INDONESIA • 2018

ISSN 2411-0183
VOL. 44 NO. 2

JOURNAL OF PAEDIATRICS,
OBSTETRICS & GYNAECOLOGY

YOUR PARTNER IN PAEDIATRIC, OBSTETRIC & GYNAECOLOGY PRACTICE

GYNAECOLOGY
Endometriosis
Update

OBSTETRICS
Urogynaecological
Complications in
Pregnancy: An Overview

CME ARTICLE
Fertility Preservation
in Young Female Cancer
Patients
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 MIMS JPOG 2018 VOL. 44 NO. 2 i

2018 VOL. 44 NO. 2

Editorial Board
CONFERENCE COVERAGE
Board Director, Paediatrics
Royal College of Obstetricians & Gynaecologists
Professor Pik-To Cheung
Associate Professor, Department of Paediatrics and Adolescent Medicine (RCOG) World Congress 2018, March 21-24,
The University of Hong Kong, Hong Kong
Singapore
Board Director, Obstetrics and Gynaecology
Professor Pak-Chung Ho
Director, Centre of Reproductive Medicine 45
The University of Hong Kong - Shenzhen Hospital, China
• Heavy menstrual bleeding tied
to high prevalence of bleeding
disorders
Professor Biran Affandi Professor Seng-Hock Quak
University of Indonesia, Indonesia National University of Singapore,
Professor Hextan
Singapore 46
Yuen-Sheung Ngan Adjunct Associate Professor
Tan Ah Moy • Isoxsuprine, nifedipine similarly
The University of Hong Kong, Hong Kong
KK Women’s and Children’s Hospital, effective in preventing preterm
Professor Kenneth Kwek Singapore
KK Women’s and Children’s Hospital, birth
Singapore Dr. Catherine Lynn Silao
University of the Philippines Manila,
Professor Kok Hian Tan
KK Women’s and Children’s Hospital,
Philippines 47
Dwiana Ocviyanti, MD, PhD
Singapore
University of Indonesia, Indonesia • Ferric carboxymaltose elevates
Professor Dato’
Dr. Karen Kar-Loen Chan Hb levels in women with iron
Dr. Ravindran Jegasothy
Dean Faculty of Medicine,
The University of Hong Kong, deficiency anaemia
Hong Kong
MAHSA University, Malaysia
Dr. Kwok-Yin Leung
Associate Professor Daisy Chan The University of Hong Kong,
Singapore General Hospital, Singapore Hong Kong
Associate Professor Raymond Dr. Mary Anne Chiong
Hang Wun Li University of the Philippines Manila,
The University of Hong Kong, Hong Kong
Adjunct Associate Professor
Philippines
Dr. Wing-Cheong Leung
JOURNAL WATCH
Kwong Wah Hospital, Hong Kong,
Ng Kee Chong Hong Kong
Division of Medicine & Academic Clinical
Program (Paediatrics), c/o KK Women’s and
Children’s Hospital, Singapore
48
• Fast food tied to infertility in women
• Hypothyroidism after TKIs in women with cancer may
help boost survival
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 MIMS JPOG 2018 VOL. 44 NO. 2 iii

2018 VOL. 44 NO. 2

REVIEW ARTICLE
PAEDIATRICS
CEO Yasunobu Sakai
Managing Editor Elvira Manzano
Medical Editor Elaine Soliven
Designer Sam Shum
49
Production Tetsuya Hamaki, Agnes Chieng, Raymond Choo
Circulation Christine Chok Chronic Arthritis in Children and Young People
Accounting Manager Minty Kwan
Advertising Coordinator Pannica Goh
Arthritis affects 1 in 1,000 children and
young people (CYP), and is a major
Published by: cause of potential morbidity, with
MIMS (Hong Kong) Limited
27th Floor, OTB Building, 160 Gloucester Road, Wan Chai, Hong Kong significant long-term consequences,
Tel: (852) 2559 5888 | Email: enquiry@mimsjpog.com
joint damage, and disability if left
untreated. Diagnosing juvenile idiopathic
arthritis (JIA) can be challenging, and
relies on clinical assessment. Investigations are helpful to exclude
Enquiries and Correspondence other conditions, but are often normal in JIA at presentation. The
China Philippines
history can be vague, and the child may be too young to verbalize
Yang Xuan Rowena Belgica symptoms, detailed probing for inflammatory symptoms, and
Tel: (86 21) 6157 3888 Tel: (63 2) 886 0333
Email: enquiry.cn@mims.com Email: enquiry.ph@mims.com a comprehensive examination of the child’s joints are therefore
Hong Kong Singapore essential.
Jacqueline Cheung Josephine Cheong, Carrie Ong, Michael Hughes, Ruth Wyllie, Helen Foster
Tel: (852) 2559 5888 Wendy Soh
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Nguyen Thi Lan Huong,
60
Email: inquiry@kimsonline.co.kr Nguyen Thi My Dung
Tel: (84 8) 3829 7923 Endometriosis Update
Indonesia Email: enquiry.vn@mims.com
Fatmawati, Fransiska Simamora, Endometriosis is a common, chronic
Ruth Theresia, Sari Wiyanti
Tel: (62 21) 729 2662 condition that affects women of
Email: enquiry.id@mims.com childbearing age. It can significantly
Malaysia impact a woman’s quality of life, her
Tiffany Collar, Sumitra Pakry,
Sharon Ong, Wong Wen Dee fertility, and ability to work. Awareness
Tel: (60 3) 7623 8000 of the condition is increasing amongst
Email: enquiry.my@mims.com
the general population, with drives to
improve the services available to women. The National Institute
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iv MIMS JPOG 2018 VOL. 44 NO. 2

2018 VOL. 44 NO. 2

REVIEW ARTICLE MIMS JPOG welcomes papers in the

following categories:
OBSTETRICS
Review Articles
Comprehensive reviews providing the latest clinical information
73 on all aspects of the management of medical conditions affecting
children and women.
Urogynaecological Complications
in Pregnancy: An Overview Case Studies
The urinary tract undergoes numerous Interesting cases seen in general practice and their management.
physiological adaptions in response to
pregnancy. These normal adaptions can
Pictorial Medicine
Vignettes of illustrated cases with clinical photographs.
increase the risk of complications, such
as acute infection and urinary retention, For more information, please refer to the Instructions for Authors
which in turn increase the risk of poor on our website www.jpog.com, or contact:
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Samantha Cox, Fiona Reid E-mail: enquiry@mimsjpog.com

CONTINUING
MEDICAL EDUCATION
81
Fertility Preservation in Young Female
Cancer Patients 2 SKP

Advancement of diagnosis and treatment of cancer has increased

the disease-free interval and overall survival rate in young cancer
patients. However, anticancer treatment including adjuvant
chemotherapy and radiotherapy may be highly detrimental to the
female endocrine and reproductive function. As a consequence,
there is increasing awareness for the need to preserve gonadal
function and fertility especially in young cancer patients undergoing
gonadotoxic treatments.
Jacqueline Chung Pui Wah, Grace Kong Wing Shan, Li Tin Chiu
The Cover:
Chronic Arthritis in Children and Young People
©2018 MIMS Pte Ltd

Peggy Tio, Designer

MIMSmobileapp-New-206x276-0417-4c.pdf 3 16/6/17 11:32 am

EMPOWERING
HEALTHCARE
COMMUNITIES
CONFERENCE COVERAGE
Royal College of Obstetricians & Gynaecologists (RCOG) World Congress 2018, March 21-24,
Singapore – Elaine Soliven reports
Heavy menstrual bleeding
tied to high prevalence of
bleeding disorders
Bleeding disorders, such as Von Wille-
brand disease (VWD), platelet function
disorder (PFD), thrombocytopenia, and
clotting factor deficiencies, are more prev-
alent among adolescent girls with heavy
menstrual bleeding (HMB), according to
a study presented at RCOG 2018.
“It is important to identify bleeding
disorders in the adolescent female pop-
ulation because the obstetric and gy-
naecologic morbidity goes beyond trou-
blesome heavy periods … [as] they are
at increased risk of surgical and obstet-
ric haemorrhage,” according to study
lead author Dr Brooke O’Brien from the
Queensland Paediatric and Adolescent
Gynaecology (PAG) Service at the Chil-
dren’s Health Queensland Hospital and
Health Service, Brisbane, Australia.
Using data from the Queensland PAG
Service between July 2007 and 2017, the
researchers retrospectively analysed 124
adolescents with HMB (average age 14
years and 3 months), of whom 62.1 per-
cent (n=77) were screened for bleeding
disorder and 86.3 percent (n=107) un-
derwent an iron deficiency and/or anae-
mia screening. [RCOG 2018, abstract
KO6055]
Overall, a 35 percent prevalence
of bleeding disorder was observed in
patients with HMB, and treated with
hormonal therapies (n=96 percent),
tranexamic acid (n=87 percent), iron
therapy (n=70 percent), and combined
oral contraceptive pill (n=61 percent).
“HMB is a common gynaecologi-
cal complaint among adolescents … A
significant proportion of adolescent girls
with HMB referred to a PAG clinic will
have a bleeding disorder, and the preva-
MIMS JPOG 2018 VOL. 44 NO. 2 45
lence in this study is consistent with the
literature,” O’Brien noted.
Among HMB patients with bleeding
disorder, results showed that VWD was
the most common type of bleeding dis-
order, mainly type 1 VWD at 30 percent
and low VWD at 22 percent, followed by
other inherited platelet disorder at 19
percent, dense body deficiency at 15
percent, thrombocytopenia at 11 per-
cent, and factor deficiency at 3 percent.
Of the 49.5 percent (n=53) patients
diagnosed with iron deficiency and/or
anaemia, a 70 percent higher incidence
of bleeding disorder was noted. Two of
the patients with bleeding disorder had
a blood transfusion due to HMB-related
episodes.
O’Brien recommended that “se-
vere bleeding episodes may benefit
from directed therapies, such as desm-
opressin or clotting factor concentrates,
and these agents may be valuable in
perioperative prophylaxis and treatment
of surgical and obstetric haemorrhage,”
but highlighted that these should be
prescribed under the supervision of the
treating haematologist depending on
the condition.
“A higher level of awareness of these
conditions, especially VWD and PFD, is
needed, and close collaboration between
gynaecologists and haematologists in a
specialised tertiary centre should be es-
tablished in the management of these
patients. Accurate and early recognition
of bleeding disorders in the adolescent
is critical for the management of bleeding
complications and optimization of therapy
for HMB,” she added.
Dr Brooke O’Brien, et al, Royal College of Obstetricians &
Gynaecologists (RCOG) World Congress 2018, March 21-24,
Singapore [abstract KO6055].
46 MIMS JPOG 2018 VOL. 44 NO. 2
Royal College of Obstetricians & Gynaecologists (RCOG) World Congress 2018, March 21-24,
Singapore – Elaine Soliven reports
Isoxsuprine, nifedipine
similarly effective in
preventing preterm birth
Treatment with the tocolytic agents isox-
suprine or nifedipine was similarly ef-
fective in delaying delivery by 2 weeks
among women who were admitted for
preterm labour, according to a study pre-
sented at RCOG 2018.
“The ideal tocolytic agent should
be myometrium-specific, easy to admin-
ister, inexpensive, effective in prevent-
ing preterm birth, and improve neona-
tal outcomes, with few maternal, foetal,
and neonatal side effects … The World
Health Organization also stated that
three-quarters of neonates born pre-
maturely could be saved with current,
cost-effective interventions, even with-
out intensive care facilities,” said lead
author Dr Dhanielle E. Garcia-Ramos
from the Department of Obstetrics and
Gynecology at Far Eastern University –
Dr Nicanor Reyes Medical Foundation,
Quezon City, Philippines.
The researchers retrospectively
analysed 206 women (mean age 29
years) presenting with preterm labour
(defined as labour occurring between
28 and 36 weeks of gestation) who were
given isoxsuprine (n=142) or nifedipine
(n=64). Majority of the participants were
admitted to the hospital during their
32nd week of pregnancy. [RCOG 2018,
abstract 5638]
Both nifedipine and isoxsuprine ex-
tended pregnancy by 2 weeks in aver-
age (range 0–7 weeks), and there was
no significant difference between the
two treatment groups (mean gestation-
al age at delivery, 34.8 vs 34.9 weeks;
p=0.67).
“Both nifedipine and isoxsuprine
were comparable in reducing the risk of
CONFERENCE COVERAGE
delivery within 48 hours from initiation of
treatment and before 37 weeks age of
gestation. The delay in delivery has led
to significant improvements in clinically
important neonatal outcomes such as
the Apgar and Ballard’s score for both
agents,” Garcia-Ramos said.
The researchers found no signif-
icant difference in the Apgar scores
for 1 minute (8.6 vs 8.6; p=0.84)
and 5 minutes (9.7 vs 9.7; p=0.75),
which were usually expected from ne-
onates born at >34 weeks. Ballard’s
score (35.2 vs 35.5 weeks; p=0.32)
and birthweight (2,212.6 vs 2,159.8
grams; p=0.49) were also similar
between the infants whose mothers
were treated with isoxsuprine vs with
nifedipine.
Neonatal morbidities were higher
among infants whose mothers received
nifedipine vs isoxsuprine (14.1 percent
vs 9.8 percent), although the difference
was not statistically significant.
“We noted the associated mor-
bidities with prematurity such as sep-
sis, neonatal pneumonia, and transient
tachypnoea of the newborn to occur
among the neonates of the cases who
delivered at 33 weeks and below,” said
the researchers.
However, a significantly higher in-
cidence of tachycardia was observed
in women treated with isoxsuprine vs
nifedipine (10 percent vs 0 percent;
p=0.03). “With regards to adverse
effects, nifedipine was found to be a
favourable choice ... Thus, we can re-
port that nifedipine can be better tol-
erated than isoxsuprine,” noted Gar-
cia-Ramos.
“Nifedipine is equally efficacious
as isoxsuprine in preventing preterm
birth with better maternal tolerabili-
CONFERENCE
JOURNAL WATCH
COVERAGE
PEER REVIEWED MIMS JPOG 2018 VOL. 44 NO. 2 47

Royal College of Obstetricians & Gynaecologists (RCOG) World Congress 2018, March 21-24,
Singapore – Elaine Soliven reports

ty. Therefore, this may result in better
compliance to tocolytic therapy which
can contribute to a successful out-
come,” Garcia-Ramos added, who
suggested that future research should
include women with comorbidities, and
those at higher risk of preterm labour
such as those diagnosed with multiple
gestations and premature rupture of
membranes.
Dr Dhanielle E. Garcia-Ramos, et al, Royal College of Obstetri-
cians & Gynaecologists (RCOG) World Congress 2018, March
21-24, Singapore [abstract 5638].
rum ferritin levels (147.70 vs 98.03 µg/L;
p=0.001).
In addition, mean corpuscular hae-
moglobin values were also higher among
women on FCM compared with ISC at 28
days (33.02 vs 29.32 pg; p=0.001).
More women treated with FCM
achieved a normal mean corpuscular
volume (≥80.00 fL) compared with those
treated with ISC (100 percent, increase
from 70.14 to 84.35 fL vs 43.33 percent,
increase from 69.94 fL to 78.91 percent)
at 28 days of follow-up.
lower incidence and severity of throm-
bophlebitis was observed in women
treated with ISC.
“Intravenous FCM is more effec-
tive and safer … [for] the treatment
of IDA in women,” said lead author Dr
Garima Chaudhry from the Department
of Obstetrics and Gynaecology at Lady
Hardinge Medical College, West Delhi,
Delhi, India.
“The molecular structure of FCM
ensures controlled delivery of iron
within cells of reticuloendothelial sys-

Ferric carboxymaltose
elevates Hb levels in women
with iron deficiency anaemia
Intravenous infusions of ferric carbox-
ymaltose (FCM) may increase haemo-
globin (Hb) levels in women with iron
deficiency anaemia (IDA), according
to a study presented at RCOG 2018.
Sixty women with IDA (aged >18
years, Hb level 6–8 g/dL, serum ferritin
level <15 ng/mL) were randomized in a
1:1 ratio to receive FCM (two infusions
of 500 mg) or iron sucrose complex
(ISC; five infusions of 200 mg) intra-
venously for 2 weeks. IDA was deter-
mined in patients using microcytic hy-
pochromic peripheral smear or by low
serum ferritin levels, while the Ganzoni
formula was used to calculate iron defi-
cit. Patients were followed up every 7,
14, 21, and 28 days. [RCOG 2018, ab- The increase in aspartate transam- tem and subsequent delivery to the
stract 5808] inase and alanine transaminase levels iron binding proteins ferritin and trans-
At 28 days follow-up, Hb levels was comparable between the FCM and ferrin, with minimal risk of release of
increased by 3.17 g/dL from baseline ISC treatment groups. large amounts of ionic iron in the se-
among patients in the FCM treatment Most women in the ISC treatment rum,” Chaudhry noted.
arm (n=19). group had at least one adverse event.
Dr Garima Chaudhry, et al, Royal College of Obstetricians &
Compared with women given ISC, There was a higher incidence of head- Gynaecologists (RCOG) World Congress 2018, March 21-
24, Singapore [abstract 5808].
those who received FCM had higher Hb ache and dizziness among women
(10.14 vs 8.88 g/dL; p=0.001) and se- treated with FCM and a significantly
48 MIMS JPOG 2018 VOL. 44 NO. 2
O vs 8 percent in those with the highest con-
Obstetrics
Fast food tied to infertility
in women
Women who eat a lot of fast food may
take longer to become pregnant and
be more likely to experience infertility, a
study has shown.
In the study of almost 6,000 typical-
ly overweight women in Australia, New
Zealand, and the UK, those who ate fast
food four or more times a week before they
conceived took a longer time to become
pregnant by a month vs those who avoid-
ed fast food.
Overall, 2,204 women (39 percent)
conceived within 1 month of copulation
and 468 (8 percent) failed to conceive af-
ter a year of trying. Women who rarely or
never ate fast food had an 8 percent risk
of infertility vs 16 percent in those who ate
fast food four times weekly.
“Fast foods contain high amounts
of saturated fat, sodium, and sometimes
sugar,” said lead study author Dr Jessi-
ca Grieger from the Robinson Research
Institute at The University of Adelaide in
Australia. She added that although these
dietary components and their relationship
to fertility has not been studied extensive-
ly in human pregnancies, higher amounts
of saturated fatty acids were identified in
oocytes of women undergoing assisted
reproduction. “Hence, we believe that fast
food may be one factor mediating infertility
through altered ovarian function.”
When they looked at how often these
women ate fruits, they found that those
who consumed fruits less than once a
month took half a month longer to con-
ceive vs those who ate at least three fruit
servings a day. The risk of infertility was 12
percent in those with the lowest fruit intake
sumption.
Absolute differences between the
lowest and highest categories of intake
for fruit and fast food were in the order of
0.6–0.9 months for time to pregnancy and
4–8 percent for infertility.
The study had a few caveats – first it
was not designed to prove how the amount
of fruit or fast food women consume might
impact their fertility. Second, the research-
ers relied on dietary questionnaires com-
pleted by women during their prenatal
visits. Nonetheless, the study offers new
evidence on the role of diet in conception.”
Grieger JA, et al. Pre-pregnancy fast food and fruit intake is
associated with time to pregnancy. Hum Reprod 2018;doi.
org/10.1093/humrep/dey079.
G Patients with overt hypothyroidism
Gynaecology
Hypothyroidism after TKIs
in women with cancer may
help boost survival
Hypothyroidism that occurs following treat-
ment with tyrosine kinase inhibitors (TKIs)
in women with cancer is associated with
significantly improved overall survival (OS)
and may have important prognostic value,
a retrospective cohort study has shown.
The message from this study is
that clinicians should not hesitate to
give serial TKIs due to concern for de-
velopment of thyroid dysfunction, as it is
readily treatable with hormone replace-
ment and may correlate with improved
OS, said study author Dr Melissa Lech-
ner from the Department of Medicine,
Brigham and Women's Hospital and
JOURNAL WATCH PEER REVIEWED
Harvard Medical School, Boston, Mas-
sachusetts, US.
The study involved 538 adult patients
with advanced non-thyroidal cancer who
were treated with TKIs (axitinib, pazopanib,
regorafenib, sorafenib, sunitinib, or vande-
tanib) between 2007 and 2017 and had
data available on thyroid function testing.
Their cancers were either renal cell car-
cinoma, gastrointestinal stromal tumour,
hepatocellular carcinoma, neuroendocrine
tumour, sarcoma, or primary central nerv-
ous system tumour.
Overall, 40 percent of patients de-
veloped hypothyroidism, 13 percent of
which had subclinical hypothyroidism
(thyroid-stimulating hormone (TSH) level,
5–10 mIU/L, or a higher TSH if free thyrox-
ine levels were normal) and 27 percent had
overt hypothyroidism (TSH >10 mIU/L,
low free thyroxine, or needing hormone
replacement).
had significantly longer median OS of
1,643 days vs patients with subclinical
hypothyroidism (1,005 days) and those
with no thyroid dysfunction (685 days;
p<0.0001). The association between overt
hypothyroidism and OS persisted despite
adjustment for age, sex, race, cancer type,
stage, ECOG performance status (a meas-
ure of functional status), and checkpoint
inhibitor therapy (p<0.0001).
TKI exposure time did not significantly
differ between patients who did and did not
develop hypothyroidism. Of note, there was
also no association between hypothyroid-
ism risk and the number of TKIs received.
“Again, these data provide additional
evidence to support continuation of TKIs in
the face of hypothyroidism, which can be
easily treated,” concluded Lechner.
Lechner MG, et al. Hypothyroidism during tyrosine kinase
inhibitor therapy is associated with longer survival in pa-
tients with advanced nonthyroidal cancers. Thyroid 2018; doi
org/10.1089/thy.2017.0587.
PAEDIATRICS PEER REVIEWED MIMS JPOG 2018 VOL. 44 NO. 2 49

Chronic Arthritis in Children

and Young People
Michael Hughes, RGN BSc Nursing (Child); Ruth Wyllie, RGN BSc Nursing (Child); Helen Foster, MD FRCP FRCPCH DCH Cert Med Ed

Arthritis affects 1 in 1,000 children and young people (CYP), and is a major cause
of potential morbidity, with significant long-term consequences, joint damage,
and disability if left untreated. Diagnosing juvenile idiopathic arthritis (JIA) can be
challenging, and relies on clinical assessment. Investigations are helpful to exclude
other conditions, but are often normal in JIA at presentation. The history can be
vague, and the child may be too young to verbalize symptoms, detailed probing
for inflammatory symptoms, and a comprehensive examination of the child’s
joints are therefore essential. If JIA is suspected, early referral to specialist teams
facilitates prompt treatment and prevention of complications. The emergence
of novel and biologic agents, as well as earlier and more aggressive treatment,
has helped to optimize clinical outcomes and dramatically changed the way that
JIA has been managed over the last 15 years. The approach to management is
multidisciplinary, which includes close liaison with other specialists and primary
healthcare teams, and education and support for the family. Adolescence is a time
of physical, psychological, and emotional change, and the multidisciplinary team is
fundamental in helping adolescents cope with the implications of a chronic disease,
often complex treatment regimens, and transitional care into the adult world.
50 MIMS JPOG 2018 VOL. 44 NO. 2 PAEDIATRICS PEER REVIEWED

Table 1. The Classification of JIA with Clinical Criteria ESTABLISHING A DIAGNOSIS OF

JUVENILE IDIOPATHIC ARTHRITIS

Characteristics Clinical features History

Age at onset <16 years Making a diagnosis of JIA relies on clinical skills.
Minimum duration 6 weeks Investigations help to exclude other pathology
Subtypes including malignancy and infection, although it
Systemic Arthritis must be remembered that no investigations are

Fever, rash diagnostic. Careful clinical assessment can dif-

ferentiate between inflammatory joint conditions
Oligoarthritis • 1–4 joints affected during the first 6
months such as JIA, mechanical causes of joint pains,
• Persistent – affects no more than four and other conditions causing joint pain and
joints throughout course swelling. The differential diagnosis of JIA is ex-
• Extended – affects more than four joints tensive (Table 2), with conditions ranging from
after first 6 months benign (eg, hypermobility) to life-threatening
Polyarthritis • Rheumatoid factor-positive – affects five (eg, malignancy, such as leukaemia and solid
or more joints in first 6 months
tumours, infection, and non-accidental injury).
• Rheumatoid factor-negative – affects five The clinical assessment of a child is not the
or more joints in first 6 months
same as that of an adult, and it is essential that
Enthesitis-relateda Arthritis and enthesitis, or arthritis with at
assessors are aware of the differences in normal
arthritis least two of the following:
ranges of movement in children compared with
• Sacroiliac joint tenderness
adults, as well as the normal changes in gait, de-
• Inflammatory back pain
velopment, and motor developmental milestones.
• HLA-B27-positive
The history can be primarily from the par-
• Family history of HLA-B27-positive related ents or carers, and can initially be of vague
disease
complaints, such as “my child is not right” or
Psoriatic arthritis Arthritis and psoriasis or arthritis and at least
“she no longer wants to do x”. Consequently,
two of:
it is often difficult to localize the site of joint pa-
• Dactylitis
thology from the history alone, and assessment
• Nail changes
must include, as a minimum, a basic joint exam-
• Family history of psoriasis
ination (such as paediatric Gait Arms Legs and
Undifferentiated Arthritis of unknown cause or not fulfilling Spine [pGALS] – see below) in the context of
above categories
other systems. The young child may not be able
a
Enthesitis is the term for inflammation of the insertion of ligament, tendon, capsule or fascia
to bone, particularly around the foot and knee. to verbalize pain, and the presenting feature can
be a change in behaviour, such as being more
irritable, clingy, or reluctant to play. Assess-
ment of the child’s daily activities is important;
INTRODUCTION avoidance of activities previously enjoyed (eg,
JIA is the most common cause of chronic arthri- in play or sport) is worrying, as is regression
tis in CYP (incidence 1 in 10,000 per year, preva- of achieved motor milestones (eg, walking and
lence 1 in 1,000), and encompasses a heteroge- handwriting); this can be observed by parents
neous group of diseases of unknown aetiology. 1
or others, such as teachers or nursery workers,
The term JIA replaces previous terminologies and can suggest inflammatory joint disease.
and is classified by predominantly clinical criteria Other features in the history that suggest
(Table 1). inflammatory joint disease include morning joint
PAEDIATRICS PEER REVIEWED
stiffness and pain, and parents may notice that
their child is “slow to get going in the morning”
or experiences stiffness after periods of rest,
such as after long car rides – this is known as
“gelling”. Parents may also notice that joints ap-
pear swollen, but this can be subtle and easily
overlooked. Mechanical joint pain, in contrast,
typically worsens with physical activity, and
swelling is uncommon and often transient. The
presence of “red flags”, such as weight loss, fe-
ver, night pain, and bone tenderness, suggests
infection or malignancy that warrants urgent as-
sessment in secondary care.
Examination
The pGALS musculoskeletal examination (Fig-
ure 1) is quick and easy to perform with sim-
ple manoeuvres often used in clinical practice,
and has been validated in the school-aged child
with excellent sensitivity and specificity.2 Free
educational resources to demonstrate pGALS
are available (see www.pmmonline.org/doctor/
approach-to-clinical-assessment/examination),
as well as a pGALS app, with language trans-
lations. The pGALS is acceptable in acute pae-
diatric settings, an effective way to assess all
joints, and useful in the context of vague pres-
entations such as leg pains or limp.
Abnormalities on pGALS examination can
be followed with more detailed joint examina-
tion such as the paediatric Regional Examina-
tion of the Musculoskeletal System, which is
based on the “look, feel, move, function, and
measure” approach. Joint swelling caused by
effusion or synovitis is the most reliable physi-
cal sign of JIA, but can be subtle in very young
children, and difficult to assess in joints such
as the hip, shoulder, and ankle, especially if
changes are symmetrical.
Investigation
Laboratory tests are not diagnostic in JIA, but
help to exclude other diagnoses and are used
by specialist teams to monitor disease activity
and the adverse effects of immunosuppressive
MIMS JPOG 2018 VOL. 44 NO. 2 51
Table 2. Differential Diagnosis of Joint Pain in Children
Life-threatening conditions
• Malignancy (leukaemia, lymphoma, neuroblastoma, and bone tumour)
• Sepsis (septic arthritis and osteomyelitis)
• Non-accidental injury
Joint pain with no joint swelling
• Hypermobility syndromes (patients sometimes report transient
swelling)
• Complex regional pain syndromes (localized or widespread)
• Orthopaedic syndromes (eg, slipped upper femoral epiphysis and
Perthes disease)
• Metabolic (eg, hypothyroidism and lysosomal storage diseases)
Joint pain with joint swelling
• JIA
• Trauma
• Infection
° Septic arthritis and osteomyelitis (viral, bacterial [including
Lyme disease], and mycobacterial)
° Reactive arthritis (postenteric and sexually acquired)
° Infection-related (rheumatic fever and vaccination-related)
• Inflammatory bowel disease (Crohn’s disease and ulcerative colitis)
• Autoimmune rheumatic disease (systemic lupus erythematosus,
scleroderma, and dermatomyositis)
• Sarcoidosis
• Metabolic (eg, osteomalacia [rickets], cystic fibrosis, and
mucopolysaccharidoses)
• Haematological (haemophilia and haemoglobinopathy)
• Tumour (benign/malignant)
• Developmental/congenital (eg, spondyloepiphyseal dysplasia)
drugs. Blood tests and radiographs are initially
often normal in JIA and can provide false re-
assurance at the time of presentation. If there
is clinical concern of suspected rheumatic
disease, referral to a paediatric rheumatology
team for a specialist assessment should not be
delayed.
Raised acute-phase reactants (erythrocyte
sedimentation rate, serum C-reactive protein)
and a high serum ferritin concentration can be
present in active systemic-onset JIA. However,
52 MIMS JPOG 2018 VOL. 44 NO. 2 PAEDIATRICS PEER REVIEWED

The pGALS musculoskeletal assessment

Questions
• Do you (or does your child) have any pain or stiffness in your (their) joints, muscles or back?
• Do you (or does your child) have any difficulty getting yourself (him/herself) dressed without any help?
Or lifting an object above shoulder level?
• Do you (or does your child) have any problem going up and down steps? Or being able to squat?
Figure Manoeuvres What is being assessed?
Observe the child standing Posture, habitus, skin rashes
(from front, back, and sides) Deformity (leg length inequality, alignment, scoliosis, joint
swelling, muscle wasting, and flat feet)

Observe the child walking, turning, Feet, ankles, subtalar, midtarsal, and small joints of feet and
and returning then toes
“Walk on your tip-toes” then Foot posture (check medial longitudinal arch when on tip
“Walk on your heels” toes)

“Hold your hands out straight in front Forward flexion of shoulders

of you” Elbow extension, wrist extension, and extension of small
joints fingers

“Turn your hands over and make a Wrist supination

fist” Elbow supination
Flexion of small joints of fingers

“Pinch your index finger and thumb Manual dexterity

together” Coordination of small joints of fingers

“Touch the tips of your fingers” Manual dexterity

Coordination of small joints of fingers

Squeeze the metacarpophalangeal Metacarpophalangeal joints (for tenderness)

joints

“Put your hands together palm Extension of small joints of fingers

to palm” and “Put your hands Wrist extension/flexion
together back to back” Elbow flexion
PAEDIATRICS PEER REVIEWED MIMS JPOG 2018 VOL. 44 NO. 2 53

The pGALS musculoskeletal assessment (Continued)

Figure Manoeuvres What is being assessed?

“Reach up, ‘touch the sky’, and Neck extension
“Look at the ceiling” Shoulder abduction
Elbow extension
Wrist extension

“Put your hands behind your neck” Shoulder abduction

External rotation of shoulders
Elbow flexion

Feel for effusion at the knee Knee effusion (small effusion may be missed by patellar tap
(patellar tap or cross fluctuation) alone

Active movement of knees and feel Knee flexion/extension

for crepitus (passive flexion)

Passive movement (full flexion and Hip flexion and internal rotation
internal rotation of hip)

“Open wide and put 3 (child’s own) Temporomandibular joints

fingers in your mouth” (check deviation of jaw movement)

“Try and touch your shoulder with Cervical spine lateral flexion
your ear”

“Bend forwards and touch your Thoracolumbar spine forward flexion

toes” (check for scoliosis)

Figure 1. The pGALS assessment. This material is reproduced from the pGALS app, which is freely available and developed by Professor
Helen Foster at Newcastle University, UK. Further information about pGALS, including video demonstrations, is available at Paediatric
Musculoskeletal Matters (http://www.pmmonline.org) (see Further Reading). All figures reproduced with permission from Professor Helen
Foster, Newcastle University, UK.
54 MIMS JPOG 2018 VOL. 44 NO. 2
Table 3. Potential Complications of JIA
Chronic anterior uveitis (20%)
• Highest risk – oligoarticular-onset JIA, young girl (<6 years), ANA-
positive, and <2 years of arthritis onset.
• Asymptomatic, potentially blinding, and can be bilateral.
• Detected only by slit-lamp examination and needs regular screening
for several years.
Growth disturbance
• Generalized (short stature caused by chronic disease and use of
systemic corticosteroids).
• Localized (“overgrowth” such as leg length discrepancy from
prolonged active knee synovitis, and “undergrowth” such as
micrognathia usually seen in long-standing arthritis caused by
premature fusion of epiphyses).
Constitutional problems
• Anaemia of chronic disease (uncommon in oligoarticular-onset JIA).
• Fever, weight loss, malnutrition, caries, and poor oral health.
Osteoporosis
• Multifactorial aetiology (including reduced weight bearing,
systemic corticosteroids, delayed menarche, and dietary factors).
• Reduce risk by minimizing use of oral corticosteroids, encouraging
dietary supplements of calcium and vitamin D, and regular weight-
bearing exercise, as well as consider bisphosphonates in children
who sustain low-trauma fractures or vertebral collapse.
Macrophage activation syndrome
• A rare but life-threatening complication, most often seen in children
with systemic-onset JIA.
• Can be triggered by infection (often viral) or medication.
Amyloidosis
• Uncommon but high mortality – principally in severe refractory
systemic-onset JIA, suggested by proteinuria.
Joint failure requiring joint replacement
• Particularly patients with polyarticular disease (with or without
systemic-onset) and those with positive rheumatoid factor.
Psychosocial and educational impact
• Depression, social isolation, and unemployment are more common.
• Impact on the family (parents and siblings).
these can be entirely normal in other subtypes
of JIA, especially oligoarthritis.
Autoantibodies are not diagnostic but are
often used to inform prognosis. In the presence
PAEDIATRICS PEER REVIEWED
of JIA, positive antinuclear antibodies (ANAs)
indicate a high risk of chronic anterior uveitis,
and this complication affects 30% of children
with JIA, is invariably asymptomatic but poten-
tially blinding, and can be detected only by a
slit-lamp examination by an experienced oph-
thalmologist. However, negative ANAs do not
exclude JIA, whereas positive ANAs can also
occur in autoimmune rheumatic conditions (eg,
systemic lupus erythematosus), non-rheumatic
conditions, and healthy children.
Rheumatoid factor (RF) is a poor diag-
nostic test, being present only in a minority of
children with JIA. However, if positive in a child
with polyarticular disease, it predicts a more ag-
gressive disease course and worse prognosis.
Synovial fluid examination to exclude sepsis is
mandatory in the assessment of a child with a
single hot swollen joint.
Plain radiographs in early JIA are often
normal. Investigations such as ultrasound
scanning, magnetic resonance imaging (MRI),
computed tomography, and bone scans can be
arranged as part of their specialist assessment.
MRI is sensitive to early changes of inflamma-
tory arthritis, but availability can be limited and,
in young children, invariably requires sedation
or general anaesthetic. This procedure is usu-
ally very low risk, and additional support from
hospital play specialists may be required to pre-
pare the child (eg, needle phobia, procedural
anxiety, and learning difficulties). Ultrasonogra-
phy is sensitive to early inflammatory changes,
well-tolerated by young children, and increas-
ingly used to assess the extent and severity of
arthritis.
PRINCIPLES OF MANAGEMENT
The multidisciplinary approach
There is considerable potential for morbidity as-
sociated with JIA (Table 3), although complica-
tions are now seen less frequently, following a
trend towards earlier and more aggressive treat-
ment. Optimal management requires prompt di-
PAEDIATRICS PEER REVIEWED MIMS JPOG 2018 VOL. 44 NO. 2 55

Table 4. Cytokine Modulators Currently in use for the Treatment of Severe JIA

Generic name Mechanism of action
Etanercept TNF-α soluble receptor that binds to
circulating TNF and competes with
membrane receptor
Infliximab Human–murine chimaera antibody
that neutralizes TNF-α
Adalimumab Fully human monoclonal antibody
that neutralizes TNF-α
Anakinra IL-1 receptor antagonist
Tocilizumab IL-6 receptor antagonist
Abatacept CTLA4-antagonist to block T-cell
and B-cell interaction and initiation
of the proinflammatory pathway
Abbreviations: IL = interleukin; TNF = tumour necrosis factor
Route of administration
Subcutaneous injection twice a
week
Intravenous infusion
Various regimens, initially every 2
weeks and then every 4–8 weeks
Subcutaneous injection
fortnightly
Subcutaneous injection daily
Intravenous infusion fortnightly
or monthly
Monthly infusion
Important issues for the child
taking cytokine modulators
(apply to all cytokine modulators)
Avoid all live vaccines
Promote annual flu vaccine
Promote pneumococcal
immunization (current advice
5-yearly)
Vigilance regarding infections
(eg, varicella and shingles,
opportunistic infections such as
listeriosis)
Advice regarding travel abroad
with medicines and travel
insurance
Advice that signs of serious
infection and sepsis can be
altered or reduced with systemic
immunosuppression

agnosis, early referral to an experienced multi- Exposure to oral corticosteroids is mini-

disciplinary team and close liaison with school,
and social and primary healthcare providers.
Most patients are managed as outpatients, with
medical care integrated with education and psy-
chosocial support for the patient and family.
Management includes screening for com-
plications of disease (especially uveitis), mon-
itoring of the effectiveness and safety of medi-
cation, assessing physical growth and pubertal
status, as well as evaluating psychosocial func-
tioning, and optimizing school attendance and
family life.
Changing use of conventional therapies
Evidence has shown that joint damage can oc-
cur early in JIA and results in disability if un-
treated. There has been a marked change in
treatment over the past 15 years with the con-
tinued development of potent immunosuppres-
sive agents used early in the disease course
and to optimize long-term outcomes.1,3
mized with increasing use of intra-articular cor-
ticosteroids and early use of disease-modifying
antirheumatic drugs (DMARDs), and metho-
trexate is the agent of choice. Intra-articular
corticosteroid is highly effective, safe, and the
first-line treatment for oligoarticular JIA. Young
children require sedation or general anaesthet-
ic for the procedure, although inhaled analge-
sia (eg, nitrous oxide) is widely used in older
children.
Pulsed intravenous methylprednisolone is
often used to induce remission at disease on-
set, during flares of polyarthritis or in patients
with features of systemic-onset JIA, and it is
also a useful bridging agent while starting meth-
otrexate therapy (which takes several months to
be effective). Topical corticosteroids are used
to treat uveitis, however, in younger children
these are often challenging to administer, and
long-term use can cause secondary problems
(eg, raised intraocular pressure and cataracts).
56 MIMS JPOG 2018 VOL. 44 NO. 2
Figure 2. Swollen right knee in oligoarticular-onset JIA.
Consequently, systemic immunosuppression,
including methotrexate, is often used if uvei-
tis does not respond to topical treatment. If a
child is taking oral corticosteroids, optimizing
the dietary intake of calcium and vitamin D is
important. The role of calcium and vitamin sup-
plements to reduce the risk of osteoporosis re-
mains unclear.
Nonsteroidal anti-inflammatory drugs
(NSAIDs) can relieve symptoms in the short
term but are not disease-modifying, and sug-
ar-free preparations are advocated to reduce
the risk of dental caries. In patients requiring
long-term oral corticosteroids or NSAIDs, pro-
ton pump inhibitors can be helpful to minimize
gastrointestinal symptoms, although inflamma-
tory bowel disease-related arthritis should be
considered.
Methotrexate is the most widely used
DMARD in treatment of JIA, and is useful in
management of uveitis. It is usually started im-
mediately after the diagnosis is confirmed in
most subtypes of JIA and in oligoarthritis that is
PAEDIATRICS PEER REVIEWED
extending or failing to respond to intra-articular
corticosteroids. It is efficacious, but treatment
can be limited by nausea, and other adverse
effects such as mild and reversible elevation
of serum liver enzymes and mild bone marrow
suppression are unusual. Serious complications,
including the theoretical risk of malignancy and
infertility, have not been confirmed to date. Meth-
otrexate is increasingly given by subcutaneous
injection to improve bioavailability, efficacy, and
tolerability. The recent availability of EpiPen®-
type devices has made administration easier
and more acceptable.
In children with severe disease who are
resistant to or intolerant of methotrexate, bi-
ologic therapies are often used. However, in
many parts of the world, access to these drugs
is very limited because of their high cost,
and there is greater reliance on “traditional”
DMARDS (eg, sulfasalazine, hydroxychloro-
quine, and leflunomide).
Biologic and novel therapies
A major advance in the management of JIA has
been the advent of “cytokine modulators” or
“biologics”, to selectively block the effects of
proinflammatory cytokines.4 Table 4 summariz-
es the cytokine modulators that have been used
in severe JIA, although not all are licensed in
the UK for use in children.
Continuing evidence demonstrates dra-
matic and sustained improvement with reduced
joint damage in children with JIA who failed to
respond to, or were intolerant of, methotrexate.
Long-term safety and efficacy data continue to
be obtained through registries, and internation-
al collaboration is important to address poten-
tial theoretical concerns about infection risk,
impact on fertility, and malignancy risk. These
drugs, although initially expensive, are now pro-
duced “off patent”, and “biosimilars” (biophar-
maceutical drugs similar in efficacy and safety
to the original) have now emerged. Guidelines
for the use and monitoring of biologics are
available (see Further Reading). Clinical trials of
PAEDIATRICS PEER REVIEWED MIMS JPOG 2018 VOL. 44 NO. 2 57

biologic therapies in JIA and JIA-related uveitis,

along with data from registries, demonstrate a
good safety and efficacy profile, although there
is still the need for effective outcome measures
addressing patient/family experience and con-
cerns. For those few children with severe re-
fractory disease failing to respond to cytokine
modulators, a further option is T-cell depletion
coupled with autologous haemopoietic stem-
cell rescue, and this procedure is limited to
specialist centres and needs careful patient
selection.
Regular blood tests to monitor the effica-
cy and safety of immunosuppressive agents
are essential. Patients should also be ad-
vised to avoid live vaccines and pregnancy,
and to seek prompt medical care if they de-
velop chicken pox or shingles. Varicella vac-
cination should be considered in all patients
with incident JIA who are non-immune, and
before immunosuppression is started. Edu-
Figure 3. Typical rash of systemic-onset JIA.
cation about contraception and avoidance of
excessive alcohol consumption is essential in
young people taking methotrexate. CYP taking Methotrexate is recommended in patients with
biologic therapies, especially if combined with severe uveitis or arthritis of a critical joint (eg,
methotrexate or systemic corticosteroids, are wrist, hip, and temporomandibular joint), and in
potently immunosuppressed, and vigilance children who develop polyarthritis (extended ol-
regarding infection is important, especially as igoarticular JIA, which affects one-third of chil-
the classical symptoms and signs may not be dren with oligoarticular-onset JIA).
apparent, and urgent referral is warranted if in- Psoriatic arthritis can present with an ol-
fection is suspected. igoarticular joint disease or polyarthritis, and
uveitis is common. Patients may or may not
Specific management of subtypes of have skin disease at presentation, and the di-
juvenile idiopathic arthritis agnosis is suggested by a family history of pso-
Oligoarticular-onset JIA (70% of cases) most riasis, dactylitis ‘‘sausage digit”), nail pitting,
commonly presents in preschool girls in terms and asymmetrical small joint involvement of the
of knee or ankle involvement, and carries the hands or feet, especially involvement of the dis-
best prognosis (Figure 2). However, there is a tal interphalangeal joints. Joint injections and
high risk of asymptomatic chronic anterior uve- early introduction of methotrexate are used to
itis, which can, if undetected, result in severe treat both joint and skin disease.
visual impairment. Management involves in- Enthesitis-related arthritis can be sus-
tra-articular corticosteroid injections and phys- pected in older children, often boys (>8 years
iotherapy, which if initiated early in the disease old), who are HLA-B27 positive, develop en-
course usually avoids complications such as thesitis (Table 1), and present with oligoarthritis
leg length discrepancy and muscle wasting. affecting the large lower limb joints. A signifi-
58 MIMS JPOG 2018 VOL. 44 NO. 2
cant proportion of patients develop classical
ankylosing spondylitis as adults and are at risk
of acute symptomatic anterior uveitis (ie, pain-
ful red eye). Joint injections and methotrexate
are useful to treat the peripheral arthritis, and
biologics are used for those failing to respond
adequately.
Polyarticular JIA (20% of cases) presents
with symmetrical involvement of small and large
joints. In adolescent girls, polyarticular JIA often
follows a course similar to that of adult rheuma-
toid arthritis, with positive RF, skin nodules, ero-
sive arthritis, and an association with HLA-DR4.
Early introduction of methotrexate, often given
parenterally, is recommended, and prognosis is
variable. Many patients require biologics, often
in combination with methotrexate.
Systemic-onset JIA is the least common
subtype of JIA (10% of cases) but carries the
worst prognosis. One-third of children devel-
op severe polyarthritis, and the disease carries
significant mortality from complications, such as
carditis, macrophage activation, and sepsis, with
infection risk being compounded by system-
ic immunosuppression. Systemic-onset JIA is
characterized by an acute illness with daily (quo-
tidian) fever, maculopapular rash (Figure 3), se-
rositis, lymphadenopathy, hepatosplenomegaly,
and high acute-phase reactant and serum ferritin
concentrations. Systemic features can predate
the arthritis by several weeks, and the differen-
tial diagnosis includes infection and malignancy
(eg, leukaemia and neuroblastoma).
Treatment includes aggressive use of cor-
ticosteroids (often given intravenously during
the acute systemic illness), high-dose parenter-
al methotrexate, and biologic therapy. Tumour
necrosis factor (TNF)-α inhibitors appear to be
less effective in systemic JIA than other types
of JIA, and some of the newer agents, such as
anakinra (an interleukin [IL] receptor antago-
nist) and tocilizumab (an IL-6 receptor antago-
nist), have better efficacy. A minority of patients
with refractory disease can also be considered
for autologous haemopoietic stem-cell rescue.
PAEDIATRICS PEER REVIEWED
Transition into the adult world
JIA is clinically diverse, and although many
young people achieve remission (either on or
off treatment), at least 30% need continuing
treatment into their adult years. The literature
reports significant morbidity in adults with JIA
from sequelae of previous inflammation, includ-
ing joint damage requiring joint replacement
or visual impairment from uveitis, cardiovascu-
lar disease, and osteoporosis. However, most
reports relate to clinical outcomes before the
introduction of methotrexate and biologic ther-
apies. Furthermore, there is considerable psy-
chosocial morbidity, including unemployment,
despite good educational achievement.
Improved medical management of JIA has
markedly changed the prospects for young
people with JIA. Many patients transferring to
adult care nowadays can expect to have good
disease control, although they are likely to be
taking complex treatment regimens including
biologics and methotrexate. There is a mark-
edly reduced need for orthopaedic interven-
tion, which if needed is invariably deferred un-
til maximum growth has been attained. Such
surgery can be technically challenging (eg,
intubation can be difficult with cervical spine
disease, temporomandibular joint disease,
and osteoporosis).
Adolescence is a challenging time of phys-
ical, psychological, and emotional changes.
Thus, young people with JIA need support
to cope with the complexities of their chronic
disease at a time when they are planning their
future, developing relationships, and taking on
responsibility to achieve independence away
from the family unit. Young people with a chron-
ic disease cope in different ways, and disen-
gagement with healthcare teams can have pro-
found adverse impact on healthcare outcomes.
Uncontrolled JIA can delay puberty and the ad-
olescent growth spurt. Medications can cause
adverse effects, which can affect self-esteem
and body image, for example, corticosteroids
can worsen acne and growth retardation. Meth-
PAEDIATRICS PEER REVIEWED
otrexate poses lifestyle restrictions such as al-
cohol intake. Chronic diseases can be isolating,
and anxiety, despondency, and poor adherence
with medication and physical therapy are not
uncommon.
Transition is “the purposeful, planned
movement of adolescents with chronic phys-
ical and medical conditions from a child-cen-
tred to an adult-orientated healthcare system”,
including transition from school to workplace/
higher education, and from home to inde-
pendent living. Transitional care includes dis-
ease-specific, generic and mental health
issues (“HEADSSS” – Home, Education, Activ-
ities, Drugs, Sex, Sleep, Suicide – is a helpful
mnemonic for generic health issues), help for
the young person to develop the skills neces-
sary to function independently, and support for
the parents to help them “let go”.
Based on work by the World Health Or-
ganization, the Department of Health, England
has set out clear quality criteria for providing
adolescent-centred health services in a doc-
ument called “You’re Welcome” (https://www.
gov.uk/government/publications/quality-crite-
ria-for-young-people-friendly-health-services),
which is relevant for those working with ad-
olescents and planning services. Key themes
include accessibility, staff training, encourag-
ing shared decision-making, and confidenti-
ality. Evidence suggests that transitional care
programmes lead to improved outcomes, and
successful transitional care ultimately will lead
to empowered, independent adults with im-
proved health outcomes, and who are better
equipped to function in the adult world. 5
KEY REFERENCES
1. Webb K, Wedderburn LR. Advances in the treatment of polyarticular juve-
nile idiopathic arthritis. Curr Opin Rheumatol 2015; 27: 505–10.
2. Foster HE, Jandial S. pGALS – paediatric Gait, Arms, Legs, Spine. A
simple examination of the musculoskeletal system. Pediatr Rheumatol
Online J 2013; 11: 44.
3. Martini A, Lovell DJ. Juvenile idiopathic arthritis: state of the art and future
perspectives. Ann Rheum Dis 2010; 69: 1260–3.
4. Ungar WJ, Costa V, Burnett HF, Feldman BM, Laxer RM. The use of
biologics response modifiers in polyarticular course juvenile idio-
pathic arthritis: a systematic review. Semin Arthritis Rheum 2012; 42:
597–618.
5. Foster HE, Minden K, Clemente D, et al. EULAR/PReS standards and rec-
ommendations for transitional care of young people with juvenile onset
rheumatic diseases. Ann Rheum Dis 2017; 76: 639–46.
MIMS JPOG 2018 VOL. 44 NO. 2 59
Key Points
• In the absence of trauma or sepsis, JIA is the most likely diagnosis
of a single swollen joint in a child.
• 
Outcome is optimized by prompt referral to, and management
by, an experienced paediatric rheumatology team – referral is
recommended as soon as arthritis is suspected even if joint swelling
is not confirmed on examination.
• Careful history-taking and physical examination usually provide the
diagnosis. Laboratory tests and imaging are seldom diagnostic but
help to rule out differential diagnoses. Skill in the pGALS examination
is useful to identify abnormal joints that may not be apparent from
the history alone.
• Prompt referral to an ophthalmologist and slit-lamp examinations
to screen for asymptomatic uveitis are mandatory in all cases of
suspected JIA.
• There is increasing evidence to support earlier and more aggressive
intervention with the potent immunosuppressive medicines that are
now available.
FURTHER READING
1. Paediatric Musculoskeletal Matters. http://www.pmmonline.org – ‘a free
online resource targeting medical students and primary care with rel-
evance to all healthcare professionals involved in the care of children
and young people’. PMM was developed at Newcastle University, UK
by Professor Helen Foster and colleagues. PMM includes information
about normal musculoskeletal development, normal variants and com-
mon conditions encountered in primary care, ‘red flags’ (and when
to be concerned and refer for specialist opinion), investigations (and
their limitations), and essentials about rheumatic disease manage-
ment. PMM-Nursing was launched in 2017 http://www.pmmonline.org/
nurse#.
2. Advice on training in paediatric rheumatology in the UK. https://www.
rcpch.ac.uk/training-examinations-professional-development/post-
graduate-training/sub-specialty-training/paediatr.
3. Quality criteria for young people friendly health services. 2011. De-
partment of Health, https://www.gov.uk/government/publications/
quality-criteria-for-young-people-friendly-health-services.
4. Foster HE, Brogan PA, eds. Paediatric rheumatology. Oxford special-
ist handbooks in paediatrics. Oxford: Oxford University Press, 2012.
and second revision (in press).
5. Petty RE, Laxer RM, Lindsley CB, Wedderburn LR. Textbook of paedi-
atric rheumatology. 7th edn. London: Elsevier Saunders, 2015.
© 2018 Elsevier Ltd. All rights reserved. Initially published in Medicine
2018;46(4):222–229.
About the authors
Michael Hughes is a Paediatric Rheumatology Nurse Specialist at Great
North Children’s Hospital, Newcastle Hospitals NHS Trust, Newcastle upon
Tyne, UK. Competing interests: none declared.
Ruth Wyllie is a Paediatric Rheumatology Lead Nurse at Great North Chil-
dren’s Hospital, Newcastle Hospitals NHS Trust, Newcastle upon Tyne, UK.
Competing interests: none declared.
Helen Foster is Professor of Paediatric Rheumatology at Newcastle Univer-
sity and Honorary Consultant at Great North Children’s Hospital, Newcastle
Hospitals NHS Trust, Newcastle upon Tyne, UK. Competing interests: none
declared.
60 MIMS JPOG 2018 VOL. 44 NO. 2 GYNAECOLOGY PEER REVIEWED

Endometriosis Update
Susannah Hogg, MRCOG MBChB BSc(Hons); Sanjay Vyas, MD FRCOG

Endometriosis is a common, chronic condition that affects women of childbearing

age. It can significantly impact a woman’s quality of life, her fertility, and ability to
work. Awareness of the condition is increasing amongst the general population,
with drives to improve the services available to women. The National Institute of
Clinical Excellence (NICE) has recently published guidance for clinicians, and
it is clear that a thorough understanding of the condition is important in being
able to provide appropriate, individualised care to patients. This review provides
a background on key aspects of endometriosis, including imaging and surgical
management, as well as discussions on the impact of endometriomas on fertility
and scar endometriosis.

INTRODUCTION tion, and fibrosis result in the formation

Endometriosis is an oestrogen-depend- of endometriotic nodules and adhe-
ent, chronic inflammatory condition sions, which mediate the development
characterised by the proliferation of en- of symptoms. While pelvis remains the
dometrial glands and stroma outside most commonly affected site, distant
the uterine cavity. Bleeding, inflamma- sites can be involved and may mimic oth-
GYNAECOLOGY PEER REVIEWED
er disease processes. Prevalence is estimated at
2–10% in women of childbearing age, and as high
as 35–50% in women with pain or infertility. Peak
incidence is between 25 and 35 years old, howev-
er, it may also affect younger women presenting
with dysmenorrhoea or pelvic pain. Endometrio-
sis can be a debilitating condition which can lead
to time off work and reduced earning capacity.
The EndoCost study demonstrated its cost to the
UK economy of £8.2 billion a year in treatment,
loss of work, and healthcare costs.
RISK FACTORS AND GENETICS
What do we know?
The clinical manifestation of endometriosis and
presence of endometrial tissue outside the uter-
ine cavity is likely the endpoint of a variety of ab-
errant biological processes. Many theories exist
about the aetiology, but a single, definitive mech-
anism has yet to be agreed. The most commonly
cited theory to explain peritoneal endometriotic
lesions is Sampson’s Retrograde Transplanta-
tion Theory. This suggests endometrial cells are
driven through the fallopian tubes, via reflux ac-
tion during menstruation, and are deposited in
the pelvis where they invade serosal surfaces.
While up to 90% of women may have retrograde
menstruation, only 15% of women with retro-
grade flow have confirmed endometriosis. This
discrepancy, alongside the fact that endometrio-
sis can be found in non-pelvic sites, prepubertal
girls and in men, supports the need to consider
other theories.
The most convincing explanation for en-
dometriosis is the embryological Mulleriano-
sis Theory. This proposes that, if the basis of
endometriosis is an alteration of genital tract
structures during organogenesis, it should be
possible to see misplaced endometrial tissue
outside the uterine cavity of female human foe-
tuses at post-mortem. In a study, which exam-
ined 36 foetuses with no anatomical genital tract
abnormalities, four foetuses were found to have
primitive endometrium outside the uterine cavi-
MIMS JPOG 2018 VOL. 44 NO. 2 61
Table 1. Other Theories to Explain Endometriosis
Overview
Coelomic Metaplastic transformation of cells lining the
visceral/abdominal peritoneum into endometrium,
metaplasia
theory triggered by hormonal/environmental stimulus.
Immune Autoimmune disease more common in women
dysfunction with endometriosis. Defective immune response
in elimination of menstrual debris, inflammation,
and promotion of ectopic endometrium.
Oxidative Immune cells produce cytokines promoting
stress endometrial growth +angiogenesis. Higher levels
of cytokines/vascular endothelial growth factors
in peritoneal fluid in endometriosis.
Stem cells Undifferentiated stem cells with ability to regenerate
into endometriotic deposits.
ty, expressing oestrogen and CA125 receptors.
This 11% correlates well with the reported adult
prevalence of endometriosis alongside the fact
that low recurrence rates exist after complete
surgical excision of endometriosis. Some of the
other theories reported in the literature are sum-
marised in Table 1.
PRESENTATION
The index of suspicion
It is widely acknowledged that it can take an av-
erage of 7.5 years from the onset of symptoms
to a diagnosis of endometriosis. Pain, in the form
of dysmenorrhoea, generalised pelvic pain and
deep dyspareunia are among the most common
presenting symptoms. Other features include in-
fertility, often coexisting with bowel/bladder symp-
toms, back pain, low mood, reduced quality of
life, and fatigue. The source of delay may, in part,
be due to women concealing the severity of their
symptoms, not acknowledging their symptoms
until infertility becomes an issue or, perhaps, the
challenge of differentiating causes for pain and
dysmenorrhoea with years of empirical treatment.
A proportion of women may be falsely reassured
that they do not have endometriosis after an initial
laparoscopy. This would be particularly relevant
62 MIMS JPOG 2018 VOL. 44 NO. 2
Table 2. NICE Guidance for Suspecting Endometriosis
Presenting symptoms of endometriosis
• Chronic pelvic pain
• Period-related pain affecting daily activities
• Deep pain during or after intercourse
• P
 eriod-related/cyclical gastrointestinal symptoms, or painful bowel
movements
• Period-related/cyclical urinary symptoms or haematuria
• Infertility in association with one or more of the above
for young women having laparoscopic evaluation
in their teens, when the disease may not yet be
fully expressed.
It has been reported that more than 50%
of patients with deep infiltrating endometriosis
(DIE) present with associated symptoms of dy-
schezia and dysuria. Up to 20% of women with
endometriosis have concurrent irritable bowel
syndrome, interstitial cystitis, and migraines. The
use of a pain diary can be a useful adjunct to un-
derstanding the impact of symptoms. Given the
genetic basis of endometriosis, a family history
should also be explored. Taking a targeted histo-
ry is imperative, and NICE advice that endometri-
osis should be suspected in women presenting
with one or more of the symptoms in Table 2.
Knowing the signs
An abdominal and pelvic examination should rou-
tinely be offered to women where endometriosis
is a differential. While many cases of mild disease
may be associated with a paucity of findings, there
are subtle signs associated with deeper disease
which should be identified. These include uterine
motion tenderness, a retroverted uterus, reduced
organ mobility, tender nodules in the posterior for-
nix, or palpable thickening of the uterosacral liga-
ments. The cervix can also be laterally displaced
if there is unilateral uterosacral thickening. Occa-
sionally, lesions may be visible in the vaginal mu-
GYNAECOLOGY PEER REVIEWED
cosa or cervix on speculum examination. An en-
dometrioma may be detected through palpation
of a tender, adnexal mass. Features consistent
with deep endometriosis warrant direct referral to
a specialist endometriosis service.
DIAGNOSIS
Still the gold standard?
A diagnostic laparoscopy remains the leading in-
vestigation to confirm a diagnosis of endometrio-
sis. A systematic approach should be favoured,
with inspection of the ovaries, tubes, ovarian
fossae, uterosacral ligaments, Pouch of Doug-
las (POD), uterovesical fold, rectosigmoid, and
appendix. Adhesions and pelvic mobility should
be noted. The operation report should describe
the size, macroscopic appearance, location, and
depth of infiltration for all lesions. Images should
be available to facilitate optimal record keeping
and patient education, especially if referral to a
specialist endometriosis service is anticipated.
Biopsies can be considered during diagnostic
procedures, but negative histology does not ex-
clude endometriosis. Specialist experience is key
in ensuring a correct diagnosis of endometriosis
is being made from visual inspection alone, with
reported sensitivity of 94–97% and specificity of
77–85%.
There are no clinically useful serum markers
to diagnose or monitor disease activity in endo-
metriosis. While CA125 can be raised in severe
disease, it lacks sensitivity and is not routinely
used. Peritoneal markers have been proposed,
but these are subject to cyclical variations and
none yet exist with enough specificity to corre-
late with endometriosis alone. There is no cur-
rent evidence to indicate whether endometriosis
is progressive in all cases or can remain stable
over time.
More than meets the eye
The appearances of endometriotic implants are
highly variable. Superficial disease may be easy
to identify with the classical appearances of pow-
GYNAECOLOGY PEER REVIEWED MIMS JPOG 2018 VOL. 44 NO. 2 63

der burn lesions or flame red vesicles and min-

imal anatomical distortion (Figure 1). However,
these findings will be absent in cases of more
severe disease, where nodularity, plaques, and
peritoneal tethering are present. In deep infiltrat-
ing disease, an obliterated POD may be the only
visible sign. Anatomical distortion should be eval-
uated, including relationship of the ureters and
rectosigmoid to any deep nodules. From a clinical
perspective, grading endometriosis by patholog-
ical type is considered the most effective tool, as
described in the last review.
Isolated superficial endometriosis can be
an incidental finding, diagnosed after an oper-
ative laparoscopy for another reason, and these
women may well be symptom free and no fur-
ther treatment is indicated. NICE have recently
recommended that research is required to deter-
mine whether laparoscopic treatment of isolated
superficial endometriosis with associated pain
produces a clinical, sustained improvement in
symptoms and whether this is cost effective in
the longer term.

THE ROLE OF THE

MULTIDISCIPLINARY TEAM

Providing structured care

The recent NICE document on endometriosis
emphasises how processes should be in place
for achieving prompt diagnosis of endometrio-
sis, in view of the impact that delayed diagnosis
can have on quality of life, in addition to delays in
access to effective treatment. The potential com-
plexity of endometriosis also demands high qual-
ity, multidisciplinary care, and for this reason they
encourage referral of deep infiltrating disease into Figure 1. (a+b) Examples of superficial endometriosis – powder burn appearance;
specialist endometriosis centres. These centres and (c) Examples of superficial endometriosis – flame red appearance with
are British Society for Gynaecological Endoscopy associated scarring.

(BSGE) accredited centres who provide integrat-

ed, specialist links with urology, colorectal sur-
gery, pain management services, gynaecological
radiology, fertility, and nurse specialists, in addi-
tion to providing high-level laparoscopic surgical
expertise.
It’s good to talk
While effective diagnosis and prompt manage-
ment are the foundations of good practice for
endometriosis, the importance of non-clinical,
non-surgical resources should not be over-
64 MIMS JPOG 2018 VOL. 44 NO. 2
looked. Women should receive, or be signposted
towards, up-to-date information on endometrio-
sis. It may be appropriate to recommend local or
national support groups for those with confirmed
disease, particularly in the context of infertility. For
those with severe disease, the specialist endome-
triosis nurse can offer vital support pre- and post-
operatively, as well as providing expertise in the
psychosocial impacts of the condition.
The pain management service, which in-
cludes specialist anaesthetists and clinical
psychologists, can be a valuable resource for
women experiencing chronic pain that is resist-
ant to medical or surgical therapies. Pain path-
ways and pain perceptions, activated over years
through chronic pain, can be incredibly complex
and will often require alternative modes of treat-
ment. Negative pain cognition can impair quality
of life scores and influence postoperative pain
scores. The commencement of pain modulat-
ing medications, transcutaneous electrical nerve
stimulation (TENS), acupuncture, nerve blocks,
and cognitive behavioural therapy (CBT) are
all potential treatment options. Women should
be reassured that referral to pain management
services is a well-recognised, and beneficial,
component of endometriosis management, not
a side step or undermining of their symptoms.
MEDICAL MANAGEMENT – NOT TO
BE OVERLOOKED
Medical management involves the use of hor-
mones to achieve a state of amenorrhoea, there-
by providing pain relief. It can be used successful-
ly as a long-term strategy in young women, those
with superficial disease and low pain scores, as
an interim measure between pregnancies or while
awaiting surgery, or as an adjunct to postopera-
tive management. Symptom recurrence may
occur when treatments are discontinued, and pa-
tients should be advised that this does not repre-
sent an ineffective treatment.
No single medical treatment outperforms
another in its ability to improve pain scores.
Consideration of symptoms, side-effect profiles,
GYNAECOLOGY PEER REVIEWED
anticipated duration of treatment and cost-effec-
tiveness will influence the decision. The options
include the combined pill, progesterone only
pill, Mirena coil, and gonadotropin-releasing
hormone (GnRH) agonist ± add back hormone
replacement therapy.
Medical therapy with oral contraceptives
and progestins enables satisfactory pain con-
trol in 60% of women. Norethisterone acetate
and Dienogest are the progestins with greatest
evidence supporting their use. Norethisterone
is partly metabolised to ethinylestradiol, mean-
ing there are fewer side effects from oestrogen
deficiency. Use of the Mirena coil after postoper-
ative treatment of endometriosis has been eval-
uated in several randomized controlled trials. At
1-year follow-up, most trials found use of a Mire-
na coil resulted in significant improvements in
pain scores for pelvic pain and dysmenorrhoea
compared with pre-treatment testing or expect-
ant management. It had no significant effect on
dyspareunia pain scores. It has also been shown
that surgical excision, combined with postoper-
ative hormones, leads to reduction in symptom
recurrence compared with the use of hormones
or surgical excision alone.
Medical treatment is also thought to reduce
stimulation of pain fibres leading to decreased
intra- and perilesion inflammation and production
of prostaglandins/cytokines. However, in cases of
DIE, medical therapy is less effective. It partially
treats the lesion, but not the surrounding fibrosis,
which contributes to higher pain scores and bow-
el symptoms.
IMAGING
The role of ultrasound
Transvaginal ultrasound scan (TVUS) is the prima-
ry imaging technique for evaluating endometriosis
due to its availability and cost effectiveness. This
may detect the presence of an endometrioma,
typically appearing as a unilocular, thick-walled,
and homogenous cyst with low level echogenic-
ity (“ground glass” appearance). There may be
GYNAECOLOGY PEER REVIEWED
fluid levels, septations, and calcifications. Use of
power doppler can demonstrate absent flow with-
in the cyst and scant vascularisation of the cyst
wall, differentiating it from other types of ovarian
cyst. Endometriomas are often associated with
adhesions, and application of pressure with the
vaginal probe can cause adnexal tenderness.
Bilateral endometriomas may appear as “kissing
ovaries” as they often adhere to one another in
the midline.
While ultrasound lacks adequate resolu-
tion to identify superficial peritoneal implants,
it can detect extra-ovarian endometriosis. The
uterosacral ligaments, usually barely detecta-
ble at ultrasound, may appear as stellate hypo-
echoic nodules located near the uterine cervix
if they contain infiltrating endometriosis. Hae-
matosalpinx, identified as low-level echoes in a
dilated fallopian tube, may be an isolated ultra-
sound finding in a patient with endometriosis.
TVUS has been shown to be more accurate than
transabdominal ultrasound in detecting endo-
metriotic bladder nodules and remains the first
line of investigation in patients with suspected
bowel endometriosis. Transrectal ultrasound
can be utilised, but is not considered superior
to TVUS. The overall accuracy of ultrasound in
evaluating endometriosis has improved in recent
years but the severity, and sites, of endometri-
osis identified remains dependent on levels of
ultrasound expertise.
Magnetic resonance imaging
Magnetic resonance imaging (MRI) should not
be utilised as a primary investigation to diagnose
endometriosis. However, it is a useful adjunct in
diagnosing endometriomas and helpful in dis-
tinguishing them from haemorrhagic cysts and
dermoids. Endometriomas typically present as
solitary, thick-walled masses with homogenous,
hyperintense T1 signal intensity, and low T2 sig-
nal intensity, reflecting the haemoconcentration of
the cyst.
MRI is also excellent in assessing the ex-
tent of deep infiltrating endometriosis. MRI has
MIMS JPOG 2018 VOL. 44 NO. 2 65
reported accuracy of 98% in identifying bladder
endometriosis. Such endometriotic implants
may be confined to the bladder serosa, but can
invade detrusor muscle and bladder lumen. MRI
confers similar benefits in identification of recto-
sigmoid disease and can determine the depth
of bowel wall infiltration, length of affected area,
and distance of the lesion from the anus.
SURGICAL MANAGEMENT
Who is suitable?
While medical management can offer excellent
short-term pain relief, the presence of ongoing
endometriotic lesions, or DIE, mean that symp-
toms can worsen or recur over time. Laparoscop-
ic excision of these lesions is the most effective
long-term management. In fact, there is much ev-
idence that surgery reduces pain associated with
endometriosis in all stages of the disease. Howev-
er, in cases of superficial peritoneal disease only,
it is important to consider hormonal treatments
first line, as potential benefits of excision must be
balanced against surgical risks and adhesions
formation.
With advances in laparoscopic equipment
and techniques, even the most complex cases
can be carried out safely and effectively. It is
imperative that women are counselled preop-
eratively about their surgery, with emphasis on
potential complications to urinary tract, bowel,
blood vessels, and other viscera, along with av-
erage symptom improvement of 60%. Discus-
sion should also include the potential impact of
the proposed surgery on future fertility and im-
pact on ovarian reserve. Bowel preparation and
the need for joint procedures with colorectal/uro-
logical teams should be anticipated in advance.
Complication rates in specialised centres are re-
ported as 2–4% in the immediate postoperative
period, with rate of serious complications being
7–9%. Estimated symptom recurrence is 8–13%.
Surgery is not clinically indicated for all
women. In teenagers, early surgical excision is
not recommended as the disease may not be
66 MIMS JPOG 2018 VOL. 44 NO. 2
Obliterated POD
Right fallopian tube
Left ovary /
endometrioma
Rectum
Uterus
Obliterated
POD
Rectovaginal nodule
Figure 2. (a+b) Obliterated POD with rectovaginal nodule.
fully expressed, meaning repeat excision, and its
associated complications, may be required later
in life. These women may be best managed in
conjunction with paediatric and adolescent gy-
naecology service. In women with infertility and
moderate-to-severe endometriosis, or in those
with bowel involvement, it has been shown that
excision of endometriosis does not improve
pregnancy rates. This may be in part due to
burial of DIE in the POD, and the effects of the
inflammatory endometriotic response on the fer-
tilisation process.
Deep infiltrating endometriosis
DIE is defined by the presence of lesions pene-
trating more than 5 mm beneath the peritoneal
surface and affects 20–35% of women with en-
dometriosis. Surgery is the mainstay of treat-
GYNAECOLOGY PEER REVIEWED
ment for DIE and this can be conservative or
definitive. Conservative surgery is the excision
of endometriotic lesions, endometriomas, ad-
hesiolysis, and restoration of anatomy with the
goal of completely excising all affected tissues.
Definitive surgery is hysterectomy ± bilateral
salpingo-oophorectomy, combined with excision
of endometriotic lesions. The latter is often most
suitable for those who have completed their fam-
ilies, have had limited benefit from medical and
conservative surgical treatments or in those with
suspected adenomyosis.
Uterosacral ligaments
The uterosacral ligaments are the most frequent
location of DIE, occurring in 83% of cases, and
can be managed with laparoscopic excision. The
ipsilateral ureter should always be identified prior
to and following dissection, as well as ensuring
the dissection plane does not extend towards the
rectosigmoid or bladder junctions.
Potential complications include postoper-
ative voiding dysfunction caused by autonom-
ic nerve damage. This can occur iatrogenically
from injury to the inferior hypogastric plexus at
the proximal portion of the uterosacral ligament
during excision of proximal nodules. In most cas-
es this spontaneously resolves but may require
short-term use of intermittent self-catheterisation
and bladder retraining exercises.
Rectovaginal septum
Rectovaginal lesions typically coexist with oth-
er disease sites, with strong association with
bilateral endometriomas and obliteration of the
POD (Figure 2). Endometriomas are therefore a
marker for rectosigmoid endometriosis. Resec-
tion of rectovaginal lesions is associated with an
overall complication rate of 10%. Preoperative
sigmoidoscopy to identify any infiltrating lesions
within the sigmoid or rectum is often favoured,
facilitating optimal surgical planning and patient
counselling.
There are several techniques available for
excision of rectovaginal lesions. If the anteri-
GYNAECOLOGY PEER REVIEWED MIMS JPOG 2018 VOL. 44 NO. 2 67

or rectal wall is involved, resulting in stenosis

or rectal wall infiltration, a colorectal surgeon
should be present to guide management. This
may involve shaving excision (for lesions that
does not invade beyond the serosa), disc ex-
Left ureter
cision with suturing of the muscularis/serosa Rectal nodule
(for deeper lesions) or a segmental resection/
anastomosis. The latter is reserved for larger or
multifocal lesions, with the smallest resection re-
quired to fully excise the lesion being achieved. Right ureter
There are marked differences in postop-
erative complication rates, with shave excision
associated with fewest complications. Resection Figure 3. Mobilisation of rectovaginal septum revealing endometriotic nodule.
can be associated with a risk of rectovaginal
fistula formation in up to 10% of women.
Should the nodule involve the posterior
vaginal wall, the vagina can be opened to excise
the nodule and the space closed with interrupt-
ed monofilament or Vicryl sutures. There is good
evidence of symptom relief postoperatively, with Bladder nodule
60–80% of women achieving both short- and
long-term improvement.

Bowel
Bowel lesions occur in 3–37% of cases, with
the majority affecting the sigmoid, rectum, or
rectosigmoid junction. The main symptom is
pelvic pain radiating into the rectum and anus,
rather than bowel dysfunction. Management of
bowel endometriosis may be radical, involving
complete resection of endometriotic nodules to
prevent recurrence (Figure 3). A conservative
approach may be favoured, where risk of re-
currence is balanced against risk of developing
functional bowel disorders. However, if lesions
are multifocal, >3 cm in size, involve >50% of
bowel wall circumference, there is evidence of
stenosis or sigmoid involvement, then a radical
approach may be indicated.
Removal of bowel lesions should only oc-
cur at specialist centres. Patients should be ap-
propriately counselled and aware of the risk of
colostomy. Preoperative bowel preparation may
be needed. A rectal probe, or rigid sigmoido-
scope, should be used during the procedure to
Uterus
Figure 4. Endometriotic bladder nodule
adherent to uterus.
define the rectosigmoid junction and ensure that
there is no stenosis at the end of the procedure.
An underwater bowel test, using normal saline
in the pelvis and air introduced into the rectum
(via bladder syringe or sigmoidoscope) should
be performed to ensure patency. Prophylactic
antibiotics are imperative due to the risk of en-
tering the bowel lumen. In the unlikely event that
bowel endometriosis is an unexpected finding,
women should be brought back for a secondary
procedure.
Urinary tract
Urinary tract endometriosis occurs in 1–2% of
women and, of these, 85% occur in the bladder.
The ureter is affected in 10% of cases, with kidney
and urethral lesions occurring in less than 5% of
68 MIMS JPOG 2018 VOL. 44 NO. 2
Double
ureter
Ureteric nodule
Hydronephrosis
Figure 5. Extrinsic endometriotic lesion causing hydronephrosis.
cases. Urinary tract lesions usually coexist with
other sites of disease.
Bladder endometriosis involves lesions infil-
trating the detrusor muscle. It typically results in
dysuria (42%), recurrent urinary tract infections
(18%), and haematuria (10–15%). However, it
can also be an incidental finding during a diag-
nostic laparoscopy. Symptom severity can corre-
late with the size of the bladder nodule, and may
be palpable in some cases (Figure 4).
Definitive treatment of bladder endometrio-
sis involves laparoscopic excision of the nodules.
This is associated with symptom improvement
in 70–80% of cases. Recurrence rates are also
low and depend upon the extent of the original
resection. Preoperatively, urological assessment
and outpatient cystoscopy should be undertaken,
with consideration of bladder biopsy to confirm
the histology. Excision should be planned as a
joint procedure, with intraoperative cystoscopy
available, in addition to ureteral double-J stents.
Stents can be used to improve visualisation of the
ureters, reducing the potential for injury, or if the
nodule is close to the ureteric ridge.
Ureteric endometriosis is reported to occur in
3% of endometriosis patients. It is usually unilateral
(left side), affecting the distal third of the ureter and
associated with other sites of endometriosis. Ipsi-
lateral uterosacral ligament involvement is com-
mon. There are two subtypes of disease: intrinsic
GYNAECOLOGY PEER REVIEWED
and extrinsic with a ratio of 1:4, although they can
coexist. Intrinsic lesions infiltrate directly into the
muscularis or uroepithelial layers, causing fibro-
sis and ureteric wall thickening. Extrinsic lesions
invade the ureteral adventitia or connective tissue
layers only, with compression of the ureteric wall
(Figure 5).
Symptoms of ureteric involvement include
colicky flank pain (25%) or cyclical haematuria
(15%), however most patients remain asympto-
matic. Lesions are often found incidentally at lap-
aroscopy, and routine imaging of the urinary tract
is not currently indicated as a screening measure
in endometriosis. Ureteral involvement should be
suspected if there is a rectocervical nodule >2 cm.
Hysterectomy
Women with a suboptimal response to medical
or surgical management, who have completed
their families, or who have suspected adenomy-
osis, may require consideration of hysterectomy
and excision of residual endometriosis. Bilateral
oophorectomy can also be performed, but should
be balanced against the patient’s age, with dis-
cussion about impact of menopausal symptoms
and need for hormone replacement therapy
(HRT) occurring in younger women. Total laparo-
scopic hysterectomy is the procedure of choice.
ENDOMETRIOMAS AND FERTILITY
The scale of the impact
The association between endometriosis and in-
fertility is well described in the literature, with up
to 40% of women with infertility being affected.
Women with DIE may present with decreased
ovarian reserve, low oocyte quality, and poor rates
of implantation. This is thought to be secondary to
the enhanced inflammatory state, which causes
reduced folliculogenesis, and the direct effect of
severe disease on the anatomy of the tube and
ovary, and this results in a significant reduction in
spontaneous fertility rates.
Ovarian endometriomas, cysts lined with
ectopic endometrium invaginated through the
GYNAECOLOGY PEER REVIEWED MIMS JPOG 2018 VOL. 44 NO. 2 69

ovarian cortex, account for 30% of benign ovarian Table 3. Surgical Approaches to Endometriomas
cysts requiring surgery. Endometriomas involve
prolonged stretching of the ovarian cortex in
conjunction with the presence of proteolytic en-
Surgical Benefits Risks
approach
zymes and inflammatory molecules that can dif-
Drainage Does not require Higher recurrence rate.
fuse through the cyst wall and damage the pool specialist skill set.
of neighbouring primordial follicles. Morpholog- Less ovarian damage.
ically, the ovarian cortex of endometriomas has Diathermy Does not require Vascular injury/heat
been shown to be fundamentally altered, where- specialist skill set. damage to ovarian cortex.
as the cortex in teratomas and benign cystade- Higher recurrence rate.
nomas is not. Bilateral endometriomas are also Greater decline in ovarian
reserve.
associated with a reduced response to gonado-
trophins during assisted reproduction because Cystectomy Less recurrence. Loss of ovarian tissue.
of the loss of primordial follicles. Greatest improvement Impact on ovarian
in pain scores. reserve.
Improved spontaneous
To operate or not? conception rates.
The presence of endometriomas can present a
challenge to management. The main predicament
is the balance of improving pregnancy rates/pain
scores against the potential for reduced ovarian widely accepted approach to surgical manage-
reserve. Classically, surgical management has ment of large endometriomas. This consists of
been performed for women with pain symptoms, laparoscopic cyst drainage, followed by use of
endometriomas >3 cm, or those undergoing fer- GnRH for 3 months to reduce cyst diameter, and
tility treatment. then laparoscopic CO2 laser vaporisation of the
While surgical treatment has historically been cyst wall. This method is associated with less
thought to improve spontaneous pregnancy rates impact on AMH levels than a single procedure
by restoring pelvic anatomy, there are concerns laparoscopic drainage and cystectomy alone.
that the pre-existing inflammatory effects of the en- Ovarian reserves after cystectomy are thought to
dometrioma on the ovary continue in spite of this. be dependent on surgical skill and therefore me-
Ovarian cystectomy is also associated with inad- ticulous technique, and the use of laparoscopic
vertent, or unavoidable, removal of adjacent ovar- suturing, may prevent unnecessary damage. In
ian parenchyma as cleavage planes can be chal- some cases, no treatment for haemostasis may
lenging to develop due to fibrosis. Laparoscopic be required at all after excision and therefore
excision of endometriomas has been shown to cases should be assessed independently. This
cause follicle loss, leading to low levels of an- supports the need for women with severe endo-
ti-mullerian hormone (AMH), with the potential for metriosis to be managed in specialist endometri-
premature ovarian failure, and can be associated osis centres (Figure 6).
with peri-ovarian adhesion formation. The literature From a fertility perspective, however, there is
also suggests that spontaneous ovulation is not af- currently no evidence to support routine cystecto-
fected by the presence of an endometrioma, inde- my prior to assisted reproductive treatment as it is
pendent of the size, and number of cysts. not shown to improve pregnancy rates, in addition
A Cochrane review reported excisional sur- to a poor response to gonadotrophin stimulation
gery of the cyst capsule is associated with bet- and less codominant follicles developing in affect-
ter outcomes than ablative treatment, see Table ed ovaries. This emphasises the importance of tak-
3. A three-step technique is currently the most ing a targeted history from a patient with endome-
70 MIMS JPOG 2018 VOL. 44 NO. 2
Figure 6. (a) Typical contents of endometrioma; (b) Exposed cavity of endometrioma;
and (c) Cyst cavity/ovarian tissue planes indistinct.
triomas. If a woman is asymptomatic, of advancing
maternal age, has a history of previous ovarian
surgery, and achieving pregnancy is her primary
aim, a more conservative approach should be con-
sidered. The European Society of Human Repro-
GYNAECOLOGY PEER REVIEWED
duction and Embryology guideline group reports
that if a decision is made to proceed with surgery,
then preoperative counselling must include dis-
cussion about impact on ovarian reserves and, the
potential for oophorectomy. This may be the case
for larger endometriomas that require surgery to
facilitate egg collection.
A future role for anti-mullerian hormone?
Serum AMH produced by the granulosa cells of
the pre-antral and antral follicles is considered
the most reliable indicator of primordial follicles
and therefore marker of ovarian reserve. This is
because it demonstrates less intracycle and inter-
cycle variations than follicle-stimulating hormone
(FSH) and oestradiol.
AMH levels have been shown to be reduced
in women after ovarian surgery. While the use of
AMH is not routine in the general gynaecology
setting, it does offer the potential to be used as
a preoperative measure of assessing ovarian
reserve in women contemplating pregnancy, for
which ovarian cystectomy may be indicated.
ABDOMINAL WALL ENDOMETRIOSIS
Abdominal wall endometriosis is defined as the
presence of endometriosis in sites above the per-
itoneum, which includes the skin, subcutaneous
tissues, and abdominal/pelvic wall musculature.
This ectopic tissue is hormonally stimulated in the
same way as pelvic endometriosis and usually
arises as a result of surgical procedures to the uter-
us. Lower segment caesarean section (LSCS) is
the most common site reported, but hysterectomy,
myomectomy, amniocentesis, and laparoscopic
trocar tracts are also implicated. The incidence of
this type of endometriosis is rare, with reports of
LSCS scar endometriosis being in the region of
0.03–0.47%. While this currently equates to a very
small number of women presenting to gynaecolo-
gy outpatients, with increasing LSCS rates in the
United Kingdom, it is a condition that is likely to
become more prevalent. However, it is important to
note that scar endometriosis is not linked to an in-
creased incidence of underlying pelvic endometri-
GYNAECOLOGY PEER REVIEWED
osis. Women do therefore not require routine diag-
nostic laparoscopy, unless there are other features
to suggest concomitant disease.
Reaching a diagnosis
In view of the uncommon nature of the condi-
tion, it can be difficult to diagnose, with incisional
hernia, haematoma or lipoma being favoured as
initial differentials. A targeted history and thor-
ough examination have been shown to have high
reliability for diagnosis. Women will classically
describe the presence of a discrete, non-reduc-
ible mass within or adjacent to a scar, which is
associated with cyclical tenderness, progressive
enlargement, and occasionally leakage of brown
fluid. This is usually in the absence of dysmen-
orrhoea. Transabdominal ultrasound is the radio-
logical investigation of choice, although MRI may
be required in more complex cases. Important
features to identify are the size of the lesion and
whether it lies above or below the rectus sheath,
which is pertinent if surgical excision is planned. If
the diagnosis remains unclear, fine needle aspira-
tion can be considered, although theoretically this
may result in further deposits being introduced.
Management
A proportion of women may achieve acceptable
control of symptoms through use of the combined
or progesterone only pill. However, complete sur-
gical excision offers the opportunity for definitive
diagnosis, resolution of symptoms, and preventive
recurrence. One of the difficulties with excision is
being certain of margins of the lesion. Radiologi-
cal marking can be performed prior to excision, in
addition to the use of intra-operative transabdom-
inal ultrasound. If the lesion lies above the rectus
sheath, then the defect can be closed routinely with
an absorbable suture. If it lies below the sheath, or
involves excision of a large area of tissue around
the sheath, the insertion of a mesh may be indicat-
ed. This is where preoperative imaging plays an
important role. Recurrence rates are in the region
of 4–7% but often relate to incomplete excision,
rather than development of new lesions.
MIMS JPOG 2018 VOL. 44 NO. 2 71
More recently, ultrasound guided high-in-
tensity focused ultrasound (HIFU) has been
reported in the literature as a new noninvasive
technique. This uses extracorporeal low-intensi-
ty ultrasound to form a high-intensity ultrasound
focus to cause coagulative necrosis and reso-
lution of the lesion, without peripheral tissue
damage. For lesions that incompletely resolve,
the loss of surrounding blood supply is said to
enable gradual shrinkage and resolution of the
lesion over time.
CONCLUSION
Endometriosis is an important condition that af-
fects young, healthy women, and can result in
chronic pain and poor quality of life if suboptimally
managed. Early diagnosis is key, with individual-
ised management options dependent on symp-
tom profiles, disease stage, and patient expecta-
tions. The role of specialist endometriosis centres,
specialist radiological imaging and advanced
laparoscopic surgical techniques, is essential for
management of severe disease. The overlap be-
tween endometriosis and fertility must be consid-
ered when planning management and thorough
risk-benefit analysis should be undertaken for all
patients considering surgery, balancing the poten-
tial of symptom relief versus surgical risks.
CASE SCENARIOS
Case 1: Start from the beginning
A 39-year-old nulliparous woman was referred to
a specialist endometriosis centre to discuss lapa-
roscopic excision of endometriosis. This had been
diagnosed on history and imaging two years prior
in another region. The patient had been counselled
about the risks and listed for surgery but she de-
clined on the day due to anxiety. On further ques-
tioning, the patient had low pain scores and her
primary issue was the desire to achieve a pregnan-
cy. Ultrasound assessment revealed bilateral hae-
matosalpinx but no evidence of endometriomas
and a normal looking uterus. She had a thickened
left uterosacral ligament on per vaginal examina-
72 MIMS JPOG 2018 VOL. 44 NO. 2
tion. She had self-referred to the fertility service and
was awaiting an appointment to discuss assisted
reproduction. The patient wanted to proceed with
“anything” that might improve her fertility chanc-
es. After careful discussion, the patient understood
that while there was the potential to offer laparo-
scopic excision of endometriosis, ± bilateral sal-
pingectomy, based on previous assessment and
the recent imaging results, the clinical benefit did
not favour surgery at this stage. The woman went
on to have a successful twin pregnancy, with deliv-
ery by caesarean section at 36 weeks, after three
cycles of in vitro fertilization (IVF). She subsequent-
ly opted for medical management with a Mirena
coil and has avoided the need for further surgery.
Case 2: Dig a little deeper
A 27-year-old woman, para 2, with a BMI of 42 was
under the care of gynaecology outpatients with
chronic pelvic pain. She had undergone three pre-
vious laparoscopies: one diagnostic, one ablation
of endometriosis, and one excision of mild endo-
metriosis. She had trialled medical management
since then with no benefit. She reported high pain
scores in all domains and was signed off work long
term due to pain. She was taking paracetamol,
nonsteroidal anti-inflammatory drugs (NSAIDs),
and a fentanyl patch in addition to mebeverine.
She had recently been started on sertraline for
anxiety, which she attributed to the constant lack of
control over her pain. She requested a hysterecto-
my. She was initially referred for a pelvis MRI which
showed no evidence of DIE or adenomyosis. She
was counselled against hysterectomy and referred
to the pain management service. At the end of
the first session, she disclosed that she had been
sexually abused by her stepfather as a child, her
mother never believed this had happened, and she
had ended up living in sheltered housing by the
age of 17. Her pelvic pain had commenced shortly
after this. After 6 months of CBT and acupuncture,
her pain scores had halved and she required oc-
casional paracetamol and NSAIDs only. She had
returned to work part-time and had commenced a
weight loss programme.
GYNAECOLOGY PEER REVIEWED
Case 3: The importance of
pre-operative review
A 35-year-old nulliparous woman who worked as
an accountant was added to a pooled waiting list
for laparoscopic ovarian cystectomy after a gen-
eral gynaecology outpatient appointment. She
had a six-month history of left-sided pain and was
found to have a unilateral 5 cm endometrioma on
ultrasound. At her preoperative review on the day
of surgery, the admitting consultant who was an
endometriosis specialist enquired about her fertil-
ity status. The patient admitted that she had been
trying to conceive for 18 months and had her AMH
level checked privately a year ago, which was 1.1
ng/mL. She was consented for diagnostic lapa-
roscopy, drainage of the endometrioma and dye
hydrotubation instead. She had moderate endo-
metriosis but a normal POD and free fill and spill
of both tubes. She went on to receive 3 months
of downregulation with GnRH and was referred to
the fertility team. Further investigations revealed
female factor infertility only and the decision was
made to not excise the endometrioma as it would
further compromise her ovarian reserve. She went
on to commence IVF treatment and fell pregnant
on the second cycle, although suffered a first tri-
mester miscarriage. She is currently awaiting em-
bryo transfer after her third cycle. She remains pain
free.
FURTHER READING
1. Jayaprakasan K, Becker C, Mittal M, on behalf of the Royal College of
Obstetricians and Gynaecologists. The effect of surgery for endometri-
omas on fertility: Scientific Impact Paper 55. BJOG, 2017; https://doi.
org/10.1111/1471-0528.14834.
2. Maggiore ULR, Gupta JK, Ferrero S. Treatment of endometrioma for im-
proving fertility. Eur J Obstet Gynecol Reprod Biol 2017; 209: 81–5.
3. Stochino-Loi E, Darwish B, Mircea O, et al. Does pre-operative Anti-mul-
lerian hormone influence postoperative pregnancy rate in women under-
going surgery for severe endometriosis. Fertil Steril 2017; 107(3): 707–13.
4. Van Aken MAW, Oosterman JM, van Rijn CM, et al. Pain cognition versus
pain intensity in patients with endometriosis: toward personalised treat-
ment. Fertil Steril 2017; 108(4): 679–86.
5. Zhu X, Chen L, Deng X, Xiao S, Ye M, Xue M. A comparison between high
intensity focused ultrasound and surgical treatment for the management
of abdominal wall endometriosis. BJOG 2017; 124(3): 53–8.
© 2017 Elsevier Ltd. All rights reserved. Initially published in Obstetrics,
Gynaecology and Reproductive Medicine 2017;28(3):61–69.
About the authors
Susannah Hogg is an ST7 Registrar in Obstetrics and Gynaecology at
Southmead Hospital, Bristol, UK. Conflicts of interest: none.
Sanjay Vyas is a Consultant Gynaecologist at Southmead Hospital, Bristol,
UK. Conflicts of interest: none.
OBSTETRICS PEER REVIEWED MIMS JPOG 2018 VOL. 44 NO. 2 73

Urogynaecological
Complications in Pregnancy:
An Overview
Samantha Cox, MRCOG; Fiona Reid, MD MRCOG

The urinary tract undergoes numerous physiological adaptions in response to

pregnancy. These normal adaptions can increase the risk of complications, such
as acute infection and urinary retention, which in turn increase the risk of poor
outcomes for the pregnancy. Other urogynaecological complications, for exam-
ple urological injury at caesarean section, can significantly increase long-term
morbidity. Therefore, it is important that obstetricians are aware of the potential
complications that can occur. This article aims to give a general overview of ur-
ogynaecological complications that can arise in pregnancy and how to manage
them.

PHYSIOLOGICAL CHANGES is also widespread dilatation of the

TO THE URINARY TRACT
DURING PREGNANCY
Renal plasma flow increases in preg-
nancy by 60–80%, leading to increased
glomerular filtration rate, creatinine
clearance and protein excretion. There
collecting system, thought to be sec-
ondary to the progestogenic effect on
ureteral smooth muscle in combination
with mechanical obstruction from the
gravid uterus. This results in dilatation
of the upper ureter and renal pelvis.
74 MIMS JPOG 2018 VOL. 44 NO. 2
Box 1. Risk Factors for Developing a UTI in Pregnancy
• Sexual activity
• Low socioeconomic status
• Increasing age
• Urinary tract abnormalities (congenital and acquired)
• Diabetes mellitus
• Sickle-cell disease
This physiological hydronephrosis is present in
up to 90% of pregnant women. It is seen more
commonly in the right than the left kidney. The
bladder also undergoes change, with detrusor
tone decreasing, resulting in increased capacity
and incomplete emptying. The net effect is of in-
creased stasis of urine. This incurs an increased
risk of vesicoureteric reflux and subsequent as-
cending infection.
URINARY TRACT INFECTION IN
PREGNANCY
Urinary tract infection (UTI) is extremely com-
mon in pregnancy, with an overall incidence of
up to 8%. It can be asymptomatic and is associ-
ated with an increased risk of preterm prelabour
rupture of membranes, preterm labour, and foe-
tal growth restriction. Increased bladder capac-
ity, incomplete emptying, and stasis of urine in
combination with dilated ureters all facilitate the
migration of bacteria to the upper urinary tract.
Urine is normally bacteriostatic; in pregnancy
however, the osmolality of urine is decreased
and it becomes relatively alkali. Therefore, part
of the defence system against bacterial prolifer-
ation is lost. Box 1 shows other risk factors for
developing a UTI in pregnancy.
UTI is diagnosed when there are bacterial
counts >x105 colony forming units (CFU)/mL
and a single strain of pathogen is identified on
culture. When urine flows over the perineum it
can be contaminated with bowel commensals,
hence the need for a midstream sample. It is im-
OBSTETRICS PEER REVIEWED
portant that the staff inform women clearly how
to obtain a midstream sample.
UTI is split into three subgroups: asympto-
matic bacteriuria, acute cystitis, and pyelonephritis.
Asymptomatic bacteriuria
Asymptomatic bacteriuria (ASB) is diagnosed
when there is clinically significant numbers of
bacteria in the urine but the patient is asymp-
tomatic and remains clinically well. Significant
bacteriuria is defined as 2 voided urine samples
with greater than x105CFU/mL of a single organ-
ism. It affects between 4% and 7% of pregnant
women, and of these significant numbers will go
on to develop acute cystitis and pyelonephritis.
Therefore, it is a common problem that must be
identified and treated in order to prevent these
potentially serious sequelae. ASB is most com-
monly seen in early pregnancy, with only small
numbers of women developing it in later preg-
nancy. In recognition of this, it is a standard
antenatal practice to send a urine sample for
microscopy and culture at the initial booking ap-
pointment in order to highlight any women with
ASB.
The most common organism found in wom-
en with ASB is Escherichia coli (E. coli), which
is responsible for up to 90% of all cases. The
next most frequently observed pathogens are
Proteus mirabilis, Klebsiella pneumoniae, and
Enterococcus, all of which are gram-negative
bacteria. However, gram-positive pathogens,
such as Staphylococcus aureus and Group B
Streptococcus can also underlie ASB.
The treatment of ASB should ideally be
based on the sensitivities of a urine culture,
with penicillins and cephalosporins being safe
choices during pregnancy. A recent Cochrane
review analysed 5 randomized control trials
comparing different antibiotic regimens from
classes safe in pregnancy in a total of 1,140
women with ASB. It concluded that there was
no definite advantage of any of the antibiotics
studied. There is still debate as to how long
antibiotics should be prescribed, although it is
OBSTETRICS PEER REVIEWED
generally accepted that a 5–7 day course will
effectively treat ASB. Once treatment has been
completed, it is advisable to repeat a urine cul-
ture as a test of cure. If there is a recurrence
or persistent bacteriuria on urinary cultures, it
is an indication for commencing long-term sup-
pressive antimicrobial prophylaxis. Low-dose
nitrofurantoin or beta-lactam antimicrobials,
such as penicillin or cephalosporins, are safe
choices during pregnancy. There is a docu-
mented risk with nitrofurantoin of haemolysis in
babies affected by glucose-6-phosphate dehy-
drogenase (G6PD) deficiency, and therefore it
must be used with caution in the third trimester.
Trimethoprim, a folate antagonist, is also an op-
tion for treatment of UTI in the second and third
trimester. It is not an option in the first trimester
as it increases the risk of miscarriage.
However, a Cochrane review concluded
that there were no significant differences in the
prevention of recurrent UTI when comparing
long-term suppressive treatment with nitrofuran-
toin and close surveillance of urinary cultures.
Therefore, the decision to commence long-term
antimicrobial prophylaxis must be made on care-
ful evaluation of individual cases and agreement
of the patient.
Acute cystitis
Acute cystitis is defined as having significant
bacteriuria with a single organism on a urine cul-
ture associated with clinical symptoms, such as
dysuria, urinary frequency, urgency, haematuria,
and suprapubic pain in the absence of systemic
illness. It complicates 1% of all pregnancies and is
more commonly seen in women with diabetes, on
immunosuppressant medications and those who
have had previous UTIs. As with ASB, the most
commonly isolated organism responsible is E.
coli, followed by the previously mentioned bacte-
ria. Nitrites are commonly found on urine dipstick,
but this is not diagnostic of acute cystitis, with the
gold standard being urine culture. However, the
presence of nitrites in combination with clinical
history and symptoms may prompt the clinician
MIMS JPOG 2018 VOL. 44 NO. 2 75
to initiate treatment. A 5–7 day course of antibiot-
ic treatment is the accepted course to fully treat
acute cystitis. A repeat urine culture should also
be sent following treatment in order to test that the
organism has been fully treated.
Pyelonephritis
Pyelonephritis is the most serious complication
of UTI, with significant bacteriuria present in ad-
dition to systemic illness and clinical symptoms
such as fever, rigors, abdominal pain, vomiting,
and headache. Ascending infection in the urinary
tract results in inflammation of the kidney and
renal pelvis, which left untreated can develop
into global kidney infection (pyonephrosis) and
ultimately a perinephric abscess. It is associated
with an increased risk of premature labour, pre-
mature rupture of the membranes, and low birth
weight. It also has serious implications for mater-
nal health, causing complications such as septic
shock and acute respiratory distress syndrome.
Therefore, it is of vital importance that pyelone-
phritis is diagnosed and treated as quickly as
possible. It is most commonly caused by E. coli
(present in 80% of cases).
The diagnosis is clinical, based on clinical
history of abdominal and flank pain with urinary
symptoms, examination and results of blood
tests. Urine culture should be sent, along with
blood cultures, if the patient is pyrexial or show-
ing signs of sepsis. Pyelonephritis is mostly
managed in hospital and is currently the second
most common cause for hospitalisation not relat-
ed to delivery. Outpatient management with oral
antibiotics can be considered if the patient has
few symptoms and there are no signs of sepsis.
The majority will, however, require admission.
Most units in the UK have adopted the use
of the “Sepsis Six” developed by Dellinger, et al.
The Sepsis Six consists of three diagnostic
and three therapeutic steps – all to be delivered
within 1 hour of the initial diagnosis of sepsis:
1. Titrate oxygen to a saturation target of 94%.
2. Take blood cultures.
3. Administer empiric intravenous antibiotics.
76 MIMS JPOG 2018 VOL. 44 NO. 2
Urolithiasis is the second most common urological complication affecting
pregnant women.
4. Measure serum lactate and send a full blood
count.
5. Start intravenous fluid resuscitation.
6. Commence accurate urine output measurement.
Paracetamol should be used for its analge-
sic and antipyretic properties. An ultrasound scan
(USS) of the urinary tract should be performed in
order to identify hydronephrosis, urinary stones,
or other urinary tract abnormalities that could be
underlying the pyelonephritis. Once the episode
of pyelonephritis has been successfully treated,
it is essential to monitor for recurrence of bac-
teriuria by repeating urinary cultures throughout
the rest of the pregnancy. The recurrence rate
for pyelonephritis in the same pregnancy has
been quoted to be as high as 10–18%, therefore
there is an argument for commencing long-term
suppressive antimicrobial prophylaxis for the re-
mainder of the pregnancy.
Recurrent urinary tract infection
It is estimated that UTI will reoccur in 4–5% of
cases and still incurs the same risk of devel-
OBSTETRICS PEER REVIEWED
oping pyelonephritis. It is not fully understood
how reinfection occurs. Due to the afore dis-
cussed serious sequelae of UTI in pregnancy,
low-dose suppressive antimicrobial prophylaxis
could be considered for the remainder of preg-
nancy for women suffering with recurrent UTI.
In some women, there may be a clear trigger
associated with the recurrent UTI such as sexu-
al intercourse. These women may benefit from
a short course of post-coital antibiotics, but this
depends on the frequency of coitus. For women
who have a number of antenatal UTIs, it is pru-
dent to investigate postnatally for urinary tract
structural abnormalities as these can be an un-
derlying cause.
UROLITHIASIS
This is the second most common urological
complication affecting pregnant women, com-
plicating 1/200 to 1/2,000 pregnancies. This in-
cidence is no different from non-pregnant wom-
en, leading to the conclusion that pregnancy
does not increase a woman’s risk of develop-
ing stone disease. However, a major complica-
tion of stone disease in pregnancy is preterm
labour. Therefore, it is an important diagnosis
during pregnancy.
Urinary tract stones are seen more com-
monly in the ureter during pregnancy and they
are mostly composed of calcium phosphate
or calcium oxalate. Renal plasma flow increas-
es dramatically during pregnancy, leading to
increased filtration of both stone forming sub-
stances (eg, calcium, sodium, uric acid, and
oxalate) and stone inhibiting substances (eg,
citrate, magnesium, and glycosaminoglycans).
This is thought to be the reason why the inci-
dence of renal stones in pregnancy is the same
as in the non-pregnant population.
Symptomatic stone disease is seen most
commonly in the second and third trimester, with
the most common signs and symptoms being col-
icky flank pain and haematuria. Other symptoms
include fever, nausea and vomiting, and signs of
UTI. The colicky pain is secondary to obstruction
OBSTETRICS PEER REVIEWED
caused by the stone, leading to increased pres-
sure and overdistension of the collecting system.
There may also be an element of infection com-
plicating the renal stone, which can lead to pyelo-
nephritis, pyonephrosis, and reduced renal func-
tion. Initial investigations should include full blood
count, CRP, and urea and electrolytes. If there
are any signs of fever or sepsis, a blood culture
should also be sent. Urine dipstick and culture is
useful to investigate for infective complications
of a stone, but is not diagnostic. Urolithiasis can
only be diagnosed if a stone has been visualised
by imaging. At present, the most common imag-
ing modality used during pregnancy is ultrasound
scanning. It does have some disadvantages how-
ever, having a low sensitivity for detecting stones
and limiting factors, such as body habitus and
bowel gas. It can also be difficult to determine
hydronephrosis secondary to obstruction by a
stone versus the gestational hydronephrosis seen
in pregnancy. Magnetic resonance imaging (MRI)
can be considered as a second-line imaging mo-
dality during pregnancy, having a reasonable
sensitivity and specificity. However, it has the dis-
advantages of having limited availability and does
not directly visualise calculi but instead a signal
void and associated collecting system obstruc-
tion. A plain radiograph with lead protection for
the foetus is another option to image calculi, but it
may be technically difficult to gain a good quality
image in practice. In the non-pregnant popula-
tion, computed tomography (CT) with contrast is
an option, however this is not recommended in
pregnancy due to the high dose of ionising radi-
ation and the ability of certain contrast agents to
cross the placenta.
The initial management of renal calculi in
pregnancy is conservative, with up to 80% pass-
ing spontaneously with analgesia, hydration,
and antibiotics for any infective complications.
If, however, the symptoms are refractory to this
treatment, or there is sepsis or a single obstruct-
ed kidney with deteriorating renal function, ac-
tive management is indicated. The options for
active management are as follows:
MIMS JPOG 2018 VOL. 44 NO. 2 77
• Percutaneous nephrostomy
• Ureteric stenting
• Ureteroscopy and stone removal
Percutaneous Nephrostomy (PCN) is the
method most frequently used to treat obstruc-
tion caused by calculi. It can be inserted under
local anaesthetic and is a temporising measure
to prevent further deterioration in renal function
until definitive treatment can be performed fol-
lowing delivery. Urinary stents (double J stents)
are also effective at relieving obstruction, howev-
er they can become infected or encrusted and
may need changing several times throughout
the pregnancy. Stone removal with uroscopy
has been found to be safe during pregnancy and
has good success rates, and is therefore a treat-
ment option. The decision for which intervention
is most appropriate is case dependent and re-
quires specialist input from urology.
UROLOGICAL INJURY AT
CAESAREAN SECTION
The urological system is at risk of trauma dur-
ing obstetric surgery due to the proximity of the
bladder to the lower uterine segment and the
ureter to the uterus and uterine artery laterally.
Injury to the urological system, although relative-
ly uncommon, can result in increased morbidity
for the patient. Potential complications include
long-term catheterisation, prolonged infections,
fistula formation and, most seriously, renal ob-
struction and loss of a kidney. Therefore, knowl-
edge of how to recognise and manage injury to
the urological system is vital in order to minimise
long-term morbidity.
The incidence of bladder injury at caesar-
ean section is relatively low, being quoted as be-
tween 0.14% and 0.94%. Inadvertent cystotomy
is the most common bladder injury encountered
and below are recognised risk factors:
• Repeat caesarean section
• Labour prior to caesarean section
• Low gestational age
• Rupture of membranes prior to surgery
• Emergency procedure
78 MIMS JPOG 2018 VOL. 44 NO. 2
Increasing number of caesarean sections is associated with increased
incidence of visceral injury due to the presence of adhesions.
• Midline, rather than transverse lower abdom-
inal, incision
Increasing number of caesarean sections
is associated with increased incidence of vis-
ceral injury due to the presence of adhesions,
which can displace the bladder caudally and
obliterate the vesicouterine fold of peritoneum.
During emergency procedures, there may not be
adequate time to dissect the bladder fully from
the uterus, therefore increasing the risk of cys-
totomy. Bladder injury at the time of caesarean
section is frequently diagnosed immediately, as
the urinary catheter balloon is often identified
or there is a high index of suspicion following a
difficult dissection and emerging haematuria. If
bladder damage is suspected, the extent of the
trauma can be further defined by instillation of
methylene blue – coloured saline into the blad-
der. Trauma to the ureters can be more difficult
to diagnose, with injury being caused by par-
tial or complete transection, crush injuries from
clamps, and incorrectly placed sutures obstruct-
ing or angulating the ureters into altered ana-
OBSTETRICS PEER REVIEWED
tomical positions. The incidence of ureteric inju-
ry during emergency caesarean section is very
small, being quoted as between 0.027% and
0.09%, with the majority of injuries being diag-
nosed postoperatively. The incidence of ureteric
injury is so small because they are displaced lat-
erally when the bladder is adequately reflected.
A ureteric injury can complicate uterine incision
extensions, and therefore there should be a high
index of suspicion in these cases.
For small bladder dome injuries, a 2-lay-
er repair with a continuous absorbable suture,
such as 2-0 Vicryl, may be all that is needed. This
should be followed by prolonged drainage of the
bladder for at least 48 hours if the injury is small.
However, with larger bladder tears or if there is
concern about damage to the ureter then this
should be investigated. A specialist urological
opinion should be sought immediately. The aim
is to fully evaluate any damage that has occurred
and repair any defect. There are various meth-
ods of doing this, including dissecting out the
ureters, cystoscopic examination, and observing
for urinary jets from the ureteric orifices, passage
of ureteric stents, and retrograde urography. It
is up to the discretion of the investigating urol-
ogist to decide which is necessary and to ad-
vise on repair strategy. It is important to ensure
urologists are involved in the postoperative care
and follow-up of these cases. For simple bladder
dome injuries that have been repaired intraoper-
atively, a follow-up cystogram may be requested
to ensure complete resolution of the defect.
Repair of the ureter will depend on the type of
injury and where it has occurred. Complete tran-
sections of the distal ureter near the entrance to
the bladder can be repaired by direct end-to-end
repair, as long as there is no tension on the ureter.
If a direct repair would result in tension, the blad-
der can be mobilised and the ureter reimplanted
via a Boari flap or psoas hitch procedure. A stent
should be left in situ to prevent ureteric stenosis.
Incomplete transections may be repaired over a
stent, and obstructive sutures can be removed
and stents inserted to maintain ureteric patency.
OBSTETRICS PEER REVIEWED
As described above, many urological inju-
ries are diagnosed postoperatively. Therefore, it
is of great importance to recognise the signs and
symptoms of injury. These include:
• Fever
• Flank pain
• Anuria
• Haematuria
• Abdominal distension and ileus
• Progressively abnormal U + Es
• Urinary leakage from the vagina or abdomi-
nal drain or wound
Any of these in the context of a complicated
caesarean section should prompt urgent imaging
of the urinary tract to investigate for any defects.
URINARY RETENTION
Incarcerated gravid uterus
Up to 20% of women have a retroverted uterus,
and during pregnancy, the retroversion naturally
corrects itself as the uterus enlarges and rises
out from the hollow of the sacrum. In very rare
cases, the fundus of the retroverted uterus be-
comes trapped under the sacral promontory as
it increases in size. It, therefore, becomes fixed
in the retroverted position and continues to en-
large. This progressively displaces the cervix an-
teriorly and superiorly, placing increasing pres-
sure on the urethra and moves the bladder neck
superiorly. One consequence of this is urinary
retention, which is the most common presenting
feature of this condition.
Incarcerated gravid uterus is rare, occur-
ring in 1 in 3,000–10,000 pregnancies. It typically
presents in early pregnancy, between 14 and 18
weeks’ gestation and is diagnosed by a combi-
nation of history, examination, and USS findings.
Women will complain of urinary retention or void-
ing difficulties, lower abdominal and back pain,
and possibly rectal pressure and constipation
if the uterus is putting pressure on the rectum.
Findings on examination include a difficult to pal-
pate uterus and a very anterior cervix on specu-
lum examination. USS findings include:
MIMS JPOG 2018 VOL. 44 NO. 2 79
• Elongated cervix in an anterior position
• 
Uterine fundus seen in the hollow of the
sacrum
• Flat and long bladder
Risk factors for developing incarcerated
uterus include pelvic adhesions, uterine malfor-
mations, and differing pelvic anatomical dimen-
sions, such as a deep sacral concavity. Although
a rare condition, it carries the risk of urinary
retention, spontaneous miscarriage, preterm
labour, and accidental injury to the cervix and
bladder at caesarean delivery.
In most cases, the urinary retention resolves
as the uterus grows out of the pelvis. However,
patients may need to have an indwelling catheter
following acute retention and learn to self-cathe-
terise for a few weeks.
In very rare cases, the incarceration does
not resolve and can be treated by manually
freeing the fundus from the sacral hollow whilst
the patient is under anaesthetic. This is per-
formed via a vaginal approach, with upward
pressure applied to the retroverted fundus via
the posterior fornix. A laparoscopic approach
has also been described, with the uterus being
freed by gentle traction on the round ligaments.
If incarceration persists, normal vaginal delivery
is contraindicated and therefore a caesarean
should be performed, taking into account the
high risk of damage to the bladder and cervix,
and risk of hysterectomy.
Postpartum voiding dysfunction
Postpartum urinary voiding dysfunction is rela-
tively common, occurring in 0.7–4% of all deliv-
eries. Risk of this is increased with instrumental
delivery, a prolonged second stage and region-
al anaesthesia. It can occur in women with no
risk factors and it is thought to be secondary
to a combination of factors including trauma to
the pudendal nerve, trauma to the pelvic floor,
over distension of the bladder during delivery,
and increased urine production due to the fluid
shift from the extravascular to the intravascu-
lar space. Intrapartum bladder care is of vital
80 MIMS JPOG 2018 VOL. 44 NO. 2
Practice Points
• Normal physiological changes to the urological system in pregnancy
include physiological hydronephrosis, increased bladder capacity,
and incomplete emptying.
• Progesterone and relaxin cause relaxation of smooth muscle and
alteration to pelvic connective tissue.
• UTI in pregnancy is common and can have serious complications,
such as preterm labour, prelabour rupture of the membranes, and
small birth weight.
• Renal stones are as common in pregnancy as in non-pregnant
women, and can be complicated by infection and reduced renal
function.
• Urinary tract damage is relatively rare during caesarean section,
but the risk of damage is increased with repeat caesarean sections.
• If retention occurs in early pregnancy, consider incarcerated gravid
uterus.
• 
Urinary retention in the postpartum period is common, and if
undiagnosed can cause permanent damage.
• Persistent haematuria in pregnancy should be investigated if no
underlying cause, such as UTI or renal stone, is found as it could
potentially herald an underlying malignancy.
importance, with regular voiding ensuring the
bladder does not become overdistended. This
reduces the risk of postpartum urinary reten-
tion and the associated risk of ongoing urinary
dysfunction.
There is no single definition of urinary re-
tention in the immediate postpartum period, al-
though it is generally accepted that a worrying
feature is the lack of spontaneous micturition 6
hours post-delivery or removal of Foley cathe-
ter. Other signs of progressive retention include
dribbling/slow stream, incontinence, and incom-
plete emptying. However, pain is rarely a feature
due to the neuropathy caused by the mechanical
pressures of labour.
Failure to monitor postpartum urine output
can result in painless retention which can cause
permanent bladder damage and a lifelong need
to self-catheterise.
Women who do not spontaneously mic-
turate 6 hours following delivery or catheter re-
OBSTETRICS PEER REVIEWED
moval should have the residual volume of urine
checked, which can be achieved either via an
in-out catheter or a bladder scan. If the residual
volume of urine is greater than 150 mL, it is ac-
ceptable to replace an indwelling catheter for a
further 24 hours and repeat the trial without cath-
eter. A urine sample should be sent for microsco-
py to rule out possible UTI that could be causing
or contributing to the retention. If this is again
unsuccessful, with no spontaneous micturition
within 6 hours of catheter removal and residual
volume of urine greater than 150 mL, the bladder
should be emptied via an indwelling catheter or
intermittent self-catheterisation. A follow-up ap-
pointment should then be arranged with a urog-
ynaecology specialist.
UROLOGICAL CANCER IN
PREGNANCY
Cancers of the urological system are very rare
in pregnancy. One of the presenting features of
bladder cancer is persistent haematuria, either
macroscopic or microscopic. Haematuria is a
relatively common finding in pregnancy, with the
most common cause being an underlying UTI.
However, if haematuria is persistent and no alter-
native cause, such as UTI or renal stones, can be
identified, further investigation is warranted. Re-
ferral to a urologist for further investigation with
USS and flexible cystoscopy is prudent to prevent
a missed diagnosis and delay in treatment.
FURTHER READING
1. Charalambous S, Fotas A, Rizk DEE. Urolithiasis in pregnancy. Int Ur-
ogynaecol J 2009; 20: 1133–6.
2. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign:
international guidelines for management of severe sepsis and septic
shock: 2008. Intensive Care Med January 2008; 34: 17–60.
3. Jha S, Coonmarasamy A, Chan KK. Ureteric injury in obstetrics and
gynaecological surgery. Obstetrician Gyanecologist 2004; 6: 203–8.
4. Kearney R, Cutner A. Postpartum voiding dysfunction. Obstetrician
Gynaecologist 2008; 10: 71–4.
5. McCormick T, Ashe RG, Kearney PM. Urinary tract infection in preg-
nancy. Obstetrician Gynaecologist 2008; 10: 156–62.
© 2017 Elsevier Ltd. All rights reserved. Initially published in Obstetrics,
Gynaecology and Reproductive Medicine 2017;28(3):78–82.
About the authors
Samantha Cox is a Clinical Research Fellow in Urogynaecology at Saint
Mary’s Hospital, Manchester, UK. Conflicts of interest: none.
Fiona Reid is a Consultant Urogynaecologist at Saint Mary’s Hospital,
Manchester, UK. Conflicts of interest: none.
CONTINUING MEDICAL EDUCATION MIMS JPOG 2018 VOL. 44 NO. 2 81

Fertility Preservation in
2 SKP

Young Female Cancer Patients

Jacqueline Chung Pui Wah, MBChB (CUHK), MRCOG, FHKCOG, FHKAM (O&G); Grace Kong Wing Shan, MBChB (CUHK), MRCOG, FHKCOG, FHKAM (O&G);

Li Tin Chiu, FRCOG, FRCP (Glasgow), MD (HK), PhD (Sheffield)

INTRODUCTION
Advancement of diagnosis and treat-
ment of cancer has increased the dis-
ease-free interval and overall survival
rate in young cancer patients.1 However,
anticancer treatment including adjuvant
chemotherapy and radiotherapy may
be highly detrimental to the female en-
docrine and reproductive function. As a
consequence, there is increasing aware-
ness for the need to preserve gonadal
function and fertility especially in young
cancer patients undergoing gonadotoxic
treatments.

EFFECT OF GONADOTOXIC
AGENTS ON FEMALE
FERTILITY
Ovaries are very sensitive to gonado-
toxic treatment. Women have a finite re-
serve of primordial follicles that progres-
sively depletes during their reproductive
life. Gonadotoxic agents increase the
rate of loss of these primordial folli-
cles, inducing premature ovarian fail-
ure leading to early menopause and
infertility. The effect of chemotherapy
or radiotherapy can be transient or per-
manent. Its gonadotoxic effect depends
on patient’s age, ovarian reserve, the
type of gonadotoxic agent used, and
the cumulative total dose administered.
Combination of gonadotoxic treatment
further increases gonadal toxicity and
impairment.1-2
Objective assessment of the ovarian reserve before and after gonadotoxic treatment is
useful to further guide fertility counselling, influence the type of gonadotoxic treatment,
and assess the impact of gonadotoxic therapy on future reproduction.
CHEMOTHERAPY lites like methotrexate are less damaging
Different chemotherapeutic agents have as it only affects the developing follicles
different effects on the follicular devel- and causes transient amenorrhoea with-
opment of the ovary. Among all chem- out altering the ovarian reserve. The risk
otherapeutic agents, alkylating agents of gonadotoxicity of the commonly used
carry the highest risk of gonadotoxicity. 3
chemotherapy is listed in Table 1.1-4
Alkylating agents like cyclophosphamide
are non-cell specific agents, it not only RADIOTHERAPY
affects the growing follicles but also the Radiation not only damages the ovaries
non-proliferating primordial follicle re- but also the uterus. Radiation is more
serve. On the other hand, antimetabo- gonadotoxic when the irradiation is giv-
82 MIMS JPOG 2018 VOL. 44 NO. 2
Table 1. Risk of Gonadotoxicity of Different Chemotherapeutic Agents
Low risk Moderate risk
Methotrexate Adriamycin
5-Fluorouracil Cisplatin
Actinomycin D Carboplatin
Bleomycin
Vincristine
6-Mercaptopurine
en as a single dose compared with frac-
tionated doses.2 Women who receive to-
tal body irradiation, abdominal, or direct
pelvic radiation at high doses are also
at greater risk of subsequent infertility. It
is estimated that a dose of about 2 Gy
applied to the gonadal area may de-
stroy up to 50% of the ovarian reserve.1
Radiotherapy of the uterus also affects
the uterine elasticity and vasculature of
the uterus leading to higher risk of mis-
carriage, preterm delivery, intrauterine
growth restriction, and low birth weight
babies. Irradiation to the vagina also
4
leads to sexual dysfunction due to lack
of vaginal lubrication and vaginal steno-
sis.1 The combination of chemotherapy
further increases the risk of premature
ovarian failure.
OVARIAN RESERVE
ASSESSMENT
Objective assessment of the ovarian re-
serve before and after gonadotoxic treat-
ment is useful to further guide fertility
counselling, influence the type of gon-
adotoxic treatment, assess the impact of
gonadotoxic therapy on future reproduc-
CONTINUING MEDICAL EDUCATION
High risk
Cyclophosphamide
Busulfan
Chlorambucil
Melphalan
Nitrogen mustard
Dacarbazine
Ifosfamide
Thiotepa
Procarbazine
tion, and predict the success of fertility
preservation techniques. Assessment of
the ovarian reserve can be performed
using antral follicle count, anti-mullerian
hormone (AMH) and follicle-stimulating
hormone (FSH). AMH is a promising
and reliable marker. It is produced by the
granulosa cells and correlates well with
the number of primordial follicle count,
and it is now accepted as a useful mark-
er for predicting ovarian response during
ovarian stimulation in many assisted re-
productive centres.5-7
FERTILITY PRESERVATION
OPTIONS
With the increasing survival rate of young
cancer patients, the ability to start a family
and have children is a key quality of life
issue. The option of fertility preservation
method should be individualized for every
patient and taking into account the pa-
tient’s age, ovarian reserve, type of gon-
adotoxic therapy, time available before
anticancer treatment, presence of a part-
ner, presence of previous live births, the
available expertise and facilities, financial
status, and religious background of the
patient. Figure 1 shows the algorithm for
an individualized approach to the various
options of fertility preservation. Early re-
ferral to a fertility specialist at the time of
diagnosis of cancer is the key to maximiz-
ing the success of fertility preservation.1,7-8
Every young cancer patient undergoing
treatment should be clearly counselled
about the effect of gonadotoxic agents.
In addition, the various possible fertility
preservation options available, including
their nature, success rate, risk, and cost,
as well as ethical implications should be
discussed.1, 8-14
FERTILITY-SPARING
SURGERIES
Fertility-sparing surgeries are less rad-
ical and spare the reproductive organs
as much as possible while removing all
cancer. This option is appropriate when
the cancer is diagnosed at early stages
or in those cases with low malignant po-
tential.8-10
Radical trachelectomy involves
the removal of the entire cervix, upper
third of vagina, and parametrial tissues
together with or without bilateral pelvic
lymphadenectomy laparoscopically. It
has become a treatment of choice for
women with early stage cervical cancer
(stage 1A2 to 1B cervical cancer with
diameter <2 cm and invasion <10 mm)
at childbearing age with a desire to pre-
serve their fertility.11 Although cervical
stenosis and subfertility may occur af-
ter this procedure, successful live births
have been reported.1
Studies have shown that patients
with FIGO stage 1 grade 1 ovarian ep-
ithelial carcinoma can be treated con-
servatively with unilateral salpingo-oo-
phorectomy. Yet, these women require
full surgical staging as metastasis may
occur in 15–20% of cases and 10–29%
CONTINUING MEDICAL EDUCATION MIMS JPOG 2018 VOL. 44 NO. 2 83

Diagnosis of cancer

Alternative options:
Multidisciplinary meeting Gamete donor/Gestational
Counselling and risk assessment of gonadotoxicity carrier/Adoption/Accepting
childlessness

Consideration for fertility preservation? No

Yes

Type of anticancer treatment receiving

Radiotherapy Chemotherapy Surgery

Ovarian shielding Time available for ovarian No Fertility-sparing surgery

possible? stimulation? Fertility-sparing
if possiblesurgery
if possible
Yes No Yes

Ovarian shielding Ovarian transposition Partner available/willing In

In-vitro
vitro maturation
maturation of
of Ovarian tissue
to use donor’s sperm? immature oocytes cryopreservation
Yes No

Embryo Mature oocyte Partner available/willing

cryopreservation cryopreservation to use donor’s sperm?

Yes No

Embryo Mature oocyte

cryopreservation cryopreservation

Figure 1. Algorithm showing the individualized approach for fertility preservation in young female cancer patients.

may have coexisting endometrial can-
cer. Unilateral salpingo-oophorectomy
1
can be considered in those with bor-
derline epithelial ovarian tumours as
oncological outcome has been shown
to be comparable to those when treat-
ed with traditional radical surgery.1
Hysterectomy, bilateral salpin-
go-oophorectomy together with or
without lymph node dissection has
been the standard surgical treatment
for endometrial cancer. Use of pro-
gestogens has been reported to treat
very early stage endometrial cancer
in young women as a fertility-sparing
option with successful pregnancies
reported. Nonetheless, the patients
should be warned about the limitation
of this treatment including the high re-
currence rate and the 10–29% chance
of coexisting ovarian cancer.
tients should be fully informed that
oral progestogens are not a standard
treatment and that there is a high risk of
recurrence and their survival chances
may be compromised in order to pre-
serve fertility.
PELVIC SHIELDING AND
OVARIAN TRANSPOSITION
Shielding the pelvis away from radiother-
1,9,11
Pa- apy can reduce the gonadotoxic effect.
When shielding is not possible, patients
84 MIMS JPOG 2018 VOL. 44 NO. 2
With ovarian transposition, preservation of ovarian function has been shown in 90%
of the cases.
undergoing gonadotoxic radiotherapy
can have their ovaries transposed out of
the field of irradiation laparoscopically or
via laparotomy.15-18 Ovaries can be trans-
posed medially behind the uterus or lat-
erally to the paracolic gutters. The most
simple and effective method is performing
lateral ovarian transposition laparoscopi-
cally just before initiating radiotherapy. In
this case, the ovaries are transposed to
the paracolic gutters after the division of
the utero-ovarian ligament and tubes, ly-
ing 3 cm above the upper border of the
radiation field. With ovarian transposition,
preservation of ovarian function has been
shown in 90% of the cases. 17
EMBRYO CRYOPRESERVATION
As shown Figure 1, in those patients with
a partner or those who are willing to use
donor sperm for fertilization, embryo cry-
opreservation is the first choice for fertil-
ity preservation if there is adequate time
for ovarian stimulation. Embryo cryo-
preservation involves ovarian stimulation
with gonadotrophins to produce mature
CONTINUING MEDICAL EDUCATION
oocytes for retrieval prior to gonadotoxic
treatment. Following in vitro fertilization
(IVF), embryos are produced either us-
ing partner’s sperm or donor’s sperm.
These embryos are then subsequently
cryopreserved for future use when the
patient is ready for pregnancy.
Embryo cryopreservation is by far
the most established method for fertility
preservation. It is used whenever there
are surplus embryos generated during
IVF programmes. Embryos are much
more resistant to cryodamage than oo-
cytes. It has promising results with high
post-thaw survival rate of 35–90%, im-
plantation rate of up to 30% and cumula-
tive pregnancy rate between 30–40%. 2,9
However, this procedure requires
ovarian stimulation for 2–3 weeks and
thus causes a possible delay in cancer
treatment. Hence, it is not suitable for
patients who require chemotherapy im-
mediately. The patient should be of pu-
bertal age with a preferably good ovarian
reserve in order to have sufficient embry-
os cryopreserved. Ideally, they should
have a partner, if not, donor’s sperm is
required. In addition, ovarian stimulation
also poses a risk of temporary increase
in oestradiol levels leading to regrowth
of tumour cells, especially in oestro-
gen-sensitive tumours.
OOCYTE PRESERVATION
In cases where the patient has adequate
time for ovarian stimulation but without a
partner, oocyte preservation can be con-
sidered. In oocyte preservation, ovarian
stimulation is required to harvest ma-
ture eggs with subsequent freezing of
unfertilized eggs. This is the only option
applicable to those who do not have a
male partner or would not consider the
use of donor sperm. It is also acceptable
to those who have religious or ethical
objections to embryo cryopreservation.
Yet, again it requires ovarian stimulation
causing possible delay in cancer treat-
ment while exposing the patient to a tem-
porary increase in oestradiol levels. In
addition, mature oocytes are more sus-
ceptible to cryodamage than embryos
due to the sensitivity of the spindle appa-
ratus and higher lipid content of the cells.
Cooling and exposure to cyroprotecting
agents may also increase the incidence
of aneuploidy rate.2 Cryopreservation
also causes hardening of the zona pel-
lucida and thus oocyte cryopreservation
protocols often involve intracytoplasmic
insemination as a precaution to increase
fertilization rates in assisted reproductive
programmes.8-14
Oocyte preservation is no longer
an experimental process.10 With the use
of intracytoplasmic injection and vitrifi-
cation, higher rates of post-thaw surviv-
al, fertilization and pregnancy are seen.
A recent report showed that pregnancy
rate per transfer with vitrification is 29%
compared with slow freezing.2 However,
CONTINUING MEDICAL EDUCATION
at least 20 vitrified oocytes are required
to achieve a live birth as the live birth
rate per vitrified oocyte is only ~5%.19
Thus, the patient may need to undergo
more than one cycle of stimulation and
be counselled on a realistic figure for
pregnancy.
IN VITRO MATURATION
In those cases where the patient needs
to undergo chemotherapy immediately,
collecting the immature oocytes for cryo-
preservation may be considered. These
immature oocytes can then be matured
in vitro with subsequent cryopreserva-
tion. It can also be fertilized with the part-
ner’s or donor’s sperm for embryo cryo-
preservation. When compared to mature
oocytes, immature oocytes are more re-
sistant to cryodamage due to lower cell
volume and the absence of metaphase
spindle. Additional research is required
2
to determine the potential pregnancy
rate and the safety of its use. 8-14
NOVEL STIMULATION
PROTOCOLS
Typical ovarian stimulation requires
10–14 days of stimulation with gon-
adotrophins to achieve multifollicular
development and causes an elevation
of serum oestradiol up to 10–15 times
higher than physiological levels. In or-
der to minimize the oestrogen expo-
sure during ovarian stimulation, oocyte
retrieval can be performed during a
natural IVF cycle. However, natural IVF
cycles are associated with a lower yield
of oocytes, embryos and subsequently
poorer pregnancy rates. Novel IVF stim-
ulation protocols with tamoxifen or aro-
matase inhibitors have been developed
to increase the safety margin of ovarian
stimulation, especially for those patients
with oestrogen-sensitive tumours.
In those cases where the patient needs to undergo chemotherapy immediately,
collecting the immature oocytes for cryopreservation may be considered.
Tamoxifen is a selective oestrogen
receptor modulator. Other than its an-
ti-estrogenic action on breast tissue,
it has an antagonist action in central
nervous system and interferes with
the negative feedback of oestrogen
in hypothalamic/pituitary axis leading
to an increase in gonadotrophin-re-
leasing hormone (GnRH) secretion
from the hypothalamus. The subse-
quent release of FSH from the pituitary
can stimulate follicular development.
In doses of 40–60 mg daily starting on
day 2–3 of the cycle for 5–12 days, it can
be used together with gonadotrophins
for ovulation induction and should be
considered to be used in hormonally
sensitive cancer patients.20-23
Aromatase inhibitors (eg, letrozole)
significantly suppress plasma oestro-
gen levels by competitively inhibiting
activity of the aromatase enzyme. Cen-
trally, it releases the hypothalamic/pi-
tuitary axis from oestrogenic negative
feedback, increasing secretion of FSH
by the pituitary gland. Combined letro-
MIMS JPOG 2018 VOL. 44 NO. 2 85
zole-FSH protocol (letrozole doses of
2.5–5 mg daily during day 2–3 of men-
ses with gonadotrophins started 2 days
later) can be used for ovulation induc-
tion.2 With this protocol, the oestradiol
levels has been reported to be even
lower than those seen in natural cycles
with outcome similar to standard IVF
protocols.24-25
GnRH antagonist protocols are
usually the stimulation protocol of
choice for cancer patients as the oestro-
gen level produced is lower when com-
pared with the agonist or flare protocol.
Conventional controlled ovarian stimu-
lation is usually initiated at the beginning
of follicular phase. Due to the urgent
need for starting anti-cancer treatment,
random start protocols have been pro-
posed to provide the shortest time for
oocyte collection and have been shown
to be as effective as conventional start
protocols. 26-28
In case patient comes in
during the luteal phase, GnRH antago-
nist can be given to cause rapid fall of
progesterone from the corpus luteum
86 MIMS JPOG 2018 VOL. 44 NO. 2 CONTINUING MEDICAL EDUCATION

Key Points in width and 1–1.5 mm in depth are taken

from each ovary.32-36
• 
Gonadotoxic anticancer treatment can cause premature ovarian failure Reimplantation can then be per-
and infertility, which significantly compromises the quality of life of a young formed orthotopically (in the pelvic cav-
cancer patient. ity) or heterotopically (distant sites).33 In
• Fertility preservation is an important issue and physicians should address this orthotopic transplantation, if the ovary
early in the course of a patient’s care to ensure success. is present, the pieces of thawed ovarian
• 
Multidisciplinary care is required involving the oncologist, oncological cortex are fixed to medulla after decorti-
surgeon, fertility specialist, pathologist, radiologist, nurse and psychologist. cation of ovary or inserted beneath the
• 
Embryo cryopreservation is the most established technique; oocyte cortex. If the ovary is not present, the
cryopreservation can be considered in single women. Both methods require ovarian tissues are placed in a peritoneal
at least 2 weeks of ovarian stimulation and may delay treatment. window where small retroperitoneal ves-
• Novel stimulation protocols using tamoxifen and letrozole can be used to sels are visible for vascular supply. This
increase safety margin in oestrogen sensitive breast tumours. procedure allows for natural conception.
• If there is no time available for ovulation induction, ovarian tissue can be In heterotopic transplantation, the
cryopreserved for future transplantation without delay. ovarian cortical strips are implanted in
subcutaneous tissue of the forearms or
• Benefit of ovarian protection by GnRH analogues is unproven and should not
be recommended as a sole method of fertility preservation. abdomen. This procedure is less inva-
sive and easier for tissue monitoring. It
is the only possible choice for cases un-
and gonadotrophin injections can be sive procedure and is possible to use in dergoing pelvic radiation. However, the
started after 3–4 days to stimulate folli- combination with other treatment strate- main limitation is considerable loss of fol-
cular growth. Once the leading follicles gies. However, it causes severe hypoes- licles during the revascularisation period.
reach 12 mm, GnRH antagonist is start- trogenic symptoms. In addition, patients Follicular viability after cryopreser-
ed again to prevent premature second- may experience bone loss if used for vation has been shown in almost all of
ary luteinizing hormone surge. In case more than 6 months. Although available the cases. It often takes 3–6 months af-
there is no time left for luteolysis before meta-analysis showed a uniform bene- ter transplantation before follicular viabil-
starting of ovarian stimulation, combina- fit of administration of GnRH analogues ity is evident. Moreover, there is a limited
tion of both gonadotrophins and GnRH in prevention of chemotherapy-induced life-span of 4–5 years. Up to date, there
antagonist can be started together and premature ovarian failure, at present, are a total of 60 live births reported and
this does not affect oocyte quality. 29
the American Society of Clinical Oncol- the pregnancy rate per transplantation is
ogy and European Society of Medical 20–30%.19 Ovarian tissue cryopreserva-
OVARIAN SUPPRESSION WITH Oncology does not recommend it as a tion is currently the only acceptable op-
GONADOTROPHIN-RELEASING sole strategy for fertility preservation.31 tion for prepubertal patients. This method
HORMONE ANALOGUES not only restores fertility but also restores
Chemotherapy affect tissues with a OOCYTE TISSUE gonadal function. There is no need for
rapid cellular turnover and inducing a CRYOPRESERVATION ovarian stimulation, it is particularly suit-
prepubertal hormonal milieu and put- The ovarian cortex is abundant in primor- able for patients in whom chemotherapy
ting the follicles dormant may protect dial follicles. These primordial follicles cannot be delayed. However, at least two
the ovaries from damage. Gonadal in- inside the ovarian cortex are more resist- surgical operations are required, one for
hibition with GnRH analogues during ant to cryodamage than mature oocytes. removal, another for future reimplantation
exposure of cytotoxic drugs has been Studies have shown that ovarian cortical and there is a potential risk of reimplan-
postulated to be effective in protect- strips can be excised and frozen for fu- tation of malignant tissue cells together
ing the ovaries but its use is still highly ture reimplantation to restore endocrine with the grafted tissue. This risk can be
controversial.30-31 This method is easily and reproductive function. Cortical biop- reduced by proper histological exam-
accessible, does not require any inva- sies measuring 1 cm in length, 4–5 mm ination for malignant cells in the grafted
CONTINUING MEDICAL EDUCATION MIMS JPOG 2018 VOL. 44 NO. 2 87

tissue. Further research is required to as-
sess the optimal site for transplantation,
improve methods in detecting residual
disease, ascertain the optimal size of
ovarian grafts, optimize freezing/thawing
techniques, and promote revasculariza-
tion of the transplanted tissue.
WHOLE OVARY
CRYOPRESERVATION
There is increasing research interest in
fresh or cryopreserved whole ovary trans-
plantation as a method to increase the
longevity of ovarian transplant as larger
pool of follicles would be available and
lower the concerns for ischemic dam-
age. Researchers have also explored the
possibility of xenografting human ovarian
follicles to immunodeficient mice to grow
primordial follicles to mature stages.33,36
ALTERNATIVES
Women, who have a reduced ovarian re-
serve but are able to carry a child, can
consider using donor eggs fertilised by
either partner’s semen or donor sperm.
Alternatively, women with a healthy ovar-
33-36
ian reserve who are unable to success-
fully carry a pregnancy due to hysterec-
tomy or previous pelvic radiotherapy to
the uterus may undergo hormonal stimu-
lation and IVF with the resulting embryos
being carried by a gestational surrogate.
As a last option, young cancer patients
with good prognosis may consider
adoption. 1,22
CONCLUSION
The need for fertility preservation be-
fore anticancer treatment is on the
rise. Development of a good fertility
preservation service is required. This
should involve a multidisciplinary
team consisting of the oncologist, sur-
geons, fertility specialist, pathologist,
radiologist, nurse and psychologist.
The government should consider pro-
viding funding for patients seeking fer-
tility preservation treatment and sup-
port clinicians and scientists involved
in researching in this field. Better ed-
ucation and advertisement of fertility
preservation should also be provided
not only to the patients, but also to
clinicians dealing with cancer patients
so that early referral to a fertility spe-
cialist can be made.
About the authors
Assistant Professors Jacqueline Chung Pui Wah and Grace
Kong Wing Shan, and Professor Li Tin Chiu are specialists in
the Department of Obstetrics and Gynaecology, The Chinese
University of Hong Kong, Hong Kong.

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88 MIMS JPOG 2018 VOL. 44 NO. 2 CME QUESTIONS

Program pendidikan kedokteran berkelanjutan ini dipersembahkan oleh

MIMS, bekerjasama dengan Ikatan Dokter Indonesia.
Setelah membaca artikel ‘Fertility Preservation in Young Female Cancer
Patients’, jawab pertanyaan berikut kemudian kirimkan dengan
menggunakan formulir jawaban yang sudah disediakan ke CME MIMS
Journal of Paediatrics, Obstetrics & Gynaecology, untuk mendapatkan 2 SKP.

ARTIKEL CME 2 SKP

Fertility Preservation in Young Female

Cancer Patients
Jawab pertanyaan di bawah ini dengan Benar atau Salah.

1. Chlorambucil and vincristine do not cause significant damage to the patient’s ovarian reserve.
2. Radical trachelectomy should be considered in stage 2A cervical cancer patients with fertility wish.
3. Embryo cryopreservation is the option for fertility preservation in married couples while oocyte
cryopreservation should be considered for patients who are single.
4. Mature oocyte cryopreservation requires ovarian stimulation and causes subsequent delay of starting
anticancer treatment.
5. Mature oocyte cryopreservation is still considered experimental at this stage.
6. Oocyte cryopreservation is currently the only acceptable option for prepubertal patients.
7. Tamoxifen is a suitable option for ovarian stimulation in breast cancer patients.
8. Conventional ovarian stimulation protocols allow patients to receive ovarian stimulation irrespective of the
time of the menstrual cycle.
9. GnRH analogues should be given during chemotherapy to reduce the risk of gonadotoxicity alone.
10. Heterotopic ovarian tissue transplantation allows natural conception.