). Using
the role of HPV testing has been evalu- ious studies showed that HPV-based cancer as the study endpoint, Ronco,
ated in different settings such as prima- screening strategies had approximate- et al, had pooled the results of four
ry screening either as a stand-alone test ly 95% sensitivity in detecting CIN 2+, European randomized trials including
or co-test, triage for low-grade lesions, when compared with cytology tests the Swedescreen, POBASCAM, AR-
and follow-up after treatment of CIN. where the sensitivity was between 55– TISTIC, and NTCC, and found that the

ative for both can be co-tested again

in 12 months.
A survey conducted in April 2012
by the Department of Health in Hong
Kong found that, only 69.2% of women
had ever had a cervical smear and near-
ly 44% did not have a cervical smear in
the last 3 years.26 With HPV co-testing or
triage with HPV testing can potentially
Figure 1 (A): High-grade squamous intraepithelial lesion (CIN II) involving cervix; and (B): reduce the number of repeating cytolo-
Cell cycle marker p16 immunostain shows diffuse block staining, serves as a surrogate
gy and may alleviate the problem of de-
marker for high-risk HPV infection.
faulting. HPV testing using self-collect-
ed samples may be an another option to
study-adjusted rate ratio for invasive copy and treatment. Primary screening improve screening coverage, although
cervical carcinoma after a median fol- by HPV testing alone is also not rec- this is slightly less sensitive and spe-
low-up of 6.5 years was 0.60 (95% CI, ommended because of concerns about cific compared with samples taken by
0.40–0.89) for HPV-based screening the possible increase in colposcopy clinicians.27
compared with cytology-based screen- referrals.
ing.22 Although there was no difference Currently there are five HPV tests HUMAN PAPILLOMAVIRUS
in the detection rate of cancer between approved by the US FDA to detect VACCINES
the two methods during the first 2.5 the presence of high-risk HPV. Some There are two HPV vaccines available
years, it became significantly lower in have found that it is more sensitive in the world. The bivalent vaccine cov-
the HPV-based screening arm thereaf- than cytology alone in detecting CIN ers HPV 16 and 18, and is approved
ter (0.45, 95% CI, 0.25–0.81). 3+ (92.0% vs 53.5%; p<0.0001), and to prevent cervical cancer and its pre-
Because of the better sensitivity the sensitivity was further increased cursors in females 9 years and above.
and negative predictive value of HPV to 96.7% when combining the two The quadrivalent vaccine prevents HPV
testing than cervical cytology, it is rec- methods compared with HPV testing 6-, 11-, 16-, and 18-related diseases,
ommended by the American Cancer alone. 24 In a recent review, using the including cervical, vulval, and vaginal
Society (ACS), the American Society New Mexico HPV Pap Registry, 35.7% cancers and their precursors, as well
for Colposcopy and Cervical Pathology of CIN 2+ and 30.9% of CIN 3+ were as genital warts in females and males
(ASCCP), and the American Society of diagnosed following normal cytology, 9 years and above. It is noteworthy that
Clinical Pathology (ASCP) that women among which 62.3% and 78.2%, re- direct comparison between the two
be screened every 3 years with cytolo- spectively, were positive for high-risk vaccines is not possible without proper
gy alone or at 5-year interval using cy- HPV.25 The ACS/ASCCP/ASCP advo- trials due to different vaccine prepara-
tology and high-risk HPV co-testing. 23
cates testing the HPV 16 and 18 gen- tions, study design and cohorts.
For patients with ASCUS, those posi- otypes specifically in order to triage
tive for high-risk HPV will be referred for women over 30 years who have nor- Efficacy
colposcopy, while those negative are mal cytology but positive pooled high- Multiple phase III trials have confirmed
advised to have co-testing in 3 years. risk HPV tests.23 These women can ei- the efficacy of the two vaccines. For biva-
HPV testing is not recommended for ther be followed up in 12 months with lent vaccine, the PApilloma TRIal against
women below the age of 30 because repeat cytology and HPV test, or be Cancer In young Adults (PATRICIA)
of the high prevalence and clearance genotyped for HPV 16 and 18. For the study showed an efficacy up to 90.4%
rate of HPV infection in young patients latter, if either HPV 16 or 18 is positive, (97.9% CI, 53.4–99.3; p<0.0001) against
which may otherwise lead to over-diag- women would then be referred for col- CIN 2 or 3, adenocarcinoma (AIS), and
nosis and hence unnecessary colpos- poscopy, whereas those who are neg- invasive carcinoma associated with HPV

16 and 18 in the total vaccinated cohort

(TVC)–naïve group (ie, those who were
DNA and serum negative at entry) after a
mean follow-up of 14.8 months.28 Using
CIN 3 and AIS or worse as endpoints, the
4-year end-of-study of the PATRICIA trial
showed that the efficacy against those
HPV 16/18-related lesions was 100%
(95% CI, 85.5–100) in the TVC-naïve
group and 45.7% (95% CI, 22.9–62.2) in
the TVC group (ie, those who received at
least one vaccine dose including those
who were sexually active irrespective of
baseline HPV status).29 The HPV vaccine
also reduced the number of colposcopy
referrals by 29.0% (95% CI, 21.6–35.8)
and 14.8% (95% CI, 8.9–20.3), and cer-
vical excisional procwedures by 70.2%
(95% CI, 57.8–79.3) and 33.2% (95% CI,
20.8–43.7) in the TVC-naive and TVC, re-
Combining the data of four similar
studies including the Females United
to Unilaterally Reduce Endo/Ectocervi- There are two HPV vaccines available in the world. The bivalent covering HPV 16 and 18
cal Disease (FUTURE) I and II studies, is approved for females 9 years and above.
a recent review evaluated the efficacy
of quadrivalent vaccine in prevent- vaccines based on the combined re- Cross-protection
ing HPV 16/18-related CIN 2–3, AIS in sults of the FUTURE I and II trials, with As HPV 16 and 18 constitutes only about
those aged 16–26 years after a 3-year an efficacy of 96% for CIN I (95% CI, 70–80% of cervical cancer, cross-protec-
follow-up.30 In the per-protocol suscep- 91-98) in the per protocol susceptible tion against other non-vaccine oncogen-
tible group (ie, those who were naïve group. 31
The results were similar to ic HPV types can potentially further pre-
to HPV 16/18 as shown on DNA or the PATRICIA trial, which also showed vent cervical cancer. The end-of-study
serologic tests at enrolment, received modest efficacy against HPV 16/18-as- analysis of the PATRICIA study after 4
all vaccine doses within 1 year with- sociated CIN 1+ (89.2%, 97.9% CI, years of follow-up evaluated the efficacy
out protocol violations, and remained 59.4–98.5; p<0.0001). 28
of bivalent vaccine in its cross-protection
DNA-negative for the specific HPV A recent randomized controlled trial in- against HPV 31, 33, 35, 39, 45, 51, 52, 56,
types through 1 month after the admin- volving 1,781 sexually naïve boys and girls 58, 59, 66, and 68. The efficacy against
istration of the last vaccine or placebo). aged 9–15 years showed that anti-HPV re- 6-month persistent infection with HPV 31
The overall efficacy against these le- sponse induced by quadrivalent HPV vac- was 76.8%, 77.1%, and 46.3% in accord-
sions was 99% (95% CI, 93–100), while cine persisted over 96 months. Besides,
ing-to-protocol cohort for efficacy (ATP-E,
it was 44% (95% CI, 31–55) in the inten- none of the 429 adolescents who received ie, those who were HPV DNA negative at
tion-to-treat group (ITT) (ie, including the vaccine at mean age of 12 developed enrolment and at 6 months for the spe-
those with previous infection). HPV 6/11/16/18-releated diseases or cific HPV type being analysed, adhered
On the other hand, low-grade le- persistent infection of ≥12 months’ to the protocol and had a normal or low-
sions could also be prevented by HPV duration. grade baseline cytology), TVC-naïve (ie,

those who received at least one vaccine which were comparable to those with- Acceptability
dose and HPV DNA for all 14 HPV types out vaccination. 28-29,36
The Global Advi- Any programme will become futile with-
and seronegative for HPV 16 and 18 and sory Committee on Vaccine Safety of out public awareness and acceptability.
had a negative baseline cytology) and the World Health Organization (WHO) A questionnaire study involving more
TVC, and that with HPV 33 was 44.8%, advised that the vaccine is safe though than 1,000 mothers in 2008 and 2012
43.1%, and 26.3%, respectively. 33
For continuous surveillance is necessary. 37
showed that 68.5% (95% CI, 65.5–71.3)
CIN 2+ lesions not related to HPV 16/18, mothers in 2012 had heard of HPV, in
consistent protective effect was ob- Cost-effectiveness comparison of 40.5% (95% CI, 37.5–
served in HPV 31 in all cohorts and was Despite the heterogeneity among differ- 43.6) in 2008.42 Vaccine cost, low family
up to 84.3% (95% CI, 59.5–95.2) in the ent studies, most concluded that HPV income, low maternal education level,
ATP-E and 83.4% (95% CI, 43.4–96.9) in vaccination is cost-effective especially uncertainty about the effect duration,
the TVC-naïve. Efficacy against HPV 33 in young girls before sexual debut, and low perceived risk of HPV infection, an-
was also noted in the ATP-E (59.4%, 95% in middle-low and low-income countries ticipated family or peer disapproval, fear
CI, 20.5–80.4) and TVC-naïve (76.3%, where there is a high burden of cervi- of pain, and lack of support from the
95% CI, 35.5–93.0). On the other hand, cal cancer, and the screening system is care providers and the government, can
quadrivalent HPV vaccine could reduce not well established. 38-39
A WHO-funded all hinder the vaccine uptake.43-44 Inten-
HPV 31/45 infection by 40.3% (95% CI, study estimated that vaccination of 58 tion of the adolescents to receive HPV
13.9–59.0) and CIN 1–3 or AIS by 43.6% million 12-year-old girls before sexual vaccination and the acceptability of the
(95% CI, 12.9–64.1) in patients negative debut across 179 countries could pre- mothers could be improved by enhanc-
for 14 non-vaccine HPV types. 34
Similar vent 690,000 cases of cervical cancer ing their knowledge using information
to bivalent vaccine, the most remarkable and 420,000 deaths during their lifetime pamphlets and education programs.43-45
protective effect was observed in HPV at a net cost of US$ 4 billion. By com-

31. Nevertheless, it appears that these paring the cost per disability-adjusted CONCLUSION
cross-protective effects fade with time life-years (DALYs) averted with the gross The introduction of cervical cytology
and further study and vaccine modifica- domestic product (GDP) per capita, screening and HPV vaccine has not
tion are definitely needed. HPV vaccination was considered to be been translated into a decrease in cervi-
very effective in 156 (87%) countries. cal cancer mortality in Hong Kong. One
Safety Medical expenses may further be of the possible reasons is the relatively
Although early post-licensure reviews reduced by herd protection from male low screening and vaccination cover-
reported that the incidence of venous vaccination, protection against non-cer- age. There has been robust evidence
thromboembolism appeared higher vical diseases, reduction of abnormal that HPV co-testing can improve the
than expected, this phenomenon could cervical smear results and hence col- effectiveness of cervical cancer screen-
not be confirmed by other series. 35
In poscopic examinations and excision- ing, where colposcopy referral can be-
fact, HPV vaccines are relatively well tol- al procedures, and the introduction of come more efficient and the screening
erated. Those receiving vaccines tend nonavalent HPV vaccine. In addition, interval may also be lengthened. Nev-
to have more fatigue, headache, and the Strategic Advisory Group of Experts ertheless, a stringent tracking system
myalgia within 7 days of vaccination on Immunization (SAGE) has just an- on women’s adherence is mandatory.
compared with the control group. 28
Se- nounced that the two-dose schedule The impact of other novel tests such
rious complications related to the vac- given within a minimum of 6-month in- as testing for mRNA of high-risk HPV
cine was rare and occurred in <0.1% of terval is not inferior to the convention- and immunostaining of p16INK4a and
the vaccination population.28-29 Adverse al 3-dose schedule (at 0, 1–2, and 6 Ki-67 remains to be further elucidated.
pregnancy outcomes such as sponta- months) especially in girls younger than On the other hand, until now HPV vac-
neous miscarriage and abnormal in- 15 years. This, in turn, may reduce the cination is still not incorporated into the
fants occurred in 7–10% and 1–2.5%, number of visits and hence the cost of government-funded routine vaccination
respectively, in the vaccination group, vaccination.41 programme, and many women are not

aware or have misconceptions about long-term efficacy, cost-effectiveness, About the authors
Dr Ka Yu Tse and Dr Karen Kar Loen Chan are specialists at
HPV infection. Improving public knowl- and public attitude of these strategies, the Department of Obstetrics and Gynaecology, Queen Mary
edge can enhance the acceptability and is required to facilitate policy-makers to Hospital, the University of Hong Kong, Hong Kong.

uptake of cervical cancer screening and define a better algorithm to prevent cer- Philip Pun Ching Ip is a specialist at the Department of Pa-
thology, Queen Mary Hospital, the University of Hong Kong,
HPV vaccination. More research on the vical cancer. Hong Kong.

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Program pendidikan kedokteran berkelanjutan ini dipersembahkan oleh

MIMS, bekerjasama dengan Ikatan Dokter Indonesia.
Setelah membaca artikel ‘Human Papillomavirus and Cervical Cancer’,
jawab pertanyaan berikut kemudian kirimkan dengan menggunakan
formulir jawaban yang sudah disediakan ke CME MIMS Journal of
Paediatrics, Obstetrics & Gynaecology, untuk mendapatkan 2 SKP.


Human Papillomavirus and Cervical

Cancer 2 SKP

Jawab pertanyaan di bawah ini dengan Benar atau Salah.

1. E6 protein of high-risk HPV inactivates retinoblastoma TP53 while E7 protein inactivates TP53.
2. HPV testing can improve the sensitivity and specificity in detecting high-grade cervical intraepithelial
3. Women who are found to have ASCUS but are negative for high-risk HPV can be followed up with
cytology and HPV-testing again in 12 months.
4. According to the ACS/ASCCP/ASCP guidelines, women who have negative cytology but positive pooled
high-risk HPV test still require a colposcopy referral.
5. HPV testing is not recommended for women below the age of 30 due to the high prevalence and
clearance rate of HPV infection in young patients.
6. The most remarkable cross-protection effect of the bivalent and the quadrivalent vaccines is against HPV-
33 with an efficacy of up to 90 percent.
7. There have been reports that the incidence of venous thromboembolism was higher than expected for
those receiving HPV vaccination.
8. HPV vaccination is still more cost-effective in young girls before sexual debut than those who are sexually
9. Until now there is still no evidence for reducing the vaccination schedule from three-doses to two-doses.
10. Vaccine cost and fear of disapproval by family and friends can negatively affect the acceptability of HPV