Current 26.4

Obstetrics,
Gynaecology
and Reproductive
Medicine
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Editor-in-Chief
Alec McEwan BA BM BCh MD MRCOG
Consultant in Fetal and Maternal Medicine, Department of Obstetrics and Gynaecology,
Queens Medical Centre, Nottingham, UK
Associate Editors
Sabaratnam Arulkumaran MBBS MD PhD FRCS (Ed) FRCOG
Professor of Obstetrics and Gynaecology,
Department of Obstetrics and Gynaecology,
St. Georges Hospital Medical School, London, UK
Tahir A Mahmood MD FRCOG FRCPI MBA FACOG(Hon)

Consultant Obstetrician and Gynaecologist,
Victoria Hospital, Kirkcaldy, Fife, UK
Philip N Baker FRCOG, FMedSci

Pro-Vice-Chancellor and Head of the College of Medicine,
Biological Sciences and Psychology,
Dean of the School of Medicine, University of Leicester, UK
Fiona Reid MD MRCOG

Consultant Urogynaecologist,
St Marys Hospital, Manchester, UK
Shreelata Datta BSc(Hons) MBBS MRCOG LLM

Consultant Obstetrician and Gynaecologist,
Kings College Hospital, London, UK
Mahmood I Shafi MB BCh MD DA FRCOG

Consultant Gynaecological Surgeon and Oncologist,
Addenbrookes Hospital, Cambridge, UK
Trainee Editor
Catherine Aiken MB/BChir MA PhD MRCP MRCOG
Specialist Registrar (ST5) and Academic Clinical Lecturer in Obstetrics and Gynaecology,
Addenbrookes Hospital, Cambridge, UK
Obstetrics, Gynaecology and Reproductive Medicine has an eminent editorial board, all of whom are recognized experts in their field.
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REVIEW
Pruritus vulvae
3) Neoplastic conditions:
Squamous: VIN usual type (Warty, Basaloid, Mixed), VIN
differentiated type
Non-squamous: Pagets disease, Tumours of melanocytes
4) Hormonal: atrophic vaginitis, breast feeding
5) Urinary or faecal incontinence
6) Systemic causes: secondary to renal (chronic renal failure),
Haematologic (Iron deficiency, Polycythaemia rubra vera,
Hypereosinophilic syndrome, essential thrombocythemia,
Myelodysplastic syndrome), Hepatic (Cholestasis), Endocrine (Hyperthyroidism, Hypothyroidism, Diabetes mellitus,
Hyperparathyroidism, Hypoparathyroidism), Malignancies
(Hodgkins disease, Leukaemia, carcinoid syndrome),
Immunosuppression leading to vulvovaginal candidiasis
7) Psychosexual disorders
8) Others: regrowth of pubic hair after shaving
Gomathy Gopal
Essam Hadoura
Tahir Mahmood
Abstract
Community-based surveys indicate that 1 in 5 women presenting to
their GP with vulval symptoms have pruritus vulva. Pruritus vulva is
the predominant symptom for 1:10 women in their lifetime. Most
women associate pruritus with infection, but in the majority of cases
there is a non-infective cause. The condition affects quality of life; socially, psychologically and sexually. Multiple visits to health professionals including the General Practitioners, Gynaecology,
Dermatology and GUM clinics are commonly required. This article
gives an update of classication of vulval pruritus and its management.
Causes of pruritus vulvae in different age groups:
Keywords lichen sclerosus; pruritus vulvae; vulval dermatoses;
Prepubertal girls: poor hygiene, Streptococcal infection,

Escherichia coli infection, pinworms, scabies and allergic contact
dermatitis.
vulval eczema; vulval intraepithelial neoplasia; vulval itch
Introduction
Young women in reproductive age: vaginitis, allergic contact

dermatitis, hidradenitis suppurativa, lichen simplex chronicus.
Pruritus in Latin means itch. Vulvae in Latin mean the external

female genitalia. It includes the clitoris, the vaginal orifice,
mons pubis and the labia on both sides. Itch on the external
female genitalia is a symptom and not a pathological diagnosis. It affects about 1 in 10 women during the course of their
lifetime. Pruritus in vulva is caused by various factors, but
most often there is an identifiable cause. In this article the
causes for pruritus vulvae have been categorized according to
their incidence. In a community-based sample of 303 women
in the USA, about 7% reported a history of persistent lower
genital tract itching or burning lasting longer than 3 months
(Table 1).
Postmenopausal women: atrophic vaginitis, lichen sclerosus,

vulvar cancer, Pagets disease, females with diabetes mellitus,
candidiasis, other dermatophyte infections.
Pathophysiology of pruritus vulvae:
Pruritus vulvae can present as an acute or chronic condition.
The sensation of pruritus is transmitted through C fibres to the
dorsal horn of the spinal cord to the cerebral cortex via the spinothalamic tract. Pruritus generates a spinal reflex response, the
scratch, which is as innate as a deep tendon reflex. Regardless of
the cause, pruritus often is exacerbated by skin inflammation,
dry or hot ambient conditions, skin vasodilatation, and psychological stressors.
The mechanisms in acute presentation vary depending on
the under lying pathophysiology some examples include
1) Histamine released by mast cells in Allergic dermatitis
2) Cytokines and immune mediated pro-inflammatory agents
are involved in Atopic vulvitis
3) Nerve paraesthesia in Herpes simplex
4) Serotonin mediated pruritus occurs in polycythaemia vera,
uraemia, cholestasis and lymphoma (Table 2).
Etiological classification of pruritus vulvae:

Pruritus vulvae has multiple etiological causes as listed below,
and full investigation should always be considered:
1) Dermatological: the International Society for the Study of
Vulvar Disease (ISSVD 2006 classification, as below) along
with hidradenitis suppurativa
2) Infections and infestations: candidiasis-vulvovaginal,
Trichomoniasis, Bacterial Vaginosis, Herpes simplex, Pubic
lice (Phthirus pubis), Scabies (Sarcoptes scabiei hominis),
Thread worm (Enterobius vermicularis)
Management
Women with vulval symptoms should be encouraged to examine
themselves for monitoring the skin appearance and to highlight
any change. Patient information material has been developed by
the British Society for the Study of Vulval Disease, Worldwide
Lichen Sclerosus Support, the Vulval Pain Society and The International Society for the Study of Vulvovaginal Disease. These
web sites provide information on self-vulval examination as
well.
Women with pruritus vulvae quite often present with symptoms, which are not always specific to one clinical diagnosis, and
Gomathy Gopal MRCOG is an ST5 in Obstetrics and Gynaecology at

Victoria Hospital, Kirkcaldy, UK. Conicts of interest: none declared.
Essam Hadoura FRCOG is a Consultant in Obstetrics and
Gynaecology at Victoria Hospital, Kirkcaldy, UK and Honorary Senior
Lecturer at St Andrews University, Fife, UK. Conicts of interest:
none declared.
Tahir Mahmood MD FRCOG FRCPI MBA FRCPE FACOG is a Consultant in
Obstetrics and Gynaecology at Victoria Hospital, Kirkcaldy, UK.
Conicts of interest: none declared.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:4
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2016 Elsevier Ltd. All rights reserved.
REVIEW
Secondary referral is advised for expert opinion for further

investigation and biopsy or advice for management.
The correlation between clinical appearance of vulval

lesion and its pathological features
Clinical condition
Pathologic correlates
Spongiotic pattern
Acanthotic pattern
Atopic, allergic, irritant dermatitis

Psoriasis, lichen simplex chronicus,
primary (idiopathic), secondary
(superimposed on lichen sclerosis,
lichen planus, or other vulvar
disease)
Lichen sclerosus, lichen planus
Lichen sclerosus
Lichenoid pattern
Dermal homogenization/
sclerosis pattern
Vesiculobullous pattern
Acantholytic pattern
Granulomatous pattern
Vasculopathic pattern
Clinical evaluation
Gynaecological history should include eliciting the duration of
presenting symptoms, severity, impact on quality of life and any
past or present treatment. A detailed history of treatment with
any medication and response is important as it will influence
future treatment plans. Information regarding personal or family
history of autoimmune conditions, atopic conditions, and urinary
or faecal incontinence, smoking and cervical smear abnormalities are highly significant. The clinician should also enquire
about the impact of symptoms on social, psychological and
sexual life. A full examination of the anogenital region and other
skin and mucosal sites should also be carried out.
Pemphigoid (cicatricial type), linear

IgA disease
HaileyeHailey disease, Dariers
disease, papular genitocrural
acantholysis
Crohns disease, Melkersson
eRosanthal syndrome
Aphthous ulcers, Behcets disease,
plasma cell vulvitis
Investigations
Investigations for thyroid disease, diabetes and sexually transmitted infections should be considered. Although the RCOG
Green-top guideline 58 on the management of Vulvar skin Disorders advises to check serum ferritin, a recent case control study
on women with pruritus vulvae in Sheffield concluded that there
is no evidence to support routine determination of serum iron
status in their population. The decision to perform serum ferritin
estimation should be made on a case-by-case basis.
Skin patch testing could be performed for women seen with
vulval dermatitis in a general gynaecology clinic. Vulval biopsy is
indicated if there is a suspicion of VIN or there is no response to
first line treatment in a general gynaecology clinic.
Table 1
new symptoms may evolve with the passage of time. Such

chronicity of symptoms can make a diagnosis of the condition
challenging even for an experienced clinician. If correctly diagnosed, most underlying causes can be successfully treated.
The majority of patients are managed in primary care setting.
Referrals to secondary care (Specialist vulval clinic) are indicated
in following situations:
1) No obvious cause has been identified
2) Poor response or persistence of symptoms to preliminary
treatment (see Table 3)
3) Premalignant conditions e review of suspicious lesions like
unexplained vulval lump, ulceration or bleeding
4) Suspicion of malignancy e suspected cancer pathway
referral within 2 weeks
General measures
The following general advice should be provided at every initial
consultation to any patients with vulval symptoms (Table 3).
Complications
Fewer than 5 in 100 women (5%) pruritus vulvae if diagnosed
with lichen sclerosus or lichen planus might develop vulval
cancer. Chronic itch can be debilitating psychologically, sexually
and socially. Women might feel embarrassed and stigmatized to
talk about their symptoms. Pruritus can cause insomnia and
when insomnia leading to somnolence, could cause occupational
Common clinical presentation in pruritus vulvae and possible clinical diagnosis

Clinical presentation
Associated conditions
Percentage of clinical work load
Itch, soreness, excoriation, ulceration, skin

scaling, whitening and changes in the
appearance of affected
Itch and discomfort particularly if not well
controlled
Itch and soreness
Psoriasis, leucoderma, lichen sclerous/planus,

intertrigo, scabies
5%
Diabetes
5%
Allergic dermatitis to soaps, deodorants,

sanitary wear, detergents, fabric conditioners
Candidiasis and trichomoniasis
Mental stress and sexual anxiety in the
absence of physical disease, seen most
commonly in younger age group
5%
Vaginal discharges
Psychosomatic conditions
50%
35%
Table 2
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REVIEW
yeast) and, rarely, Trichosporon spp. Candida is a normal

commensal organism in the vagina. Pathological infection usually follows a change in the local environment or a decrease in
the hosts susceptibility to infection. Recent research suggests
that symptomatic candidiasis is due to an exaggerated immunological response to the presence of Candida rather than a
failure of immune mechanisms. Treatment is usually with topical
azole (Clotrimazole or Miconazole) or oral triazole (Fluconazole
150 mg stat dose can be given or Itraconazole 200 mg twice daily
for a day). Recurrent candidiasis (at least four episodes per year)
can be distressing for the women and challenging for the
physician. Treatment should include an induction period of 1e2
weeks, with at least 1 week of treatment either with an oral agent
or with a topical antifungal lasting for 1e2 weeks. This should be
followed by a maintenance treatment lasting for a period of 6
months with either oral Fluconazole 100 mg weekly or topical
Clotrimazole 500 mg weekly.
Practical tips
Dos
Donts
Use soap substitute
Shower
Gently dab vulval area

Dry with soft towel or hair
dryer on a cool setting held
away from skin
Wear loose-fitting silk or
cotton underwear
Sleep without underwear

Wear white or light colours
of underwear
C
C
Wash with plain water. Use

small amount of emollient with
water, to avoid dry skin.
Bath e Add bath emollient if
bathing.
Avoid sponges or flannels to
wash but use emollients and
apply with hand.
Avoid fabric conditioner, bio
logical washing powder, soaps,
shower gel, scrubs, bubble
bath, deodorants, baby wipes
and douches.
Avoid coloured toilet paper,
panty liners, and dark coloured
under-wear s dark textile dyes
may cause allergies.
NB: maintenance therapy with triazole is unlicensed. Treatment

can be stopped after 6 months and, if recurrent infection returns,
then repeat induction/maintenance should be considered.
Approximately 90% of women will remain disease-free at 6
months and 40% at 1 year. Non-albicans infections are harder to
treat. Boric acid, Nystatin or Flucytosine may be used in secondary care setting (Table 4).
Table 3
hazard. Itching and scratching can lead to skin breakdown and

secondary bacterial infection.
Summary
Pruritus vulvae are one of the commonest gynaecological presentations. A majority of these cases resolve with simple measures such as general care of vulvae and avoiding irritants or
triggers. Those who fail to respond to these measures should be
offered supportive therapy with oral antihistamines and H1 antagonists and moderate or potent steroids. This approach will
resolve 90% of cases. Clinical cases resistant to preliminary
treatment or if there is suspicious of VIN or malignancy should
Specic conditions and management

Candidiasis e vulvovaginal
Affects 75% of women in reproductive years with the peak
incidence at 20e40 years, 90% cases are due to Candida albicans
and 5% are due to Candida glabrata. Other fungal infections of
the vagina are caused by Saccharomyces cerevisiae (brewers
Clinical presentations and treatment of various underlying causes for pruritus vulvae
Cause
Clinical presentation/Investigation
Treatment
VIN
Intractable itch
Usual type: warty, Basaloid or mixed. Common
in women aged 35e55 years and usually
associated with human papilloma virus.
Differentiated type: rare, often associated with
other skin lesions (lichen sclerosus & planus)
e Single lesion usually ulcer/plaque.
Common in women aged 55e85 years.
Acute: red rash, swelling, blisters, papules.
Chronic: lichen, ill-defined border, some
scaling, with or without involvement of other
sites, such as axillae, face (eyebrows or nasolabial folds), anterior chest or scalp.
Patch test (if severe or uncontrolled
symptoms).
Topical imiquimod cream (an immune

modulator), and LASER. Surgical excision
usually for VIN2-3.
In differentiated lesions, 12e16% have
unrecognized invasion.
Follow-up e annual surveillance.
Atopy/Allergy/Irritant/Seborrhoeic
Avoid irritant.
General measures.
Topical steroids (1% hydrocortisone e 2e4
weeks then review, if severe lichen then high
dose steroid treatment locally applied initially,
then low dose thereafter) to break itch-scratch
cycle and sedating anti-histamines e to
prevent night time scratching.
(continued on next page)
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REVIEW
Table 4 (continued )
Cause
Treatment
Lichen sclerosus
Severe itch at night. Figure of eight

distribution involving perianal area. White
plaques papules associated with areas of
bruising and usually found on the interlabial
sulci, labia minora, clitoral hood, clitoris,
perineal body, and perineum. Bleeding into
the affected areas produces red or purple
purpuric lesions. Scarring & narrowing of
introitus. <5% risk of developing squamous
cell carcinoma, Common among
postmenopausal women.
More pain than itch. Erythema and or erosive
pattern, ulceration with pruritus, destruction
of vulval architecture (possibly with other sites
involved such as the nails and buccal mucosa).
Lesions are bluish-purple, shiny, flat-topped
papules with small white dots or lines
(Wickhams striae). <3% risk of developing
squamous cell carcinoma.
Intractable itch at night. Thickened plaques
with exaggerated skin markings over the hairbearing labia majora and sparing the mucosal
vulval skin and labia minora (the end result of
an itch-scratch-cycle, regardless of the initial
underlying cause of the itch).
Very rare. Itchy and uncomfortable. Vesicles
erupt causing pruritus, with or without
involvement of the axillae and sides of the
neck. It is also known as familial benign
chronic pemphigus, and it is an inherited
autosomal dominant condition. It is easily
mistaken for intertrigo or dermatitis.
Itch and unpleasant smell. Warty plaques,
which may be macerated and malodorous,
possibly with the involvement of seborrhoeic
areas of the trunk, flank, and face. An
autosomal dominant condition, which may be
confused with HaileyeHailey disease.
1st line e 0.5% clobetasol propionate

ointment/cream once at night for 1 month,
followed by alternate night for 1 month, the
twice a week for 1 month, then once a week or
as required and review at 2e3 months.
2nd line e calcineurin inhibitors and
tacrolimus have not been licenced and do not
have established safety data. Could be an
option in research setting.
Lichen planus
Lichen simplex chronicus
HaileyeHailey disease (Familial benign chronic

pemphigus)
Dariers disease (very rare)
Psoriasis
Well demarcated border, absence of scale

when affecting vulval area, smooth, pinkish
lesions (not involve vaginal mucosa).
Examination of nails and scalp may help to
diagnose.
FoxeFoydyce disease (very rare)
Itchy rash in high stress or emotional

situation. Small dome shaped papules,
involvement of axillae; intensely itchy & often
presenting as lichenification (grossly
thickened skin with accentuated skin
markings).
0.025% betamethasone valerate cream/

ointment e twice a day
General care of vulva, emollients, soap

substitutes. Avoid irritants. Antihistamines
and antipruritics may be helpful. Moderate to
ultra-potent steroids may be necessary to
break itchescratch cycle.
Avoid sunburn, and friction. Steroid cream for
treating lesions and prevent exacerbations.
Antibiotics to treat secondary infection.
Complete cure not reported.
Symptoms can resolve in 1/3rd as they grow

older. Topical: antibiotics for secondary
infection, Emollients topical steroids to
reduce irritation. Topical 5 fluorouracil may be
used in some cases. Oral: oral antibiotics or
oral acyclovir. Retinoid tablets may be tried.
Cyclosporin is used off-licence. Laser
treatment, photodynamic therapy and surgical
excision (dermabration) occasionally used.
Emollients, soap substitutes, vitamin D
(calcipotriene) analogues and 0.05%
clobetasone butyrate ointment/cream, or 0.1%
hydrocortisone 17-butyrate ointment/cream
applied twice a day. Coal tar should not be
used.
No single treatment very effective. Avoid pick
or scratch. Topical: steroid cream, calcineurin
inhibitors, retinoids, antibiotics and
phototherapy. Oral: antihistamine, oral
contraceptive pill or isotretinoin. Surgery:
excision or laser.
Symptomatic dermatographism
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Table 4 (continued )
Cause
Thread worms
Treatment
Localized urticaria triggered by a direct firm

touch, scratching or rubbing.
Avoid triggers, self resolution in 5 years.

Antihistamines, H1 (fexofenadine, loratadine
or cetirizine) or H2 antagonists or steroids.
Recurrence is common. Leukotriene
antagonist known to be useful. Cyclosporine
and narrow band UVB phototherapy.
Mebendazole 100 mg oral stat dose. If reinfection 2nd dose after 2 weeks.
Pubic lice
Intense itching around anal opening, which

can spread to perianal or vulvovaginal area.
More noticeable at night.
Nits in pubic hair.
Viral warts
Rare cause.
Scabies
Burrows alongside of fingers and front of

wrists.
Herpes simplex
Pain predominant itching, smear shows

multinucleated giant cells. Screen and treat
other STI.
Trichomonas vaginalis
Frothy green-white discharge. Direct

microscopy shows protozoa.
Gardnerella vaginalis (BV)
Fishy smell in discharge. Wet mount shows

clue cells (bacteria within epithelial cells),
gram negative rods.
Sore & itchy, thick white discharge. Spores &
hyphae on direct microscopy. If positive
culture, and exclude diabetes. Can cause
satellite lesions on inner thighs.
Candida
Behcet syndrome
Hidradenitis suppurativa
Atrophic vaginitis
Plasma cell (Zoons vulvitis)
Extra mammary Pagets disease
Recurrent ulcers. Cervix and vagina can be

involved. More pain, less itchy and scar
formation occurs.
Deep nodules which can rupture to form sinus
tracts, leading to widespread scarring, and
may present with pruritus.
Thinning and dryness of vulva & vagina. Itch
and dyspareunia. Vulva e atrophic. Vagina e
pale.
Itch, burning, dyspareunia, dysuria. Dermal
infiltration of plasma cells, vessel dilatation
and hemosiderin deposits.
Common among postmenopausal women. Itch
with florid eczematous lichen, erythema and
excoriation. Check GI and urinary tracts for
adenocarcinoma.
0.5% malathion lotion or 1% lindane lotion/

cream applied to pubic hair for 12 hours and
washed off, repeat after 7 days.
Cryotherapy, 10% podophyllin applied once a
week. Should be washed off after 4 hours.
Zinc pyrithrone or malathion lotion or cream
applied whole body surface except face, scalp
on two successive nights oral ivermectin.
Primary e oral acyclovir 200 mg five times e 5
days.
Recurrent e oral acyclovir 400 mg Bid e few
months.
Topical acyclovir 5% cream, useful if applied
early.
Metronidazole 400 mg oral twice daily for 5 to
7 days or 2 g stat dose.
Partner treatment.
Metronidazole 400 mg oral twice daily for 5 to
7 days or 2 g stat dose.
Partner treatment.
Miconazole or nystatin ointment/clotrimazole
cream applied to vulva twice a day. Oral
fluconazole 100 mg daily for 3 days. May
consider partner treatment.
Topical and systemic immunosuppressant.
Skin hygiene, lose weight, long term

antibiotics treatment with doxycycline 100 mg
daily for 6 months.
Tropical or intravaginal oestrogens and review
after 3 months.
Ultra-potent steroids and supportive
antihistamine treatments have been reported.
Surgical excision to exclude adenocarcinoma
of skin appendage. Photodynamic therapy and
topical imiquimod has been used with some
success. Recurrence is common, due to
subclinical disease.
Table 4
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be referred to a specialized vulva clinic. Correct recognition of

these conditions at first presentation is a key to managing these
conditions successfully.
A
Dermatol Venereol Leprol 2011 MayeJun; 77: 294e9. http://dx.doi.

org/10.4103/0378-6323.79698.
Lynch PJ, Moyal-Barrocco M, Bogliatto F, Micheletti L, Scurry J. 2006
ISSVD classication of vulvar dermatoses: pathologic subsets and
their clinical correalates. J Reprod Med 2007; 52: 3e9.
Management of vulvovaginal candidiasis, British Association for Sexual Health and HIV 2007.
NICE. Referral guidelines for suspected cancer: quick reference guide.
NG12, London: NICE, 2015.
RCOG. The management of vulval skin disorders. Green-top guideline
No. 58. 2011. Royal College of Obstetricians and Gynaecologists,
www.rcog.org.uk.
Edwards Sarah K, Bates Christine M, Lewis Fiona, Sethi Gulshan,
Grover Deepa. 2014 UK national guideline on the management of
vulval conditions. Int J STD AIDS 2015.
FURTHER READING
BAD. British Association of Dermatologists guidelines for the management of lichen sclerosus 2010. 2010, www.bad.org.uk.
BASHH. UK national guideline on the management of vulval conditions. British Association for Sexual Health and HIV. 2007, www.
bashh.org.uk.
Bohl TG. Overview of vulvar pruritus through the life cycle. Clin Obstet
Gynecol 2005; 48: 786e807.
Kelekci KH, Adamhasan F, Gencdal S, Sayar H, Kelekci S. The impact
of the latest classication system of benign vulvar diseases on the
management of women with chronic vulvar pruritus. Indian J
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Management of a woman
with a previous
spontaneous preterm
birth
complications and neurodevelopmental disability. Furthermore,

being born preterm increases the risk of developing chronic diseases in adulthood, including obesity, type II diabetes, hypertension and cardiovascular disease. The consequences of prematurity
are most grave for those born at the earliest gestations, with the
majority of long term adverse outcomes occurring at gestations of
less than 33 weeks. For example, perinatal mortality is 2% for
those babies born at 32 weeks, but approaches 90% for those born
at 23 weeks.
Preterm birth may be broadly considered as either medically indicated or spontaneous. Indicated preterm birth accounts for approximately one third of preterm deliveries, and
occurs when complications arise that put mother or fetus at
risk unless delivery is expedited, for example: severe intrauterine growth restriction, massive antepartum haemorrhage,
or severe preeclampsia. The remainder of preterm births are
considered spontaneous, and include those which are preceded
by preterm pre-labour rupture of membranes. The processes
culminating in spontaneous preterm labour can be initiated by
a wide range of aetiologies such as infection, uterine stretch,
placental ischaemia, haemorrhage and other inflammatory
stimulus. Spontaneous preterm birth represents a final common pathway of a heterogeneous group of conditions. This is
likely to explain why, despite considerable healthcare advances, successful prediction and prevention of spontaneous
preterm birth has remained so elusive e as each predictor or
intervention is likely to only identify or improve outcomes for
a subset of cases.
There are many risk factors for preterm birth, however a
prior history of spontaneous preterm birth is the most significant and consistently identified clinical risk factor, and the
identification of women with a history of preterm birth gives an
opportunity to optimise care for subsequent pregnancies. This
article will review and discuss risk assessment and management of pregnancies where there is a history of a prior preterm
birth.
Charlotte Oyston
Katie Groom
Abstract
Preterm birth is an important cause of neonatal morbidity and mortality, and is associated with long term adverse health consequences.
Worldwide close to 15 million babies are born preterm each year,
and there are no signs that the rate of preterm birth is slowing. A history of a previous spontaneous preterm birth is a signicant risk factor
for a subsequent spontaneous preterm birth; identifying these women
provides an opportunity to optimize care in future pregnancies. Interventions such as progesterone and cervical cerclage appear to be
benecial in women at high risk of preterm birth; however uncertainties
remain as to how best to screen women, the optimal treatment
regimen, and whether these treatments improve perinatal outcomes.
Tests that accurately identify asymptomatic women who go on to
deliver preterm are lacking. Research is underway to develop biomarkers that can accurately predict women who will deliver preterm.
However, without effective strategies that diminish rates of preterm
birth and improve perinatal outcomes, the clinical role of these tests
is less well dened.
Keywords Cervical cerclage; cervical length; fetal bronectin;

preterm birth; prevention; progesterone
Introduction
Predicting recurrent preterm birth
Preterm birth is defined as birth occurring prior to 37 weeks

gestation. Worldwide, every year close to 15 million babies are
born preterm. Despite extensive ongoing research into causes,
predictors and treatments for preterm birth, there is no evidence
that rates of preterm birth are falling. In fact, a recent systematic
review of preterm birth rates suggested that worldwide, preterm
birth rates are stable or increasing.
The consequences of preterm birth include increased risk of
mortality, and short and long-term respiratory and gastrointestinal
Mrs PT is a 32 year-old G3P1 who attends your clinic prepregnancy. Her notes document an elective early surgical
termination in her first pregnancy, and a previous delivery at
27 weeks, with her baby spending time in the neonatal unit.
She is considering becoming pregnant again, but is extremely
anxious given her history. She wants to know the likelihood of
this baby being born preterm again.
At present, risk scoring tools based on clinical history alone
perform poorly. However, details of the circumstances leading to
the previous preterm birth may aid prediction and so a full history and case note review of the previous births is important to
assess future risk. It may identify areas where there is opportunity to reduce or eliminate risk factors for recurrent preterm birth
as well as other pregnancy complications.
Charlotte Oyston MB ChB BMedSci (Hons) Dip OMG is a Clinical Research

Fellow and PhD Candidate at The Liggins Institute, University of
Auckland, Auckland, New Zealand. Conicts of interest: none
declared.
Number and timing of previous deliveries

The risk of recurrent spontaneous preterm birth reflects the
aetiology of the previous preterm birth, the number of previous
preterm births, and the severity of prematurity. The likelihood of
having a preterm birth in a given pregnancy increases with the
Katie Groom MB BS BSc FRANZCOG PhD CMFM is a Senior Lecturer and

Maternal Fetal Medicine Subspecialist, Department of Obstetrics and
Gynaecology, Faculty of Medical and Health Science, University of
Auckland, Auckland, New Zealand. Conicts of interest: none
declared.
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number of previous preterm births, with a reducing chance of

delivery after 33 weeks of 83, 86 and 68% after one, two or three
prior preterm births. Risk of preterm birth also increases as the
gestational age of previous preterm births declines, with the
greatest risk for those with a previous delivery at less than 28
weeks gestation. If the previous preterm delivery was an indicated delivery, the risk of recurrence will be related to the
recurrence risk of the condition leading to the indicated delivery;
however a history of previous indicated preterm birth is also
associated with an increased risk of spontaneous preterm birth in
subsequent pregnancy. Presumably this is due to a shared aetiology e such as placental ischaemia e between pregnancy
complications such as preeclampsia and preterm birth. The
timing of the last pregnancy should also be reviewed, as risk of
early delivery increases with reducing interpregnancy interval
(IPI). An analysis of 6181 women with a previous preterm birth
demonstrated that after adjusting for confounding factors, those
with an IPI of <6 months had the highest increase in risk of
preterm delivery (44% increase in risk of recurrent preterm
birth), IPIs of 6e12 months had a modest increase, and there was
no increase in risk of recurrent preterm birth with IPIs of 12e18
months, compared to the risk of those with an IPI of 18 months
or more.
subsequent pregnancies rises with the number of procedures

performed.
Presence of congenital uterine anomalies
Congenital uterine anomalies are found more commonly in
women with a history of second trimester loss or preterm birth,
with a prevalence of up to 25% e compared to 6% in women
from an unselected population. The risk of preterm birth varies
with the type of uterine anomaly; women with a uterine didelphys or a septate uterus have the highest risk with up to 33% of
pregnancies ending in preterm delivery. It has long been thought
that the increased rate of preterm birth results from a reduced
volume and distensibility of the uterine cavity, however it is most
likely that women with uterine anomalies may also have a cervical anomaly which contributes to cervical insufficiency in
pregnancy.
Use of assisted reproductive technologies
Several systematic reviews have shown an increase in risk of
preterm delivery in women undergoing IVF treatment
compared to those who conceive naturally, with the risk of
preterm delivery doubling for delivery prior to 37 weeks, and
tripling for delivery prior to 33 weeks for singleton pregnancies.
It is unclear whether this increase in risk evolves from the
fertility treatment itself, underlying maternal factors associated
with infertility, or iatrogenic bias in the care of these
pregnancies.
History of cervical surgery or trauma/uterine

instrumentation
Women undergoing excisional treatment for cervical dysplasia
have an increased risk of preterm birth compared to women who
have not had these procedures, although the mechanism/s
mediating this increase in risk are unclear. One hypothesis is that
these procedures reduce the mechanical support of the cervix
which may then increase susceptibility to cervical incompetence,
or spontaneous loss of the cervical mucous plug leading to
ascending infection. Cervical conization has the most consistent
and largest association with preterm birth. Women with a history
of conization are 2e3 times more likely to have a preterm birth
than healthy controls, and those conceiving within 2e3 months
of conization or large conization (>1 cm depth) may have the
greatest risk. Recent meta-analyses have also demonstrated an
increased risk of preterm birth with other excisional therapies e
such as large loop excision of the transformation zone (LLETZ)
(RR 1.70 compared to healthy controls). Although many studies
within the meta-analyses use healthy controls as the comparison
group, an increased risk of preterm birth with all excisional
therapies remains e albeit attenuated e when women undergoing cervical treatment are compared to those who had been
diagnosed with precancerous lesions, but not treated. This suggests that the increase in risk may be in part due to the underlying pathology of the precancerous lesion, as well as the cervical
procedure itself.
It is unclear as to whether cervical dilation and curettage e for
the management of miscarriage or surgical termination of pregnancy e increases the risk of spontaneous preterm birth in
subsequent pregnancies. Whilst some large cohort studies have
found no significant difference in rates, more recent good quality
studies have demonstrated a small but significant increase in risk
of spontaneous preterm birth after these procedures, with odds
ratios of up to 1.8 with evidence that the risk of preterm birth in
Demographic, socioeconomic, psychosocial and

lifestyle factors
Women who are obese or significantly underweight prepregnancy are at increased risk of preterm delivery, as well as
other pregnancy complications. A large meta-analysis of data
from over one million women found that women from developed countries with a pre-pregnancy BMI <18.5 kg m2 are
more likely to have a preterm birth e either spontaneous or
indicated e compared to women with a BMI in the normal
range (RR 1.22). Women with a BMI of 35 kg m2 also appear
to be at increased risk of indicated preterm birth (OR 1.5e1.8),
which may be partially explained by an increased prevalence of
chronic disease (such as hypertension or diabetes) in this
population.
Race and ethnicity are important risk factors for preterm
birth. After adjusting for risk factors such as age, education and
parity, black women have a two to three -fold higher risk of
preterm birth compared to non-black women. The aetiology of
this association is unclear, but is possibly interlinked with other
lifestyle factors and/or social disparities; rates of preterm birth
are increased amongst socioeconomically deprived women,
women who have high levels of anxiety or perceived stress or
low levels of support, are at the extremes of maternal age, and
those who smoke, consume alcohol, and use illicit drugs during
pregnancy.
Pre-conception strategies to reduce risk of preterm birth

What advice should be given and what medical or surgical
interventions are available pre-conception that could reduce
the risk of preterm delivery?
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Cervical cerclage: where a suture is placed around the cervix to

provide mechanical support and keep the cervix closed during
pregnancy e is typically performed vaginally, in the second
trimester for at risk pregnancies (the indications for cerclage
placement during pregnancy are discussed in more detail in the
section Antenatal strategies to reduce the risk of preterm birth
below). Abdominal placement of a cervical suture via laparotomy or laparoscopy is sometimes carried out preconception in
women with a very short or scarred cervix (where transvaginal
placement may be difficult), or women with a history of a failed
vaginally placed cervical suture. As yet there are no published
randomised studies directly comparing the efficacy of transabdominally placed with a transvaginally placed cerclage. A
systematic review of 13 case series and one controlled non
randomised study of transabdominal cervical cerclage in
women with a history of failed transvaginally placed cervical
cerclage found a lower risk of perinatal death or delivery before
24 weeks in women who had a transabdominal cerclage,
compared to those who had a repeat vaginally placed cerclage
(6 vs 12.5%). However the procedure appears to be associated
with higher incidence of serious maternal operative complications than vaginal cerclage (3.4 vs 0%) and their use should be
reserved for those at highest risk with a previously failed
vaginal cerclage.
Pre-conception identification of risk factors provides an

opportunity for behavioural changes, the optimization of
medical conditions and the provision of surgical strategies that
could improve outcomes for future pregnancies. Unfortunately,
there are few pre-conception interventions that improve outcomes in preterm birth. There are several reasons for this:
many risk factors for preterm birth are non-modifiable, many
risk factors e even in combination e minimally increase absolute risk and are poorly predictive of subsequent preterm
birth, and there is a lack of interventions proven to improve
outcomes. Of note, when assessing the impact of strategies to
prevent preterm birth, it is important to look beyond prolongation of pregnancy as an outcome and assess impact on
perinatal morbidity and mortality. This is because in some
instances, preterm birth may represent a mechanism through
which the fetus escapes an adverse intrauterine environment;
prolonging these pregnancies may be associated with neonatal
harm rather than benefit.
Pre-conception advice and medical interventions
Ideally, counselling and assistance regarding optimal pregnancy spacing, the benefits of maintaining a healthy weight,
and abstinence from smoking, alcohol and drugs should be
provided in the preconception period. Smoking cessation e
and limiting passive smoke exposure e is of particular
importance, as this is the largest modifiable risk factor for
preterm birth. Although clinical trial data is lacking, there is
indirect evidence of the benefits of smoking cessation from
observational studies. A recent meta-analysis demonstrated a
10% reduction in the population rate of preterm birth
following the implementation of smoke-free legislation in
Europe and North America. The management of chronic
medical conditions such as diabetes and hypertension should
be optimized; although this may not be associated with reductions in rate of spontaneous preterm birth, optimal control
of chronic conditions may lower the risk of additional pregnancy complications, and therefore the rates of indicated preterm birth, as well as potentially leading to better long term
outcomes for mother and baby.
Antenatal tests for prediction of preterm birth

Ms S is 24-year-old G3P2 with a history of two previous preterm
deliveries at 32 weeks. You see her in clinic at 12 weeks and she
asks if there are any tests she can have that will detect whether
she will go into labour early.
Are there any tests which can be used in pregnancy to help
stratify the risk of preterm delivery in asymptomatic women?
Several tests have been identified as potentially useful for the
prediction of spontaneous preterm birth and those currently in
use include transvaginal ultrasound measurement of cervical
length and vaginal biomarkers such as fetal fibronectin (fFN),
placental alpha macroglobulin-1 (PAMG-1) and cervical phosphorylated insulin-like growth factor binding protein-1
(phIGFBP-1).
Pre-conception surgical interventions

As uterine anomalies are associated with increased risk of
preterm birth, it is hypothesized that normalizing uterine
anatomy would be associated with a lowering of preterm delivery. For women with a septate uterus, there is evidence from
observational studies that pregnancy outcomes e including the
rate of preterm birth e may be improved with hysteroscopic
resection of the septa. However, given the paucity of
adequately powered randomised studies comparing outcomes
of hysteroscopic resection with no treatment, clear recommendations as to which women are appropriate candidates for
this procedure cannot be made. Similarly, other surgeries
aimed at normalizing anatomy in women with different
congenital uterine malformations have been described, but
evidence is limited to case reports and small observational
studies. Where surgery is considered for women with a uterine
anomaly, the benefits and risks should be carefully considered
on a case by case basis.
Fetal bronectin
Fetal fibronectin is a glycoprotein found in the amniotic fluid,
placenta, and between the chorion and amnion. It is detectable
in cervicovaginal secretions in both early and late pregnancy,
but is not normally found at elevated levels in cervicovaginal
fluids between 20 and 34 weeks. The presence of fFN between
20 and 34 weeks is thought to occur when there is disruption
of the choriodecidual interface due to inflammation or mechanical forces, and is predictive of preterm delivery. Swabs
taken at speculum examination can be used to detect the
presence of fFN in a bedside test, with results given quantitatively or qualitatively (either positive e corresponding to a
concentration of >50 ng/ml e or negative). In asymptomatic
women, fFN has a sensitivity of 68e76%, and specificity 88
e89%, with the risk of birth before 35 weeks increases with
increasing levels from >20 ng/ml to 300 ng/ml. In symptomatic women, fFN has a higher sensitivity (78e89%) but
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comparable specificity (86%). Currently, the greatest utility for

fetal fibronectin is in its negative predictive value for women
symptomatic of preterm labour, and the reassurance that
imminent delivery is highly unlikely. It is not clinically useful
as a stand-alone test for prediction of preterm birth in
asymptomatic women with or without other risk factors for
preterm birth.
length, and past obstetric history, and has the advantage that it
provides an individualized estimate of preterm delivery, rather
than just a summary estimate of risk. The algorithm is available
to clinicians as a smart phone app; further information is available at www.quipp.org.
Other biomarkers
Actim Partis is a bedside test that measures levels of phIGFBP1, a substance which is secreted by decidual cells. Detachment of
fetal membranes from the decidua causes leakage of phIGFBP-1
into the cervicovaginal fluid. Like fFN, phIGFBP-1 is a better
negative predictor of preterm birth in symptomatic women. Its
predictive accuracy in asymptomatic women is limited, with a
recent meta-analysis finding pooled sensitivity and specificity of
14e47%, 76e93% respectively.
PAMG-1 is a large protein found in amniotic fluid. Its detection in the cervicovaginal secretions has been used to detect
ruptured membranes in a bedside test marketed as Amnisure.
More recently, studies have assessed the role of PAMG-1 in
detecting preterm labour independently from rupture of membranes in women with signs or symptoms of preterm labour. The
test appears to perform with high sensitivity and specificity for
symptomatic women. However, as these studies were of relatively small sample size, further research is required to confirm
the tests accuracy, and to clarify its role in the assessment of
women who are asymptomatic.
Cervical length measurement

Large prospective studies have consistently observed an
increased risk of preterm birth for women with a shortened
cervix during pregnancy, and that the risk of preterm delivery
increases with decreasing cervical length. Transvaginal ultrasound is the gold standard method for visualizing and measuring
cervical length, with high likelihood of obtaining measurements,
and low inter-observer variability. The alternative transabdominal approach should not be used, as it may be affected by
maternal bladder filling, and is associated with a lower likelihood
of obtaining adequate measurements. Cervical length measurements are performed over a 5 minutes period with an empty
maternal bladder and in the absence of undue probe pressure.
The cervical length is taken as the shortest measurement that
displays the landmarks of internal, external os, cervical canal.
Assessment of cervical length in women at high risk of preterm
birth is usually performed between 14 and 24 weeks; risk of
spontaneous preterm birth increases as cervical length decreases
and gestational age decreases.
The National Institute of Child Health and Development
(NICHD) Preterm Prediction study was the first large prospective
study to evaluate cervical length as a predictor for preterm birth
in asymptomatic women. Cervical length was measured in 3000
women at 22e246 weeks. Compared to women with a cervical
length of more than 40 mm (the 75th centile) women with a
cervical length less than 40, 35, 26 or 13 mm (75th, 50th, 10th or
1st centile) had a significantly increased risk of delivery prior to
35 weeks (relative risk 2.4, 3.8, 9.5 and 14 respectively). It
should be noted however, that less than half the women with the
shortest cervices (less than 15 mm), delivered prior to 35 weeks.
These findings have since been replicated in other large prospective studies.
Antenatal strategies to reduce the risk of preterm birth

What antenatal strategies are proven to be effective at reducing
the risk of preterm birth in women with a prior history of
preterm birth?
Cervical cerclage
Cervical cerclage is the surgical technique where a suture is
inserted around the cervix. The original aim of cerclage was to
provide mechanical support to keep the cervix closed and prevent pregnancy loss due to an inherent weakness in the cervix
(cervical incompetence), however, its use has now been
extended and it is typically performed in the second trimester
for one of three indications e a history of recurrent preterm
losses (history indicated), cervical shortening detectable on
ultrasound (ultrasound indicated), or in women presenting with
signs of cervical dilation or visible fetal membranes (rescue
cerclage).
The most common techniques for cerclage placement are the
Shirodkar and McDonald techniques, both of which result in a
purse string suture around the cervix. The Shirodkar technique
describes dissection of the vaginal mucosa anteriorly and posteriorly to expose the cervix as close to the level of the internal os
as possible whereas the McDonald technique does not conventionally involve dissection. Most studies of cervical cerclage do
not stipulate which technique has been used and there are no
prospective studies evaluating pregnancy outcomes by comparison of the two techniques, so choice of technique is generally
governed by surgeon preference.
Combined fFN and cervical length measurements

A combination of fFN and cervical length is likely to improve
identification of women at the highest risk of preterm delivery. A
subsequent analysis of the NICHD data looked at the effect of
cervical length and fetal fibronectin at 24 weeks on the risk of
preterm delivery in women with a history of previous preterm
birth. In women with a previous preterm birth, both cervical
length and fetal fibronectin test results at 24 weeks modified the
risk of preterm delivery. The highest risk of preterm delivery was
in women with a positive fFN and a cervical length of less than
25 mm; where risk of delivery prior to 35 weeks was 64%. The
risk was lowest for women with a negative fetal fibronectin and a
cervical length of 35 mm or more (7% risk of delivery prior to 35
weeks). In women with a positive fFN but a cervix >35 mm, risk
of delivery before 35 weeks was 28%. Recently, a risk prediction
tool for both symptomatic and high risk asymptomatic women
has been developed. The tool combines quantitative fFN, cervical
History indicated cerclage: in a large international trial 1292

women were randomised to cerclage or no cerclage when there
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on preterm birth in women with a previous history of preterm birth. Furthermore, in the meta-analysis reduction in
perinatal mortality was confined to those who received progesterone IM (RR 0.5). Presently, a large randomised
controlled trial of the use of vaginal progesterone for the
prevention of preterm labour is underway, and will assess
infant outcomes up until two years of age. Hopefully, the
results from this trial will provide conclusive evidence as to
whether vaginal progesterone is beneficial to women at risk
of preterm birth, including those with a previous preterm
birth.
For women with a history of preterm birth and short cervix in
their current pregnancy evidence is more supportive of a role for
progesterone with three meta-analyses demonstrating that progesterone treatment is associated with a reduction in preterm
birth in asymptomatic women with a cervical length <25 mm on
mid-trimester ultrasound scan; importantly two of these also
demonstrated a reduction in perinatal morbidity and mortality
with treatment.
Despite the promise that progesterone is an effective preventative therapy, there are many questions still to be answered
particularly in regards to optimal dose and route of administration, (studies have administered progesterone orally, vaginally or intramuscularly, with doses ranging from 90 to 400 mg
daily to 250 mg weekly), timing of initiation, and duration
treatment.
was clinical uncertainty as to whether or not to perform a cervical cerclage. The cerclage group had significantly fewer deliveries prior to 33 weeks (NNT 25), however subgroup
analysis showed that only women with at least three previous
pregnancies ending prior to 37 weeks benefited from cerclage. In
this group, the number of preterm deliveries prior to 33 weeks
was halved; however, no differences in neonatal outcomes were
detected. It is possible that this study underestimated the
magnitude of benefit of cerclage, as it excluded women who were
potentially the most likely to benefit from cerclage e those that
clinicians were not uncertain as to whether cerclage would provide benefit.
Ultrasound indicated cerclage in women with a history of
preterm birth: a meta-analysis using individual patient level
data compared cerclage with expectant management in women
with a shortened cervix (less than 25 mm) and found that cerclage was associated with a reduction in preterm birth before 35
weeks in those with singleton pregnancies and a history of prior
preterm birth or second trimester loss (RR 0.63). A further
randomised study of women with a history of preterm birth and a
cervical length of <25 mm showed a reduction in pre-viable
delivery and perinatal mortality, although there was no reduction in delivery in less than 35 weeks unless cervical length was
below 15 mm.
Rescue cerclage: ideally, women with a previous preterm birth
should be offered elective cervical cerclage or serial surveillance
of cervical length, thereby avoiding a presentation with cervical
dilatation. However, in the event that cervical dilatation occurs, a
rescue cerclage should be considered. A small randomised study,
compared rescue cerclage to expectant management (1 week of
broad spectrum antibiotic therapy and bed rest until 30 weeks)
found cerclage delayed delivery by an average of 4 weeks, and
had a reduction in delivery prior to 34 weeks, perinatal morbidity
and a trend towards reduced perinatal mortality. Similar delays
have been seen in small non randomised studies. Cerclage may
be less likely to be effective with significant membrane prolapse
(beyond the external os), cervical dilatation of more than 4 cm,
and should never be performed when there are signs or symptoms of chorioamnionitis, fetal compromise, death or fetal
anomaly not compatible with life, PPROM or ongoing vaginal
bleeding.
Progesterone vs cervical cerclage: although there are no randomised trials directly comparing efficacy of progesterone to cervical cerclage in high risk women, a recent indirect analysis has
suggested that both interventions are equally efficacious in preventing preterm birth in singleton pregnancies where there is a
history of preterm birth and mid-trimester cervical length less
than 25 mm.
Cervical pessary
The use of pessaries for the prevention of spontaneous preterm
birth has been described since the 1950s. The main mechanism
by which the pessary is thought to prevent preterm labour is via
the alteration of the inclination of the cervical canal relative to
the uterus (resulting in a more acute utero-cervical angle),
thereby preventing direct pressure on the cervix and fetal
membranes at the level of the internal os. As pessaries are a
one-off treatment, well tolerated with minimal side effects
and are of relatively low cost, they are an attractive alternative
to cerclage and progesterone treatments e particularly for
women from developing countries where the majority of preterm births occur but resources are limited. The first randomised controlled trial using Arabin pessaries for the prevention
of preterm birth in women with a shortened cervix detected on a
mid-trimester ultrasound scan found a significant reduction in
delivery before 28, 34 and 37 weeks (RR 0.25, 0.24, 0.36
respectively) and a reduction in composite neonatal adverse
outcomes with pessary use compared to expectant management. These findings are in contrast to a subsequent randomised trial, which reported no difference in preterm delivery
rates. At present, as strong evidence of efficacy is lacking, the
cervical pessary should not be used as part of routine care.
Progesterone
Progesterone has several properties that may be important in
maintaining pregnancy, including anti-inflammatory properties, a preventative role in cervical ripening and a role in
maintaining myometrial quiescence. Several meta-analyses
provide support for the use of progesterone for the prevention of preterm birth in high risk women. In women with a
history of spontaneous preterm birth, progesterone treatment
reduced preterm birth prior to 34 and prior to 37 weeks (RR
0.31 and 0.55 respectively). However it seems possible that
the route of administration is important; with benefit only
being apparent to those who received progesterone as weekly
intramuscular (IM) injections. The largest study of the use of
vaginal progesterone has not demonstrated a positive effect
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with a careful history, examination, and investigations aimed at

determining the likelihood of preterm labour, and excluding the
presence of serious conditions in mother and baby that require
imminent delivery (for example, fetal distress, placental
abruption or chorioamnionitis). Once conditions requiring
expedited delivery have been excluded, adjunct tests such as
ultrasound assessment of cervical length (as well as determining fetal presentation and growth), fFN, phIGFBP-1 and
PAMG can be considered. This allows targeted use of therapies
most likely to improve neonatal outcomes should preterm delivery ensue; maternal administration of corticosteroids (if
gestational age is <35 weeks), maternal administration of
magnesium sulphate where delivery is imminent (if gestational
age is <30 weeks), transfer to a unit able to provide appropriate
neonatal care and the considered treatment of any precipitating
causes of labour.
Further well designed, adequately powered studies are needed

to ascertain whether cervical pessaries can prolong gestation
and improve perinatal outcomes for women at risk of preterm
birth.
Other antenatal therapies with insufcient evidence of
benet
Screening and treatment of asymptomatic women for lower
genital tract infection: although genital tract infection is associated with preterm birth, there is not consistent evidence that
the screening and treatment of asymptomatic women improves
outcomes. A recent systematic review found screening women in
the early second trimester and treating for candidiasis, BV and
trichomoniasis halved the rate of delivery before 37 weeks. In
contrast, studies assessing the effect of screening and treatment
of BV or trichomoniasis independently have found that although
treatments are effective at eradicating infection, rates of preterm
birth were either no different, or increased compared to untreated
women.
Summary and conclusions

A history of a preterm birth is an important risk factor for
spontaneous preterm birth in a subsequent pregnancy, although
the majority of women with a previous preterm birth will
deliver at term in their subsequent pregnancy. Many risk factors
for spontaneous preterm birth have been identified, however
many of these are non-modifiable; and those that can be
changed e such as smoking cessation and weight optimization
e may result in a modest reduction in risk of preterm delivery at
best. There is evidence that interventions such as progesterone
and cervical cerclage may be beneficial in certain women at
high risk of preterm birth, however questions still remain as to
how best to screen these women, the optimal treatment
regimen, and whether these treatments improve perinatal outcomes. In asymptomatic women, the best biomarkers for the
prediction of preterm delivery are cervical length measurement,
and detection of fFN in the cervicovaginal secretions. However,
without effective strategies that diminish both the rate of preterm birth and improve perinatal outcomes, the role of these
tests in the management of these women is less well defined.
These biomarkers should be used in future research to evaluate
the impact of treatments such as progesterone, cerclage and
cervical pessaries on those at the highest risk of preterm
birth.
A
Treatment of periodontal disease: increasing severity of periodontal disease is associated with increasing likelihood of preterm birth. However randomised controlled trials have not found
a reduction in the rate of preterm birth when women are treated
for this condition.
Bed-rest, relaxation, or stress reduction: although many studies
have demonstrated an association between psychological stress
and preterm birth, a limited number of studies have assessed the
effect of relaxation techniques on preterm birth rates. The studies
published use different relaxation techniques, so are difficult to
compare directly, however while studies show evidence of
reduced stress and anxiety scores, but not evidence of reduced
risk of preterm birth. Similarly, there is no evidence that reducing
work or reducing sexual activity reduces the likelihood of preterm birth.
Preterm birth clinic
Despite a growing body of evidence supporting the use of cervical cerclage and progesterone for the prevention of preterm
birth, the counselling, availability and clinical use of these interventions is inconsistent. In obstetrics (and many other areas
of medicine), there is a trend toward developing specialized
clinics which focus on prevention and provide a means for
consistent application of the most up to date evidence based
practice. While there is no clear evidence that attendance at
preterm birth prevention clinics reduce the rates of preterm
birth, such clinics are now an accepted part of service provision
in many centres, and offer other benefits such as an opportunity
for teaching of both clinicians and patients, and an ideal setting
for further research into the aetiology and prevention of preterm
birth.
FURTHER READING
Conde-Agudelo A, Romero R, Nicolaides K, et al. Vaginal progesterone vs. cervical cerclage for the prevention of preterm birth in
women with a sonographic short cervix, previous preterm birth,
and singleton gestation: a systematic review and indirect comparison metaanalysis. Am J Obstet Gynecol 2013; 208. 42.e142.e18.
Crane JM, Hutchens D. Transvaginal sonographic measurement of
cervical length to predict preterm birth in asymptomatic women at
increased risk: a systematic review. Ultrasound Obstet Gynecol
2008; 31: 579e87.
Final report of the medical research council/Royal college of obstetricians and gynaecologists multicentre randomised trial of cervical
cerclage. MRC/RCOG working party on cervical cerclage. Br J
Obstet Gynaecol 1993; 100: 516e23.
Management of women presenting with preterm

labour
The management of women who present with threatened preterm labour does not differ between those who have and have
not had a previous preterm birth. In brief, management begins
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Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and

causes of preterm birth. Lancet 2008; 371: 75e84.
Kazemier BM, Buijs PE, Mignini L, Limpens J, Groot CJM, Mol BWJ.
Impact of obstetric history on the risk of spontaneous preterm birth
in singleton and multiple pregnancies: a systematic review. BJOG
2014; 121: 1197e208.
Kuhrt K, Smout E, Hezelgrave N, Seed PT, Carter J, Shennan AH.
Development and validation of a predictive tool for spontaneous
preterm birth incorporating cervical length and quantitative fetal
bronectin in asymptomatic high-risk women. Ultrasound Obstet
Gynecol 2015 [Epub ahead of print].
Romero R, Nicolaides K, Conde-Agudelo A, et al. Vaginal progesterone in women with an asymptomatic sonographic short
cervix in the midtrimester decreases preterm delivery and
neonatal morbidity: a systematic review and metaanalysis of
individual patient data. Am J Obstet Gynecol 2012; 206.
124.e1-124.19.
Practice points
C
107
Preterm birth may be considered as either spontaneous or

indicated
For women with a previous indicated preterm birth, risk of
recurrence depends on the specific condition necessitating early
delivery. However, these women are also at slightly higher risk of
spontaneous preterm birth
For women with a previous spontaneous preterm birth, risk of
early delivery increases with the number of previous preterm
deliveries, and is more likely in those who previously delivered at
earlier gestations. However, most women with a previous preterm
delivery will not deliver preterm in subsequent pregnancies
In a general population, risk estimates for preterm delivery can be
improved by transvaginal ultrasound measurement of cervical
length, and fetal fibronectin testing. However, the role of these
investigations in women with a previous preterm birth is not well
defined, and further research is needed to clarify what optimal
cut-offs are whether available interventions provide significant
benefit for those who screen positive
Progesterone and cervical cerclage are interventions which may
reduce the risk of preterm delivery, in certain groups of high risk
women
REVIEW
Investigation and
treatment of primary
amenorrhoea
secondary sexual characteristics. It indicates an interruption in

the complex interaction between factors involved in the onset
and continuation of normal menstruation, which include:
1) Normal female chromosomal pattern
2) Functioning hypothalamo-pituitary-ovarian axis
3) Responsive endometrium
4) Anatomical patency of the outflow tract
5) Active support from other endocrine glands such as thyroid
and adrenals.
Primary amenorrhoea is often the result of chromosomal abnormalities leading to primary ovarian insufficiency (e.g. Turners syndrome) or anatomical abnormalities. The potential
causes of primary amenorrhea are detailed in Table 2.
Emily Gelson
Alka Prakash
Abstract
Primary amenorrhoea is dened as a failure to start menstruation by
the age of 16 in the presence of normal secondary sexual characteristics or by the age of 14 in the absence of secondary sexual characteristics. It can be caused by genetic, endocrine or structural disorders
during the development of reproductive organs or may be constitutional in nature. Adolescence is a time of enormous physical and
emotional development, the diagnosis and management of primary
amenorrhoea requires dedicated teams to manage the complexities
of transitioning between the paediatric and adult age group. Investigations should be offered in stepwise manner with appropriate counselling, keeping the adolescents psychological development in mind. It is
important to recognize the spectrum of normalcy before deciding to
investigate the abnormal. Treatment depends on the cause with
emphasis on the immediate and long term wellbeing of the individual.
Approach to a patient presenting with primary

amenorrhoea
Management of this group of patients should be offered in a
multidisciplinary setting as a part of a specialized clinic. Initiating consultation with an adolescent patient needs to be done
with extreme sensitivity with special consideration being given to
the adolescents psychological age and emotional maturity rather
than the chronological age. It is of paramount importance to
establish a good relationship between the gynaecologist (multidisciplinary team), the patient and her parent(s) as this forms the
platform based on which the patient perceives her illness/problems and how she subsequently interacts with healthcare providers. It is common for parents, especially mothers to get
involved during the consultation, which is also perceived by the
young patient as natural. However, the clinician should bear in
mind that there may be issues, particularly with respect to sexual
problems which the patient might want to broach in confidence
and should therefore be provided with opportunity to do so.
Keywords constitution delay; endocrine disorders; genetic abnormalities; hormone replacement therapy; primary amenorrhoea; secondary sexual characters; structural anomalies
Introduction
Pubertal change typically occurs over a three year time frame and
can be measured using Tanner staging (Table 1). At approximately 8 years the hypothalamus begins the pulsatile release of
gonadotrophin releasing hormone (GnRH) leading to gonadotrophin secretion from the pituitary gland thus triggering puberty.
The
adrenal
cortex
begins
to
produce
dehydroepiandrostenedione which initiates the start of adrenarche (the development of sexual hair). The first physical sign
of puberty is breast budding (thelarche), this usually occurs between 9 and 11 years. Puberty then progresses through accelerated growth, and the menses (menarche) approximately a year
later. There is a wide variation in the normal sequence of event
which may be affected by body weight and nutrition. Hence there
is a range of pubertal age group that may differ in different
population groups. Primary amenorrhoea is defined as a failure
to start menstruation by the age of 16 in the presence of normal
secondary sexual characteristics or by 14 in the absence of
History
A detailed history is important to determine the possible aetiology of the condition. History should include exercise levels,
eating habits, weight loss/gain, stressful events and contraceptive history. Inquiry should be made about any developmental
delays especially breast and axillary/pubic hair and other
symptoms like abdominal pain, headaches, visual disturbances,
galactorrhoea, hirsutism (or other signs of hyperandrogenism)
and vasomotor symptoms. Major systemic illness (past and
ongoing), drug history especially use of antipsychotics, antiepileptic, cytotoxic agents, recreational agents like heroin, cocaine
should be noted with care. Family history in terms of timing of
menarche or premature menopause in mother and sisters (if
present) can also give valuable information in aiding diagnosis.
Examination (Table 3)
General physical examination including assessment of secondary
sexual characteristics, different systems and the genital tract
should be considered depending on the history and relevance of
such examination. Assessment of external genitalia carried out in
the outpatient department is restricted to inspection, especially in
younger patients who are not sexually active. Verbal consent for
this should be obtained from both the adolescent and the
accompanying parent after full explanation. It may even be
Emily Gelson MD MRCOG is a Specialty Trainee Obstetrics and

Gynaecology at West Suffolk Hospital, Bury St Edmunds, Suffolk,
UK. Conicts of interest: none declared.
Alka Prakash MD MRCOG is a Consultant in Reproductive Medicine
and Surgery at Cambridge University Hospitals NHS Trust,
Cambridge, UK. Conicts of interest: none declared.
108
REVIEW
Pelvic imaging
Tanner staging of puberty
Ultrasound (trans-abdominal or trans-vaginal as appropriate)

should be carried out to identify the presence of uterus, cervix
(rules out M
ullerian agenesis) and ovaries (rules out gonadal
agenesis). Measurable endometrial thickness indicates oestrogen
responsiveness. It should be kept in mind that rudimentary
uterus that has never been exposed to oestrogen may not be
clearly visible on ultrasound and may require further imaging.
MRI and 3D ultrasound are suitable for assessing utero-vaginal
malformations. Cranial imaging is helpful in demonstrating hypothalamic tumours, non-functioning pituitary tumours causing
hypothalamic compression and micro/macroadenomas of the
pituitary.
Tanner stage
Stage I Pre-pubescent
Stage II
Stage III Pubescent
Stage IV
Stage V Post-pubescent
No pubic hair
No breast development
Bone age younger than 11 years
Minimal pubic hair
Breast buds
Bone age younger than 11 years
Pubic hair on mons
Enlargement of breasts
Axillary hair
Bone age 12e13 years
Adult pubic hair
Areola enlargement
As adult
Management
Management of primary amenorrhoea is dependent on the cause
and should focus on both medical and psychological issues.
Amenorrhoea of hypothalamic origin
Acquired causes:
Table 1
Functional: normal menstrual cycle is triggered by the pulsatile

release of GnRH (gonadotrophin releasing hormone) from the
hypothalamus and alterations in the frequency or amplitude
triggered by stressors such as excessive exercise, eating disorders, nutritional deficits, psychological stress or critical illness
can lead to amenorrhoea. The exact mechanism is yet to be
clarified and is possibly a complex interplay between various
neuropeptides. One important regulator is body weight, particularly the proportion of body fat which is essential for successful
reproduction. For those undertaking excessive exercise such as
ballet dancers, gymnasts and especially competitive endurance
sportswomen, there appears to be a chronic imbalance between
calorie intake and consumption that leads to hypothalamic
dysfunction. In severe stress, raised circulating levels of corticotropin releasing hormone (CRH) interfere and inhibit GnRH
pulsatility leading to amenorrhoea. Women have variable susceptibility and there is some emerging evidence that this may
involve genetic mutations. These patients usually present with
absence of menstrual function, low circulating gonadotrophin
levels, and hypoestrogenemia without any organic abnormality.
Prolonged oestrogen deficiency predisposes to increased osteoclastic bone resorption and eventually osteoporosis.
Lifestyle changes are the mainstay of treatment. A combination of reduced exercise and dietary changes so that the calorific
intake is sufficient to achieve a minimal goal of 30 kcal/kg of lean
body mass can help reverse these changes. Counselling by psychiatrist/psychotherapist is helpful especially in eating disorders
and severe anxiety-depression. In most cases the normal reproductive function resumes after the underlying stressors have
been eliminated however in refractory cases, induction of puberty may be achieved with gradually increasing oral oestrogen
therapy. After breast development has been optimised, replacement doses of oestradiol and progestogens should be implemented for regular cycles.
reasonable to delay this examination for a subsequent visit if the

adolescent appears nervous, as building up confidence in the
medical team is likely to go a long way in future management.
Further examination of the lower genital tract requires EUA and
often vaginoscopy.
Diagnostic workup
In all cases of primary amenorrhoea pregnancy should be
excluded. Diagnosis should follow a stepwise pattern as detailed
in Figure 1.
Causes of primary amenorrhoea

Hypothalamus
Pituitary
Hypothalamic/pituitary damage
Ovarian
Uterine
Outflow tract
Chromosomal
Systemic disorders
Delayed puberty
Weight loss
Intensive exercise
Idiopathic
Hyperprolactinaemia
Hypopituitarism
Tumours
Cranial irradiation
Head injury
Gonadal dysgenesis
Primary ovarian failure
Mullerian agenesis
Imperforate hymen
Transverse septum
Turners syndrome
Androgen insensitivity syndrome
Chronic illness
Weight loss
Endocrine disorder
Constitutional delay
Structural: head trauma or space-occupying lesions of the hypothalamus like craniopharyngioma, glioma, germ cell tumours
Table 2
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REVIEW
Examination
General
Weight, height, body mass index

Skin (evidence of androgen excess)
C
Eyes: visual field defect (present in large pituitary tumours)
C
Clinical thyroid status
C
Dysmorphic signs
C
Pubic and axillary hair stages
Tanner staging
Galactorrhoea
CVS: abnormalities present in Turners syndrome, rarely in Rokitansky syndrome
Abdomen/pelvis: presence of any lump, groin nodes/hernia
C
Clitoris (clitoral index >35 mm2 is evidence of increased androgen effect, >100 mm2 is evidence of virilization)
C
Any abnormality in positioning of anus, vagina and urethra
C
Imperforate hymen or lower transverse vaginal septum may be seen by gently separating the labia during inspection.
C
C
Breast
Systemic
External genitalia
Table 3
etc can interfere with the normal pattern of GnRH and/or

gonadotrophin secretion by a combination of compression effect
and/or local tissue destruction. The majority of patients with
hypogonadotropic hypogonadism secondary to tumours will
have multiple other symptoms e.g. growth retardation, neurological (headache, visual field defects) and evidence of other
hormone dysfunction like diabetes insipidus. Rarer causes
include infiltrative disorders of the hypothalamus such as
Stepwise approach to diagnosis of primary amenorrhoea

History and Examination
Pregnancy test, Luteinizing Hormone (LH)/

Follicle Stimulating Hormone (FSH)/
Estradiol (E2), Prolactin, TSH and pelvic ultrasonography
Pregnancy test positive

exclude ectopic if required
Abnormal TSH
order thyroid function tests
and treat thyroid disease
Abnormal prolactin
cranial imaging
Uterus present?
Yes
No
Karyotype, Free and total
testosterone levels
Low FSH/LH
Normal FSH/LH High FSH/LH
Constitutional Consider outflow Primary ovarian

delay
tract obstruction insufficiency
Rarely GnRH
secreting tumour
46, XX
46, XY
Mullerian
agenesis
Androgen
insensitivity
syndrome
Order karyotype for Turners

or presence of Y chromatin
Figure 1
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REVIEW
Drug induced: drug induced hyperprolactinaemia is due to the

blocking effect on dopamine or depletion of dopamine stores
(which inhibits prolactin) thereby increasing the circulating
prolactin, e.g. phenothiazines, antipsychotics, methyl dopa.
haemochromatosis, sarcoidosis, Wegeners granulomatosis and

histiocytosis, in which presence of characteristic systemic signs
and symptoms point towards the diagnosis. Cranial imaging
helps with diagnosis and treatment usually involves neurosurgery and/or radiotherapy. The degree of impairment is dependant on the dose and type of the radiation as well as age of the
patient Subsequent hormone replacement will depend on the
resulting deficiencies.
Others: hypothyroidism can cause hyperprolactinaemia due to

the associated high level of thyrotropin-releasing hormone (TRH)
which stimulates pituitary lactotrophs to secrete excessive prolactin. Sometimes empty sella syndrome causes hyperprolactinaemia where the pituitary gland regresses and flattens
out along the interior walls of the sella turcica cavity. This condition may be primary or secondary to injury or radiation.
Treatment depends on the condition and specific factors
including age, past medical history and overall health problems.
Medical management with dopamine agonists such as bromocriptine (often preferred when pregnancy is possible) or cabergoline is the commonest treatment modality. Response to
therapy is usually monitored by checking fasting serum prolactin
levels and monitoring of tumour size. Around 80e90% cases of
hyperprolactinaemia will resolve and nearly 80% of the microadenomas will shrink with medical management. Transsphenoidal surgery is indicated only if medical therapy produces intolerable side-effects, fails or due to pressure effect of
non-functioning macroadenomas/suprasellar extension. Pituitary irradiation is seldom required and is associated with a significant
risk
of
subsequent
medium/long-term
panhypopituitarism.
Idiopathic Hypogonadotropic Hypogonadism: this is characterized by an isolated defect in the secretion of GnRH from the
hypothalamus or defective GnRH action on the pituitary, with
otherwise normal hormonal testing and imaging of the anterior
pituitary. This is a genetically heterogeneous condition, with
possible contributions from multiple genetic defects or epigenetic
perturbations. Kallmanns syndrome is one variant characterized
by complete absence of the sense of smell (anosmia) or grossly
reduced sense of smell (hyposmia). Studies suggest disrupted
migration of GnRH producing nerve cell in the brain. This may
happen sporadically or is inherited; environmental factors also
play a role. About 50% cases are associated with some other
features including cleft palate/other midline craniofacial defects,
renal agenesis/aplasia, neural hearing defects and dental defects.
Treatment for any form of hypogonadotropic hypogonadism
can be differentiated into two categories.
Hormone replacement therapy e this helps to develop
secondary sexual characteristics and provides positive effects on bone mineral density, lipid profile, urogenital
status and overall well-being.
Fertility treatment epulsatile GnRH stimulation of intact
pituitary via subcutaneous pump can restore fertility in
women with isolated hypothalamic dysfunction when they
wish to become pregnant. The other option is administration of exogenous gonadotrophins. The later may result
in higher rates of multiple gestation and ovarian hyperstimulation syndrome whereas the former mimics natural
cycles resulting in unifollicular recruitment and spontaneous ovulation. For either approach, however, the rate of
conception is approximately 30% per ovulation cycle.
Amenorrhoea of ovarian origin

Gonadal dysgenesis: this is a group of developmental disorders
characterized by accelerated premature loss of primordial germ
cells in developing gonads whilst in utero resulting in hypoplastic
and dysfunctioning streak gonads. Accompanying hormonal
failure prevents the development of secondary sex characteristics, resulting in a sexually infantile female appearance and
infertility. The absence of both Mullerian inhibiting factor and
testosterone results in a normal uterus and vagina.
Turners syndrome: this is diagnosed by a karyotype of 45 XO
(loss of entire X chromosome) or mosaicism (X chromosome
missing in some cells). The incidence varies between 1 in 2000 to
1 in 5000 and is caused by meiotic errors in the father leading to
absent or abnormal X chromosome. One of the missing genes on
the X chromosome is the SHOX gene, which is responsible for
growth of long bones; hence girls with this disorder are usually
short. Other missing genes lead to poor ovarian development.
Some women with mosaic karyotype will begin to go through
puberty but fail to menstruate, or may suffer from early secondary amenorrhoea. Women with Turners syndrome have
characteristic physical features including stocky build, short
webbed neck, low hairline, shield chest and widely spaced nipples. There could be associated cardiac, renal, skeletal abnormalities and deafness.
Hormone replacement therapy (HRT) is the treatment of
choice. Growth hormone is recommended in children and adolescents to help them achieve desired normal height. Oestrogen
replacement therapy encourages normal sexual development and
puberty, while progesterone is added later to provide endometrial protection to avoid hyperplasia. This form of combined HRT
Amenorrhoea of pituitary origin

Hyperprolactinaemia:
Tumours: this may result from tumour arising in/near the pituitary and depending on the size are classified as microadenoma
(<10 mm) or macroadenoma (>10 mm). Up to 30% may have
galactorrhoea but there is no direct correlation with the level of
circulating prolactin or the presence of a tumour. Some will
display visual field defects if the there is suprasellar extension
leading to compression of optic chiasma. MRI is the imaging of
choice and is able to detect adenomas that are as small as 3e5
mm. The tumours themselves may be functioning (prolactinoma) or non-functioning (craniopharyngioma) variety. In the
first case there is intrinsic over-production of prolactin which
suppresses hypothalamic GnRH secretion whilst in the later there
is compression of the pituitary stalk leading to reduced dopamine
levels, thereby disrupting the tonic inhibition leading to
increased levels of circulating prolactin.
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REVIEW
Mainstay of treatment is aimed at restoration of sexual function. The first line of approach is progressive vaginal dilatation
(frank & Ingram dilators) which in some studies have shown a
success of up to 88% with continued use. Surgical creation of a
neo-vagina such as McIndoes procedure, Vecchiettivaginoplasty
and other laparoscopic modifications are other more invasive
alternatives. Surgery is often left till late adolescence or young
adulthood (ages 17e21 years) when the patient is mature enough
to be able to adhere to postoperative dilation or is ready to
engage in regular intercourse.
Fertility remains a big issue, however as ovarian function is
not compromised; these women can often use their own oocytes
for in vitro fertilization (IVF) and then use a surrogate uterus to
achieve pregnancy. Uterus transplantation has been performed in
a handful of women with MayereRokitanskyeKustereHauser
syndrome worldwide with the first live-birth after uterus transplantation reported in early 2015.
is usually continued till the average age of menopause to prevent

osteoporosis.
Few women can become pregnant without fertility treatment
very early in adulthood but for the majority fertility options are
limited to the use of donor eggs/embryos in IVF.
Pure gonadal dysgenesis: this is characterized by normal
chromosomal karyotype (46XX) but may have localized genetic
alterations. More than 60% of patients have undetectable ovaries
with no follicular growth leading to circulating FSH in the
menopausal range. The hypothesis for its causation is suggested
to be an abnormality in the FSH-receptor or mutations in the
mitochondrial enzyme structure.
Mainstay of treatment remains HRT with oestrogen replacement initially to help development of secondary sexual characters followed by initiation of menstruation. Progesterone is added
later for endometrial protection. Fertility remains an issue though
5e10% conceive spontaneously through sporadic ovulatory cycles; others require oocytes/embryo donation with IVF.
Amenorrhoea due to outow tract obstruction

Abnormalities of the outflow tract: these patients usually present with primary amenorrhoea and cyclical pain which is due to
a functioning endometrium that produces menstrual flow and an
outflow block that leads to hematocolpos and/or hematometra.
Due to the gradually enlarging uterus and vagina, these girls
sometimes present with urinary retention. Surgical resection of
the imperforate hymen or transverse septum under anaesthesia is
the treatment of choice. Transverse vaginal septum can be very
thick with a risk of re-occlusion. Input from paediatric-adolescent
gynaecologist and plastic surgeons may be necessary and should
therefore be carried out in tertiary centres.
Swyer syndrome: is caused by mutations in the SRY gene (sex

determining region of the Y chromosome), which leads to
llerian hormone and testosterone. These inabsence of anti-mu
dividuals have 46XY karyotype with normal uterus, fallopian
tubes and female external genitalia but streak gonads. Gonadotrophins are elevated above baseline.
Treatment depends on HRT and the removal of streak gonads
soon after diagnosis as they have a significant risk (25%) of
developing germ cell tumours, commonly gonadoblastoma in
early life. Fertility options remain limited to oocytes/embryo
donation with IVF.
Amenorrhoea of chromosomal origin

Turner syndrome (as above)
Premature ovarian failure (POF): POF may also result from

polyglandular autoimmune syndromes in conjunction with
combinations of hypothyroidism, hyperparathyroidism, hypoadrenalism/Addisons disease and type 1 diabetes. It is often quite
difficult to detect ovarian autoantibodies due to the poor sensitivity of available assays. An increasingly common cause of POF
in adolescence is childhood cancer requiring chemotherapy (e.g.
alkylating agents like cyclophosphamide) and/or pelvic irradiation (e.g. Hodgkins disease or Wilms tumour). More thought is
being given to fertility preservation programmes for such young
adults with a provision of oocytes or ovarian tissue preservation
becoming available outside the realms of research setting and
live-births following ovarian tissue cryopreservation have now
been reported. For those where ovarian failure is already established, use of oocytes/embryo donation with IVF is the only
fertility option at present.
Androgen insensitivity syndrome (AIS): this has an incidence

of around 1:60,000 and is caused by a mutation in the androgen
receptor gene which may lead to partial (PAIS) or complete
androgen insensitivity syndrome (CAIS). The affected individuals have XY karyotype with female phenotype. Normal
secretion of testicular mullerian inhibitory factor in utero leads to
regression of internal mullerian structures. The gonads consist of
testicular tissue which is often cryptorchid with a failure of the
spermatogenesis but retaining the ability to produce testosterone.
Due to the partial or complete lack of binding with androgen
receptors, these individuals may have some or no androgenisation respectively. Furthermore there is peripheral aromatisation
of testosterone to oestrogen which helps in the development of
female secondary sexual characters such as breast development.
Management will depend on the degree on clinical manifestation and the level of AIS, whether complete or partial. Individuals
with CAIS are usually reared as females and the testosterone
secreting gonads which may be intraabdominal or in the inguinal
canal usually removed after pubertal development followed by
hormone replacement therapy. Management of individuals with
PAIS can be more complex depending on the degree of virilization
and the sex of rearing. If reared as females, they may require
genital reconstructive surgery to reduce their clitoral size and
enlarge the vaginal orifice, followed by hormone replacement
therapy till menopause. Fertility advice is based on the use of
Amenorrhoea of uterine origin

Mullerian agenesis: this occurs in about 1/5000 cases and is
caused by sporadic genetic mutations which lead to a defect in
mullerian differentiation during embryogenesis. These patients
usually have absent upper vagina and hypolastic/aplastic uterus.
The ovarian development and function which is separate to the
mullerian system, remains normal. This condition is also called
MayereRokitanskyeKustereHauser syndrome which may be
isolated (Type 1) or associated with renal, vertebral and to a
lesser extent auditory and cardiac defects (Type 2).
112
REVIEW
donor eggs with surrogate or adoption. Due to the gender identity

issues, psychological counselling is of paramount importance.
lot of physiological unknowns around the triggering mechanism

of puberty. With the ever increasing knowledge of new molecules such as kisspeptins, the mystery around this significant
event of life keep unfolding more and creating new questions that
need further research.
A
Constitutional growth delay

This typically causes retarded linear growth within the first 3 years
of life, eventually resuming at a normal rate. The growth pattern
may be inherited from parents (familial) or occur for no apparent
reason (idiopathic). Delayed puberty is commonly associated with
short stature. However growth and development are appropriate
for biologic age (skeletal age) rather than for chronologic age and
is determined from bone age radiographic studies of the left hand
and wrist. Full hormonal profile should be carried out to exclude
other causes. They may have physiologic hypogonadotropic
hypogonadism with low circulating gonadotrophin levels. Periodic evaluation of height, weight and staging of sexual development is all that is necessary, but medical treatment in the form of
short courses of sex hormones may have to be initiated in adolescents experiencing psychological distress.
We have so far discussed the usual causes, investigation and
management of primary amenorrhoea. However, there are still a
FURTHER READING
Balen AH, Creighton SM, Davies MC, MacDougall J, Stanhope R, eds.
Paediatric and adolescent gynaecology e a multidisciplinary
approach. Cambridge: Cambridge University Press, 2004.
Dedis I. Kisspeptins and the control of gonadotrophin secretion. Syst
Biol Reprod Med 2012; 58: 121e8.
Fenichel P. Delayed puberty. Endocr Dev 2012; 22: 138e59.
Loren AW, Mangu PB, Beck LN, et al. Fertility preservation for patients
with cancer: American Society of Clinical Oncology clinical practice
guideline update. J Clin Oncol 2013; 31: 2500e10.
Practice Committee of The American Society for Reproductive Medicine. Current evaluation of amenorrhoea. Fertil Steril 2008; 90:
S219e25.
113
CASE-BASED LEARNING
Cardiovascular disease in
pregnancy
interpret cardiovascular signs and symptoms correctly as many

of these can occur in normal pregnancy. Hence, the management
of women with cardiovascular disease during pregnancy poses a
challenge to obstetricians, cardiologists and anaesthetists.
This article considers a range of cases where cardiological
conditions can complicate pregnancy.
Dipanwita Kapoor
Suzanne VF Wallace
Case 1 congenital heart disease: tetralogy of Fallot

A 26 year old primiparous woman was seen in the obstetric cardiology clinic at 11 weeks gestation. She initially had modified
BlalockeTaussig shunts and then had a repair to tetralogy of
Fallot (ToF) at the age of four. Five years ago she needed a pulmonary valve replacement (23 mm bioprosthesis) with augmentation of the main pulmonary artery and distal right ventricular
outflow tract using Vascutek patching. Her echocardiogram in
early pregnancy showed moderate pulmonary regurgitation with
good left and right ventricular function which was similar to the
one done a year previously. She complained of increasing shortness of breath in the first trimester compared to pre-pregnancy.
However, her shortness of breath was not been progressive and
remained about the same as the first trimester. There was no
significant change on the echocardiogram repeated in third
trimester. Detailed fetal anatomy and fetal cardiac scans showed
no evidence of fetal heart defects. Serial fetal growth scans in the
third trimester showed a linear growth velocity at 50th centile. Her
labour was induced at 39 weeks gestation because of complex
social reasons. She delivered vaginally a live male infant weighing
3600 g. She remained haemodynamically stable throughout the
intrapartum and immediate postpartum period.
Tetralogy of Fallot (ToF) is the most common cyanotic
congenital heart defect, occurring in approximately 0.1% of live
births. Classic tetralogy includes ventricular septal defect
(VSD), over-riding of the aorta, sub-pulmonary stenosis and
secondary right ventricular hypertrophy. However, there is a
wide range of morphological variation including minimal pulmonary stenosis to pulmonary atresia, small VSD with minimal
override and double outlet ventricle. Di George Syndrome
(chromosome 22q11 deletion) is associated with similar cardiac
defects in addition to facial abnormalities and learning
difficulties.
With the advances in medical science and improved healthcare systems, the majority of those born with ToF have now
undergone some form of surgical treatment e either shunt
palliation or radical repair. Radical repair is the treatment of
choice and involves patch closure of VSD, resection of pulmonary infundibular stenosis and often a transannular patch to increase the size of the pulmonary annulus. Patients with palliative
shunts remain cyanotic as the shunt creates a further systemicpulmonary shunt. The prognosis of ToF after primary surgical
repair is good, with majority of the women reaching child
bearing age. However, pulmonary regurgitation (PR) and progressive right ventricular (RV) remodelling have been documented in adults with repaired ToF and are associated with
cardiovascular morbidity and mortality e right ventricular failure secondary to residual right ventricle outflow tract obstruction
(RVOT), atrial or ventricular arrhythmias, sudden death. An
increasing number of successful pregnancies have been reported
in this cohort.
Abstract
Cardiac disease continues to be a major cause of maternal mortality
and morbidity. It is now the leading cause of overall and indirect
maternal deaths in United Kingdom and has accounted for 22.2% of
all maternal deaths in the UK from 2010 to 2012. Extensive haemodynamic changes that occur in pregnancy can have a profound effect on
pre-existing heart disease. Management can be challenging and often
a multidisciplinary approach involving the obstetricians, cardiologists
and anaesthetists is necessary to optimise pregnancy outcomes.
Keywords cardiac; heart disease; mitral stenosis; paroxysmal

supraventricular tachycardia; peripartum cardiomyopathy; pregnancy;
tetralogy of Fallot
Introduction
Cardiac diseases remain a major cause of complications in
pregnancy worldwide and the number of women developing
cardiac problems during pregnancy is rising. In the United
Kingdom (UK) the maternal mortality including death from direct
causes (e.g. postpartum haemorrhage, sepsis, hypertensive disease in pregnancy) has fallen dramatically over the last three
decades. However, there has been a significant increase in deaths
from indirect causes such as pre-existing or new onset medical
and psychiatric conditions. Cardiac disease remains the largest
single cause of overall and indirect maternal death. It accounted
for 22.2% of all maternal death in UK between 2010 and 2012
according to the last Confidential Enquiries into Maternal Deaths
and Morbidity 2009e12 report, which is significantly higher
when compared with the report in 1985e87. The trend of overall
maternal death and of deaths from cardiac disease in the last
three decades is shown in Figure 1. Addressing this issue remains
a challenge to the current health system and will involve a wide
range of health services including maternity services, public
health, primary and secondary care to improve awareness and
patient care. There is also a need to engage and appropriately
train physicians in the care of pregnant women.
Cardiovascular changes during pregnancy and puerperium are
summarised in Table 1 and pregnancy can have profound effects
on pre-existing heart disease. In addition, it may be difficult to
Dipanwita Kapoor MBBS MRCOG is a Post CCT fellow in Obstetrics

and Gynaecology at Nottingham University Hospitals NHS Trust, City
Hospital Campus, Nottingham, UK. Conicts of interest: none
declared.
Suzanne V F Wallace BM BCh MA MRCOG is a Consultant Obstetrician
at Nottingham University Hospitals NHS Trust, Queens Medical
Centre, Nottingham, UK. Conicts of interest: none declared.
114
2016 Published by Elsevier Ltd.
CASE-BASED LEARNING
Maternal death from cardiac disease in the UK (19852012)

Proportion of cardiac disease related death
Rate of cardiac disease related death per 100,000 maternities
Total maternal deaths per 100,000 maternities
25
20
15
10
5
0
7
85
19
88
19
91
19
94
19
97
19
00
20
03
20
06
20
09
20
10
20
Figure 1
Pregnancy in women with corrected ToF is generally tolerated

well. A small proportion of women will develop heart failure and
arrhythmias during pregnancy. It can also be associated with
fetal growth restriction. The feto-maternal risks increase in the
presence of severe PR, significant residual RVOT obstruction,
and right ventricular dysfunction. In symptomatic women with
marked dilatation of the right ventricle due to severe pulmonary
regurgitation, a pulmonary valve replacement (homograft)
should be considered before contemplating pregnancy. Recent
studies demonstrated that there is acceleration in the rate of right
ventricular remodelling, defined as an increase in end-diastolic
volume, following pregnancy in women with repaired ToF
particular for those women with severely dilated RV at baseline.
Pregnancy in women with uncorrected ToF is considered high
risk with a maternal mortality rate between 4 and 15% and fetal
loss rates are as high as 30%. The main concerns in this group
are highlighted in Box 1. The risk is significantly increased
(maternal mortality 25e40%) in the presence of pulmonary hypertension (Eisenmengers syndrome) and women should be
advised against pregnancy or to consider therapeutic termination
if pregnancy occurs. Where maternal death occurs, this is usually
in the last trimester of pregnancy and in the first months after
delivery because of pulmonary hypertensive crises, pulmonary
thrombosis, or refractory right heart failure. If a women chooses
Feto-maternal risks associated with uncorrected ToF

C
Worsening cyanosis and maternal hypoxaemia because of

increased right to left shunt secondary to decrease in peripheral
resistance, causes:

C
C
C
C
C
Worsening breathlessness
Polycythaemia and thromboembolism
Increased risk of miscarriage
Fetal growth restriction
Fetal death
Preterm delivery (spontaneous or iatrogenic)
Paradoxical embolism through the right to left shunt resulting in

cerebrovascular accidents (risk increases in pregnancy because of
physiological hypercoagulable state)
Heart failure
Tachyarrhythmias
Infective endocarditis
Cerebral abscesses
Maternal death (as high as 25e40% in presence of pulmonary
hypertension)
Box 1
Cardiovascular changes during pregnancy and puerperium

Pregnancy
Intrapartum
Post-partum
Cardiac output
[by 40%
Stroke volume
Heart rate
Blood pressure
[
[by 10e20 beats
Yfirst and second trimester
[third trimester
Y
[by 15% (1st stage)

[by 50% (2nd stage)
[
[
[
[by 60e80% in the first hour and then

Yover the next 24 weeks
Y
Returns to pre-pregnancy level over first 2 weeks
Falls initially and then increases Day 3e7.
Returns to pre-pregnancy level by 6 weeks
[by 30% over first 2 weeks above delivery values
Systemic vascular resistance (SVR)
Table 1
115
CASE-BASED LEARNING
to continue pregnancy, a multidisciplinary approach should be

adopted to achieve the best possible pregnancy outcome. These
risks can be minimised by bed rest, oxygen therapy to maintain
oxygen saturation >85% and thromboprophylaxis.
Women with ToF should be offered prepregnancy counselling
and assessment including genetic tests for 22q11 deletion. All
pregnant women with ToF should be cared for in a specialist
tertiary centre with input from obstetricians, cardiologists and
anaesthetists to improve maternal and fetal outcomes. Follow up
in each trimester is sufficient for the majority of these women.
However, monthly or bimonthly cardiac evaluation with echocardiography is indicated in women with severe PR. If RV failure
occurs during pregnancy, treatment with diuretics should be
started and bed rest advised. All women should be offered fetal
echocardiography during pregnancy as it can be familial. Additional fetal growth scans are indicated in third trimester to
exclude fetal growth restriction. The preferred mode of delivery
is vaginal in majority of the cases. Planned delivery (vaginal
delivery with incremental regional anaesthesia or caesarean
section) should be reserved for women at higher risk such as
those with worsening symptoms or with pulmonary
hypertension.
vasculature pressure can result in pulmonary oedema. The mitral

orifice normally has an area of 4e6 cm2 (2 D echocardiography
short axis). Patients start to experience valve-related symptoms
when the valve area is 2e2.5 cm2 or less, at which point moderate exercise or tachycardia may result in exertional dyspnoea.
Severe MS occurs with a valve area of less than 1 cm2. In pregnancy, the risk of cardiac compromise is further aggravated by
physiological increases in intravascular volume and maternal
tachycardia. In cases of moderate to severe mitral stenosis,
approximately 60% of women will experience their first episode
of pulmonary oedema at approximately 30 weeks gestation as
this is the time when cardiac output reaches its maximal level
during pregnancy. This risk continues during the intrapartum
and immediate postpartum period. There is also a risk of
thrombus formation because of the hypercoagulability associated
with pregnancy together with an increase in left atrial pressure.
Atrial fibrillation and stroke are also risks. Perinatal outcome
depends on symptoms and pulmonary artery pressure (PAP)
during pregnancy. The risk is higher in women with more severe
symptoms with a mortality rate of up to 12%e31%. Prematurity
rates are 20e30%, intrauterine growth restriction 5e20%, and
stillbirth 1e3%.
Pregnancy must be managed in a specialist tertiary unit with
appropriate care from cardiologists, obstetricians and anaesthetists. The aim of management of MS in pregnancy is to avoid
cardiac decompensation. The European Society of Cardiology
(ESC) guidance on treatment of MS in pregnancy is outlined in
Box 2. Pre-emptive diuresis using furosemide may be considered
Case 2 acquired heart disease: mitral stenosis

A 28-year-old, otherwise fit and healthy, Asian woman was
booked under midwife-led care during her first pregnancy. She
presented at 26 weeks gestation to the Emergency Department
with worsening breathlessness, pleuritic chest pain and productive cough for the last few days. She also gave a history of limited
exercise tolerance pre-pregnancy. On examination, she was
tachycardic, hypotensive and found to be in respiratory distress.
Her heart sounds revealed a diastolic murmur. On lung auscultation, she had bilateral wheeze and crepitations. An electrocardiogram (ECG) showed sinus tachycardia. Arterial blood gas
(ABG) measurement was suggestive of Type 1 respiratory failure.
An urgent transthoracic echocardiogram (TTE) was undertaken
which showed severe mitral stenosis (MS), likely rheumatic in
origin. She was intubated and ventilated, started on intravenous
diuretics (furosemide) and metoprolol and transferred to the
cardiac unit with a view to perform an emergency percutaneous
mitral commissurotomy (PTMC) which was uncomplicated. Her
breathlessness improved significantly following the above procedure and an echocardiogram repeated at 34 weeks gestation
showed residual mild MS. She was followed up regularly in
Antenatal Clinic with close input from cardiologists. She went
into spontaneous labour at 38 weeks gestation and delivered
vaginally a live male infant weighing 3200 g. She remained
haemodynamically stable throughout the intrapartum and immediate postpartum period.
Mitral stenosis is the commonest cause of acquired heart
disease in pregnancy. It is almost always caused by rheumatic
fever with less than 1% of mitral stenosis in pregnancy due to
congenital anomalies or endocarditis. Although rheumatic heart
disease is rare in the indigenous UK population, it remains a
major problem in developing countries and is still seen in western countries, especially within the immigrant population.
MS is a state of fixed cardiac output caused by left atrial
outflow obstruction; the increase in left atrial and pulmonary
ESC guidelines on management of pregnant woman with

mitral stenosis
C
All patients with moderate or severe MS (even when asymptomatic) should avoid pregnancy until they undergo surgery.
Clinical and echocardiographic follow-up is indicated monthly or
bimonthly depending on haemodynamic tolerance. In mild MS,
evaluation is recommended every trimester and prior to delivery.
In presence of symptoms or pulmonary hypertension, activity
should be restricted and b1-selective blockers commenced. Diuretics are indicated if symptoms persist.
Therapeutic anticoagulation is recommended in the case of
paroxysmal or permanent AF, left atrial thrombosis, or prior
embolism.
PTMC should only be considered in women with refractory disease. Closed commissurotomy remains an alternative in developing countries when percutaneous commissurotomy is not
available.
Open-heart surgery should be reserved for cases in which all
other measures fail as this is associated with a 30%e40% of fetal
mortality rate and up to 9% maternal mortality rate.
Most women are suitable for vaginal delivery. Caesarean section
is indicated in women with moderate or severe MS who have
worsening symptoms or pulmonary hypertension despite medical
therapy, in whom percutaneous mitral commissurotomy cannot
be performed or has failed.
Box 2
116
CASE-BASED LEARNING
at delivery to avoid fluid overload and pulmonary oedema secondary to autotransfusion and the relief of inferior vena caval
compression which occurs at birth and in the immediate postpartum period.
(DC) cardioversion can be safely used to terminate the tachycardia in all stages of pregnancy with close monitoring of the
fetus. In haemodynamically stable women, the preferred method
of termination is IV adenosine e 6 mg initially, and may be
followed by a dose of 12 mg if needed. Adenosine does not cross
the placenta and no adverse fetal effects have been reported.
Other AV nodal agents that may be used safely during pregnancy
for acute treatment of PSVT are digoxin and verapramil. Care
should be taken to avoid verapramil induced maternal hypotension as it can be associated with fetal distress. There is limited
data on use of flecainide to treat maternal arrhythmias and this
should be reserved for refractory cases. Beta blockers are the
drug of choice in presence of WPW syndrome as the above
mentioned AV nodal agents will further increase the ventricular
rate by favouring conduction via the accessory pathways.
Women with worsening PSVT during pregnancy, and not on any
medication, can be started on lowest effective dose of beta
blocker (e.g. sotalol, bisoprolol) or a calcium channel blocker
(e.g. verapramil) but will require fetal surveillance with growth
scans in the third trimester.
Case 3 arrhythmias: paroxysmal supraventricular

tachycardia
A 36 year old woman was booked under consultant led care in
her first pregnancy because she was diagnosed with paroxysmal
supraventricular tachycardia (PSVT) six months ago. She has
had palpitations since childhood and can usually terminate these
with a Valsalva manoeuvre. Her recent echocardiogram was
normal. She was admitted at 22 weeks gestation with severe
palpitations; the ECG showed regular narrow complex tachycardia upto 200 bpm. She remained haemodynamically stable
throughout the whole episode. She tried vagal manoeuvres but
unlike her previous episodes, the tachycardia persisted. Adenosine 6 mg iv was given to terminate this episode of PSVT. She
was started on verapamil at 29 weeks gestation because of
recurrent SVT. Since then she had occasional episodes of palpitations for remainder of the pregnancy. Fetal growth scan at 30
and 35 weeks gestation were normal. She went into preterm labour at 36 weeks gestation and delivered a live female infant
weighing 2900 g vaginally.
Cardiac arrhythmias commonly complicate pregnancy. Pregnant women who develop worsening palpitations, near syncope
or syncope should be investigated to determine the cause. A 12
lead electrocardiogram (ECG), Holters or events monitors and
echocardiogram (to diagnose structural and functional heart
disease) should be performed. Sinus tachycardia, 15 degree shift
in electrical axis to the left, supraventricular and ventricular
ectopic beats, small Q wave, non-specific ST changes such as
depression and/or an inverted T wave in leads III and aVL are
normal findings in an ECG during pregnancy. Hyperthyroidism
and serum electrolyte abnormalities should also be ruled out.
Paroxysmal supraventricular tachycardia is the most common
cardiac arrhythmia in pregnant women and is characterized by
rapid, regular narrow complex atrio-ventricular nodal re-entrant
tachycardia (AVNRT) with abrupt onset and termination. This
may be associated with WolffeParkinsoneWhite (WPW) syndrome, where the type of SVT would be AV re-entrant tachycardia (AVRT) via the accessory pathways. An echocardiogram is
usually normal. New onset PSVT are rare, however, in women
with a history of PSVT this can recur during pregnancy in up to
50% in women. PSVTs are almost always benign and are well
tolerated during pregnancy with minimal effects on maternal and
perinatal outcome. However, one recent study demonstrated a
marginal higher risk of septal defects, particularly secundum
atrial septal defect in the offspring of pregnant women with
PSVT; further research is warranted.
The principles of management of cardiac arrhythmias are no
different in pregnancy to outside of pregnancy and should be
managed in conjunction with the cardiologists. PSVT do not always require treatment but this may be needed for acute management if there is a prolonged episode with or without
haemodynamic compromise or in women who find palpitations
intolerable. All women should be taught vagal manoeuvres as
first-line therapy. If haemodynamically unstable, direct current
Case 4: peripartum cardiomyopathy

A 32 year old Afrocaribbean woman with raised BMI presented in
her first pregnancy at 32 weeks with headache. On admission,
she was also found to be hypertensive with significant proteinuria and a diagnosis of moderate pre-eclampsia was made. She
was started on labetolol 200 mg thrice daily which controlled her
blood pressure. Steroids were given for fetal lung maturation.
Whilst an inpatient, she complained of worsening breathlessness
associated with orthopnoea and paroxysmal nocturnal dyspnoea.
She became tachycardic and tachypnoeac. There was no associated chest pain. A chest X-ray revealed cardiomegaly and pulmonary oedema. An echocardiogram revealed a moderately
dilated left ventricle with severely impaired systolic function
(LVEF < 35%); this was consistent with peripartum cardiomyopathy. She was reviewed by the cardiologists and commenced
on Furosemide iv. She had a semi elective Caesarean Section at
33 weeks in view of the above diagnosis. She remained haemodynamically stable during delivery and in immediate postpartum
period. She was advised against pregnancy in the near future and
contraceptive advice was given. She was discharged home on
Day 5 on bisoprolol, cardio selective beta-blocker; perindopril,
ACE inhibitor (she had decided not to breast feed); furosemide
and low molecular heparin with a plan to follow up in cardiology
clinic in few weeks time.
Peripartum Cardiomyopathy (PPCM) is a rare but potentially
life-threatening idiopathic cardiomyopathy that presents with
heart failure secondary to left ventricular systolic dysfunction
towards the end of pregnancy or in the months following delivery, in the absence of any other cause of heart failure. PPCM is
a diagnosis of exclusion. Although the left ventricle may not be
dilated, the ejection fraction is nearly always reduced below 45%
and/or there is fractional shortening <30% on an echocardiogram. There is a wide geographic variation in the incidence of the
disease, ranging from 1 in 500 live births in Haiti to 1 in 4000 live
births in the United States; this is thought to be related to socioeconomic and genetic factors. Identified risk factors for PPCM
include advanced maternal age, multiparity, AfricaneCaribbean
117
CASE-BASED LEARNING
race, multiple pregnancy and hypertensive disorders (pre-existing, gestational hypertension or pre-eclampsia).
The aetiology of PPCM remains unclear. Several theories have
been proposed:
myocarditis
autoimmunity against fetal antigens
fetal Chimerism
genetic associations
dietary deficiencies of selenium or excessive salt intake
vascular and hormonal disease triggered by lategestational secretion of potent anti-angiogenic agents
from the placenta and pituitary (the prolactin theory).
The prolactin theory suggests that in PPCM inappropriate
secretion of cathepsin D from cardiomyocytes cleaves prolactin
into a potent antiangiogenic, proapoptotic, and proinflammatory
16 kDa fragment. This in turn, leads to cardiomyocyte dysfunction, apoptosis, metabolic insufficiency and cardiomyopathy.
The diagnosis of PPCM relies on a high degree of suspicion as
the symptoms can be confused with physiologic changes associated with advanced pregnancy. Diagnosis is made on the basis
of a combination of a temporal relationship with pregnancy,
echocardiography findings and exclusion of other causes of heart
failure. Common clinical features and investigation findings in
PPCM are summarised in Box 3. Cardiac magnetic resonance
imaging may have a role in more severe form of PPCM as it
provides valuable information about myocardial structure and
right ventricular function. The differential diagnosis includes
dilated cardiomyopathy of different aetiology, myocardial
infarction and pulmonary embolism.
Woman with PPCM may develop systemic or pulmonary
emboli from mural thrombus, fatal arrhythmias, cardiogenic
shock or death. Other complications include preterm delivery

(mostly iatrogenic) and in utero fetal death.
A multidisciplinary team approach involving the cardiologists, obstetricians and anaesthetists must be adopted in the
management of women with PPCM to optimise the pregnancy
outcomes. The principles of management are as follows: management of arrhythmia and heart failure and consider delivery if
unstable.
Heart failure should be managed according to the ESC
guidelines on acute and chronic heart failure: oxygen, betablockers, diuretics, angiotensin enzyme (ACE) inhibitors (or
angiotensin-receptor blockers, ARBs) and mineralocorticoidreceptor blockers (MRAs). Diuretics should be used with
caution in women with pre-eclampsia because of intravascular
volume constriction. During pregnancy, ACE inhibitors or ARBs
should be avoided as they are associated with fetotoxicity. Hydralazine and nitrates can be used instead of ACE inhibitors/
ARBs for afterload reduction. Captopril or enalapril is the
preferred ACE inhibiters in breast feeding. The data on use of
MRAs during pregnancy and lactation is limited and these should
be avoided if possible.
Recent studies suggested that addition of bromocriptine to
standard heart failure therapy may improve left ventricular
ejection fraction and the clinical outcome in women with acute
severe PPCM. Results from larger studies are awaited before this
can be used routinely in clinical practice.
Low molecular weight heparin (LMWH) is indicated in
women with very low LVEF, intracardiac thrombus on echocardiogram, arrhythmias or embolic phenomenon.
Anti-arrhythmic medications should be used to treat associated arrhythmias. It has been suggested that wearable cardioverter/defibrillators may have a role in selected patients with
highly reduced or persistent poor LV function as PPCM is associated with sudden death but larger studies are needed.
If a woman remains hypoxic or hypotensive, she will need
intubation, ventilation, inotropic support and immediate delivery
by Caesarean Section. If she remains dependent on inotropes
despite optimal medical therapy, she should be transferred to a
facility where intra-aortic balloon pump counterpulsation, ventricular assist devices, and transplant consult teams are
available.
Delivery should be expedited if PPCM is diagnosed antenatally. Steroids for fetal lung maturation are recommended if delivery is planned <34e36 weeks gestation. Vaginal delivery with
early regional analgesia is preferable if the patient is haemodynamically stable. Caesarean Section should be reserved for
women with severe disease with or without haemodynamic
compromise and for obstetric indications. Invasive monitoring
with arterial and central venous line is recommended during
delivery and in the immediate postpartum period.
Maternal mortality from PPCM has improved over the years,
particularly in developed countries due to increased awareness
about the disease, improved rate of diagnosis and peripartum
care. The reported long term (47e56 months) mortality varies
from 3% in United States to 30% in Haiti and South Africa. Most
deaths occur from progressive heart failure, arrhythmias, systemic or pulmonary embolism. Several studies demonstrated that
a total recovery of ventricular function can occur in 23e54%
subjects particularly if the LVEF>30 at diagnosis. Recovery
Clinical features and investigations findings for PPCM

Symptoms
Shortness of breath
Orthopnoea
Paroxysmal nocturnal dyspnoea
Cough haemoptysis
Chest and abdominal discomfort
Palpitations
Fatigue, malaise
Signs
Tachycardia
Tachypnoea
Gallop rhythm
Signs of right ventricular failure: engorgement of the neck veins,
pulmonary crepitations, hepatomegaly, pedal oedema
Investigations
Chest X-ray: cardiomegaly, pulmonary congestion or oedema
bilateral pleural effusion
Electrocardiogram: tachycardia arrhythmias
Transthoracic echocardiogram: left ventricular ejection fraction
(LVEF) <0.45 or M-mode fractional shortening <30% (or both) and
end-diastolic dimension >2.7 cm/m2
Box 3
118
CASE-BASED LEARNING
usually occurs in the first 6e12 months but can take up to 4 years
postpartum. Possible predictors for poor outcome are with
severely depressed systolic function (LVEF <30%) and a
remodelled left ventricle with greater dilatation (LVEDd 60
mm).
Subsequent pregnancy is not advised in women with persistent LV function 6 months after initial diagnosis of PPCM as it is
associated with 50% risk of worsening heart failure and a 25%
maternal mortality rate. In women where the LV function has
returned to normal, the risk of heart failure is around 26% in a
subsequent pregnancy. Effective contraception should be discussed with all women with PPCM before discharge from the
hospital to avoid unplanned pregnancy. Consider termination of
pregnancy for unplanned pregnancy if persistent LV dysfunction.
Pre-pregnancy counselling is of paramount importance in this
cohort of women.
A large prospective international registry, the ESC EURO
Observational Research Programme is collecting data worldwide
on possible risk factors, diagnosis, mode of delivery, standard
management and therapeutic interventions offered to patients
with diagnosis of PPCM. This will help in better understanding of
the prevalence and pathophysiology of the disease.
FURTHER READING
Adamson DL, Dhanjal MK, Nelson-Piercy C. Heart disease in pregnancy. NewYork, United States: Oxford University Press Inc., 2011.
Balci A, Drenthen W, Mulder BJ, et al. Pregnancy in women with
corrected tetralogy of Fallot: occurrence and predictors of adverse
events. Am Heart J 2011; 161: 307e13.
Bello NA, Arany Z. Molecular mechanisms of peripartum cardiomyopathy: a vascular/hormonal hypothesis. Trends Cardiovasc Med
2015; 25: 499e504.
Hilker-Kleiner D, Haghikia A, Nonhoff J, Bauersachs J. Peripartum
cardiomyopathy: current management and future perspectives. Eur
Heart J 2015; 36: 1090e7.
Knotts RJ, Garan H. Cardiac arrhythmias in pregnancy. Semin Perinatol 2014; 38: 285e8.
on behalf of MBRRACE-UK. In: Knight MKS, Brocklehurst P, Neilson J,
Shakespeare J, Kurinczuk JJ, eds. Saving lives, improving
mothers care e lessons learned to inform future maternity care
from the UK and Ireland condential enquiries into maternal deaths
and morbidity 2009e12. Oxford: National Perinatal Epidemiology
Unit, University of Oxford, 2014.
Pessel C, Bonanno C. Valve disease in pregnancy. Semin Perinatol
2014; 38: 273e84.
Rao S, Ginns JN. Adult congenital heart disease and pregnancy.
Semin Perinatol 2014; 38: 260e72.
Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C, et al. ESC
guidelines on the management of cardiovascular diseases during
pregnancy: the task force on the management of cardiovascular
diseases during pregnancy of the European Society of Cardiology
(ESC). Eur Heart J 2011; 32: 3147e97.
Sliwa K, Blauwet L, Tibazarwa K, et al. Evaluation of bromocriptine in
the treatment of acute severe peripartum cardiomyopathy: a proofof-concept pilot study. Circulation 2010; 121: 1465e73.
Use of uterotonic agents at delivery in women with cardiac

disease
Obstetric haemorrhage is poorly tolerated in most women with
cardiac disease due to rapid change in circulatory parameters.
Oxytocin can still be given in majority of women with cardiac
disease. However, it can cause fall in blood pressure due to peripheral vasodilatation and decrease cardiac contractility and
heart rate. Slow infusion should be used rather than bolus doses
to minimize these effects. Ergometrine should generally be
avoided as it increases SVR and can precipitate coronary vasospasm. Carboprost, a prostaglandin F2a and misoprostol, a
prostaglandin E1 can cause myocardial ischaemia/infarction and
should be reserved for patients with life threatening haemorrhage due to uterine atony. Early recourse to mechanical manoeuvres such as bimanual compression of uterus, intra-uterine
balloon tamponade and compression sutures are recommended.
Practice points
C
C
Conclusion
Cardiac disease remains the leading cause of maternal death in
the UK. Prepregnancy counselling and contraceptive advice is of
paramount importance in women with known cardiac disease to
avoid unplanned pregnancy. All pregnant women with cardiac
diseases should be looked after by a specialist team comprising of
an obstetrician with interest in high risk pregnancies, obstetric
physician or cardiologist with interest in pregnancy and obstetric
anaesthetist, to improve maternal and fetal outcomes.
A
119
cardiac disease remains a leading cause of maternal death.

women with preexisting cardiac disease should receive prepregnancy assessment and counselling to reduce morbidity and
mortality.
all pregnant women with cardiac diseases should be looked after
by specialist combined obstetric and medical and cardiac teams
in pregnancy to improve pregnancy outcomes.
early signs and symptoms of heart failure can be mistaken for
physiological symptoms of advance pregnancy.
there should be a low threshold for echocardiography in
pregnancy.
vaginal delivery is appropriate in majority of women with cardiac
disease.
void bolus dose of oxytocin and ergometrine to treat PPH due to
uterine atony.
ETHICS/EDUCATION
Salpingectomy
mutations that could lead to cancer formation. The gonadotropin

theory is another attempt to explain the origin of cancer of the
ovaries. It points to a role for elevated levels of gonadotropins
during the initiation and induction of malignant transformation.
Another causative factor could be due to inflammation as a reaction to the ascent of infectious or inflammatory agents through
the reproductive tract.
The above theories have been put to scrutiny over the last few
years with researchers citing evidence from morphological,
embryological, molecular biology and histo-pathology to try and
explain the wide variation between different histological subtypes of ovarian cancer. The current debate on whether the
fimbrial end of the fallopian tube or remnants of the mullerian
ducts are the precursor for the disease is on-going.
Of note in ovarian cancer pathology, unlike most cancers that
become less differentiated during their neoplastic makeover,
advanced epithelial ovarian cancers display four distinct histological types that resemble the well-differentiated normal cells of
the fallopian tube (serous), endometrium (endometrioid) and
endocervix (mucinous), or cells within the vagina (clear cell). It
is important to note that it was in high risk patients (see below)
undergoing prophylactic bilateral salpingo-oopherectomy (BSO)
that high-grade serous tubal intraepithelial carcinoma (STIC) was
observed in the fallopian tube, and particularly in the fimbria,
but not in the ovary that changed our perspective on EOC. See
Figure 1 for the current outlook on pathogenesis of ovarian
cancer.
Louay Louis
Mahmood Sha
Abstract
Salpingectomy is the surgical excision of the fallopian tube. Traditionally the tubes were preserved when undertaking a hysterectomy for
benign reasons when the intention is to conserve the ovaries. Recent
evidence from morphological, embryological, molecular biology and
histopathology points towards the fallopian tube; and in particular
the mbrial end, being the origin for high-grade serous ovarian cancer.
It is advocated that bilateral salpingo-oopherectomy should be the
method of choice for risk-reducing surgery in patients with high risk
of ovarian cancer, namely those with BRCA1, BRCA2 and
mismatch-repair gene mutations. Increasingly, removal of the fallopian
tubes as part of hysterectomy for benign disease, with preservation of
the ovaries, or as a method for sterilisation in selected groups, has
been shown to reduce the risk of future development of ovarian cancer
with minimal adverse effects on the patient, a process that should be
encouraged.
Keywords BRCA mutation; HGSOC; opportunistic salpingectomy;

risk-reducing surgery; salpingectomy; STIC
Introduction
Genetic and familial risk factors for ovarian cancer
Salpingectomy is the surgical excision of the fallopian tubes,

usually carried out unilaterally as a procedure for the surgical
treatment of tubal ectopic pregnancy, or if the tube is grossly
abnormal, such as with infection when it is not possible to
salvage. Conventional gynaecological surgery advocated leaving
the fallopian tubes behind when doing hysterectomy for benign
reasons when the intention is to conserve the ovaries. The
rationale was that removing the tubes would interfere with the
blood supply to the ovaries and hasten menopause as well as the
fact that conserving the fallopian tubes behind would not cause
any risks to the patient.
The most important risk factor is a family history of ovarian or

breast cancer although an identifiable genetic predisposition
(BRCA1 and BRCA2 mutations, Lynch syndrome) is recognised in
10e15% of cases. This risk is greatly increased in families where
more than one relative with breast or ovarian cancer has been
identified with BRCA1 and BRCA2 germline mutations (both
genes are responsible for double-strand DNA repair). The presence of either mutation is associated with better prognosis than
non-carriers and better prognosis with BRCA2 carriers compared
to BRCA1. Other risk factors also include mismatch repair genes
MLH1 and MSH2 in Lynch syndrome, also known as hereditary
non-polyposis colorectal cancer (HNPCC).
The risk of ovarian cancer increases to 1 in 30 (from a background of 1:70) when a first-degree relative is affected (parent,
sibling, child). The term Hereditary Breast/Ovarian Cancer Syndrome is used to describe families whereby one or more firstdegree relative is affected by either breast and/or ovarian cancers (and occasionally other specific cancers). In these high-risk
patients and following confirmatory tests of BRCA1 or BRCA2
mutation (or in highly suspected cases in the presence of mutations) a detailed discussion should include counselling about the
pros and cons of risk-reducing mastectomy and/or salpingooophorectomy.
The origin and pathology of ovarian cancer

New evidence from histopathology shed more light on the origin
of ovarian cancer. Traditionally it was thought that epithelial
ovarian cancer (EOC) derives from malignant transformation of
the simple cuboidal epithelium of the ovarian surface, which is
adjoining with the peritoneal mesothelium. The micro-trauma
theory was the standard accepted theory to explain the origin of
ovarian cancer, whereby each ovulation induces a surface
trauma in the ovary. Malfunction during the repair may result in
Louay Louis MRCOG PhD is a Specialty Registrar (ST7) in Obstetrics

and Gynaecology at Addenbrookes Hospital, Cambridge, UK.
Conicts of interest: none declared.
Ovarian cancer risk-reducing surgery

In line with the above, it was demonstrated that 50% of all
closely examined cases of serous ovarian cancer did co-exist with
serous intraepithelial tubal carcinomas regardless whether the
patients belonged to a defined risk group or were affected with
Mahmood Sha MD FRCOG is a Consultant Gynaecological

Oncologist at Addenbrookes Hospital, Cambridge, UK. Conicts of
interest: none declared.
120
ETHICS/EDUCATION
Pathogenesis of ovarian cancer

Fimbria of
fallopian tube
Ovarian surface
epithelium
p53
mutation
Cortical inclusion
cysts
p53
signature
Usual serous
borderline neoplasm
Macropapillary
variant of serous
borderline neoplasm
Serous tubal
intraepithelial
carcinoma
Non-uterine
pelvic high-grade
serous carcinoma
Benign serous
cystadenoma
Rare
Low-grade serous
carcinoma
Figure from RCOG scientific impact paper no. 44, 2014
Figure 1
who are not at high risk for BRCA mutation and have completed
their families, should be carefully considered for prophylactic
removal of the fallopian tubes with conservation of ovaries at the
time of gynaecological or other intraperitoneal surgery. A
population-based cohort Canadian study concluded that here
was a significant increase in the uptake of hysterectomy with
bilateral salpingectomy, as well as bilateral salpingectomy as a
method for sterilization over the three-year study period,
particularly in premenopausal women. There was an additional
16 minutes of operative surgical time required for hysterectomy
with bilateral salpingectomy and 10 minutes for bilateral salpingectomy for sterilization compared with hysterectomy alone
or tubal ligation, respectively. There was no significant differences in the risks of hospital readmission or blood transfusions in
the comparative groups. During the same study period there was
a steady increase in the proportion of hysterectomies with
bilateral salpingectomy performed by laparoscopic, vaginal or
combined approach with a significant decrease in open
laparotomy.
A nationwide case-control study revealed that bilateral salpingectomy reduced epithelial ovarian cancer risk by 42% (odds
ratios 0.58; 95% confidence interval 0.36e0.95), whilst tubal
ligation reduced overall epithelial ovarian cancer risk (odds ratios 0.87; 95% confidence interval 0.78e0.98) with the strongest
risk reductions associated with tubal ligation being that of
endometrioid cancer.
sporadic (non-familial) ovarian cancer. Similar picture was noted

when a thorough histopathological investigation of fallopian
tubes from women with primary peritoneal carcinomas of the
serous subtype revealed the concurrent presence of serous
intraepithelial tubal carcinomas in 47% of all cases.
Molecular genetics provided further evidence for the hypothesis that serous ovarian and peritoneal carcinomas (pelvic serous
carcinomas) originate from the fallopian tube (which is clearly
supported by the simultaneous presence of serous tubal intraepithelial carcinomas in patients at high risk for ovarian cancer
or with sporadic or familial ovarian cancer as mentioned earlier),
this is demonstrated by characteristic mutations in TP53 in more
than half of the investigated tubal tissues, irrespective of specific
genetic risk factors. High-grade serous ovarian tumours, which
represent 70% of all ovarian cancers, are characterised by TP53,
BRCA1/2, NF1 and CDK12 as well as aberrations in homologous
recombination repair genes and pathway alterations in PI3/Ras/
Notch/FoxM1. Low-grade serous tumours on the other side are
characterized by BRAF, KRAS and ERBB2 aberrations.
The recent scientific impact paper from the Royal College of
Obstetricians and Gynaecologists (RCOG) concluded that in highrisk women with an identified familial genetic mutation, riskreduction surgery in the form of bilateral salpingooophorectomy offers the best risk reduction for ovarian cancer
and significant risk reduction for breast cancer. Bilateral salpingectomy with delayed oophorectomy could be an alternative
and may be a cost-effective strategy that can possibly overcome
the consequences of oophorectomy in terms of quality of life
issues in premenopausal women, with minimal loss of the
benefit to life expectancy. The general opinion is that women
Summary
There is a consensus opinion that women who are not at high
risk for genetic mutations or those with a strong familial history
121
ETHICS/EDUCATION
of ovarian cancer who have completed their families should be

carefully considered for prophylactic removal of the fallopian
tubes with conservation of ovaries at the time of gynaecological
or other intraperitoneal surgery. It is also the case that all patients should be strongly counselled for the removal of the fallopian tubes at the time of hysterectomy for benign indications or
other intraperitoneal surgery.
A
borderline ovarian tumors: a nationwide case-control study. Acta

Obstet Gynecol Scand 2015; 94: 86e94.
McAlpine JN, Hanley GE, Woo MM, et al. Opportunistic salpingectomy:
uptake, risks, and complications of a regional initiative for ovarian
cancer prevention. Am J Obstet Gynecol 2014; 210. e471e411.
National Comprehensive Cancer Network (NCCN) clinical practice
guidelines in oncology: genetic/familial high-risk assessment.
Breast Ovarian 2015; 2, http://www.nccn.org/professionals/
physician_gls/PDF/genetics_screening.pdf.
Royal College of Obstetricians and Gynaecologists (RCOG). Scientic
impact paper no. 44: the distal fallopian tube as the origin of nonuterine pelvic high-grade serous carcinomas. Nov 2014, https://
www.rcog.org.uk/globalassets/documents/guidelines/scienticimpact-papers/sip44hgscs.pdf.
FURTHER READING
Bast Jr RC, Hennessy B, Mills GB . The biology of ovarian cancer: new
opportunities for translation. Nat Rev Cancer 2009; 9: 415e28.
Madsen C, Baandrup L, Dehlendorff C, Kjaer SK. Tubal ligation and
salpingectomy and the risk of epithelial ovarian cancer and
122
SELF-ASSESSMENT
Self-assessment questions
Which is the most appropriate next step in her
management?
A) Bromocriptine
B) Consider delivery after giving steroids for fetal lung
maturity
C) Low-molecular weight heparin
D) Oxygen, beta-blockers, furosemide
E) Review by critical care team
Question 1 (SBA)
A 29 year old girl who is currently 20 weeks pregnant is
referred to ANC by her GP with worsening palpitations.
She is otherwise fit and healthy. There is no history of chest
pain, breathlessness, cough or syncope. No medical or surgical
history of note. She is not a smoker and does not drink
alcohol. Currently she is not on any medications.
On examination, BMI e 28, pulse 106 beats/minute and
regular, blood pressure is 100/52 mm of Hg, chest clear,
normal heart sounds and there was no evidence of peripheral
oedema. Her recent haemoglobin is 13.2 gram/dl and thyroid
function test is within normal limits. An ECG has been
requested.
Which of the following statements is correct regarding ECG
changes in normal pregnancy?
A) Sinus tachycardia, a few ventricular ectopic beats, small Q
waves, T wave inversion in lead aVF
B) Sinus tachycardia, a few supraventricular ectopic beats,
inverted P wave, ST depression
C) Sinus tachycardia, left axis deviation, absence of P wave, T
wave inversion in leads III and aVF
D) Sinus tachycardia, left axis deviation, small Q waves, T
wave inversion in lead aVL
E) Sinus tachycardia, right axis deviation, T wave inversion
in chest leads, ST depression
Question 3 (SBA)
A 28 year old woman presents for pre-pregnancy counselling.
She underwent repair of Tetralogy of Fallot as a young girl and
is now 7 weeks gestation by an early scan. She is a symptomatic and a recent ECHO shows mild to moderate pulmonary regurgitation and a mildly dilated right ventricle.
Which of the following pieces of advice is appropriate?
A) Fetal loss rates are estimated to be 30% in this situation
B) She should consider termination of pregnancy
C) The fact that she is currently asymptomatic is reassurance
that the pregnancy is likely to be straightforward
D) A pregnancy may hasten progressive deterioration in right
ventricular function
E) If she remains well at 16 weeks gestation, her prognosis for
the remainder of the pregnancy will be excellent
Question 4 (SBA)
You are asked to see a 16 year old girl who has still not started
menstruating. You request some basic investigations and an
ultrasound shows that the uterus is present and bloods show
high gonadotrophin levels. Which is the most likely cause?
A) Androgen insensitivity syndrome
B) Mullerian agenesis
C) Monosomy X
D) Genital outflow obstruction
E) Constitutional delay
Question 2 (SBA)
A 41 year old woman currently 33 weeks pregnant into her
first pregnancy is admitted to labour suite with worsening
breathlessness and palpitations over the last few days. She
also mentions requiring more pillows to sleep at night. She
denies any chest pain, cough or syncope. There is no past
cardiac or chest history of note.
On examination, her BMI is 20, her pulse is 121 beats/
minute and regular, her blood pressure is 120/66 mm of Hg
and her respiratory rate is 26 per minute with oxygen saturations on air of 92%. On auscultation of her chest a few
bibasal crepitations are audible with normal first and second
heart sounds but with a gallop rhythm and mild to moderate
peripheral oedema.
ECG shows sinus tachycardia. The chest X-ray reveals an
enlarged heart with pulmonary congestion. She has normal
arterial blood gases. There is no evidence of pulmonary embolism on V/Q scan. An urgent echocardiogram is suggestive
of severe peripartum cardiomyopathy and thrombus is noted
in the left atrium.
Question 5 (SBA)
A 74-year old woman presents to her General Practitioner (GP)
with an 8-month history of vulval pruritis. She has a number
of chronic health conditions, including a history of previous
myocardial infarction, type 2 diabetes and obesity. Alongside a
careful examination and referral to gynaecology clinic, the GP
wishes to consider systemic diseases that may be related.
Which of the following conditions is NOT commonly associated with vulval pruritis?
A) Chronic renal failure
B) Type 2 diabetes
C) Hypothyroidism
D) Atherosclerosis
E) Iron deficiency anaemia
Question 6 (SBA)
A 62-year old woman is diagnosed with lichen sclerosis at the
vulval disorders clinic. She is informed of the potential for
malignant transformation and the need for surveillance. What
Alec McEwan MRCOG is a Consultant in Fetal and Maternal

Medicine at the Division of Obstetrics and Gynaecology, Queens
Medical Centre, Nottingham, UK.
123
SELF-ASSESSMENT
E) Fertility treatment may involve the use of donor eggs/

embryos
percentage of women with lichen sclerosis would be expected

to develop vulval malignancy?
A) 80%
B) 50%
C) 15%
D) 5%
E) <1%
Question 10 (EMQ)
Choose the single most likely diagnosis (AeI) for each of the
clinical cases (ieiii) described below:
A) Complete Androgen Insensitivity Syndrome
B) Anorexia nervosa
C) Primary ovarian failure
D) Turners syndrome
E) Pelvic irradiation
F) Mullerian agenesis
G) Hyperprolactinaemia
H) Imperforate hymen
I) Constitutional delay
Question 7 (EMQ)
Choose the single most likely diagnosis (AeI) for each of the
clinical cases (ieiii) described below:
A) Lichen sclerosis
B) Atrophic vaginitis
C) Lichen planus
D) Seborrhoeic dermatitis
E) Familial chronic benign pemphigus
F) Psoriasis
G) Thread worms
H) Herpes simplex
I) Behcets syndrome
i. An 18-year old girl undergoes investigation because she

has not yet started to menstruate. She is tall, with normal
BMI, and normal breast development. She is asymptomatic
and has been well throughout her childhood.
ii. A 17-year old girl who is generally fit and well presents
with primary amenorrhoea. She has poorly developed
secondary sexual characteristics, but normal female
external genitalia. She underwent successful treatment for
a Wilms tumour in infancy.
iii. A 17-year old girl is referred to gynaecology clinic
because she has never had a period, and has pain on
intercourse. She is normally grown, with normal secondary sexual characteristics, normal BMI, and normal
external female genitalia. There is no history of childhood
illness.
i. A 58-year old woman complains of superficial dyspareunia, repeated urinary tract infections and vulval itch. On
examination, the vulva is pale and thin in appearance, but
without any obvious plaques or lesions.
ii. A 38-year old woman complains of her third episode of
painful vulval ulcers. She also has ulcers in the mouth, stiff
joints in the mornings and several recent episodes of iritis.
iii. A 24-old type 1 diabetes presents with a 6-week history of
smooth, pink, well-demarcated plaques on the vulva.
There are no lesions involving the vagina. She also has
similar plaques on the skin of her upper limbs.
Question 8 (SBA)
A 19-year old girl presents with primary ammenorrhoea.
During the course of investigations, a diagnosis of idiopathic
hypogonadotrophic hypogonadism is made. Which one of the
following is likely to be true?
A) Her serum gonadotrophins are within normal range
B) Her cranial MRI scan is completely normal
C) The diagnosis of Kallmanns syndrome can be confidently
excluded
D) She should not require any hormonal therapy unless she
wishes to become pregnant
E) There is a reasonable chance of spontaneous conception
Answers
Answer 1
A
Sinus tachycardia, 15 degree shift in electrical axis to the left,
supraventricular and ventricular ectopic beats, small Q wave,
non-specific ST changes such as depression and/or an inverted
T wave in leads III and aVL are normal findings in the ECG
during pregnancy.
Answer 2
D
The principles of management of peripartum cardiomyopathy
(PPCM) are to control arrhythmias, treat heart failure and
consider delivery if unstable. Heart failure should be managed
according to the ESC guidelines on acute and chronic heart
failure with oxygen, beta-blockers and diuretics (consider
adding ACE inhibitors or ARB if delivered). Addition of
bromocriptine to standard heart failure therapy may improve
left ventricular ejection fraction and the clinical outcome in
women with acute severe PPCM. Delivery should be expedited
if PPCM is diagnosed antenatally. She also needs to be on
heparin in view of intracardiac thrombus but it is tricky to
start at this stage as she will be delivered soon; the decision
should be made in conjunction with haematologists and
cardiologists.
Question 9 (SBA)
On prenatal genetic diagnosis, a female fetus is found to have
Turners syndrome. The parents request counselling to understand the effect that this will have on their child later in life.
Which of the following statements is not correct to include in
the counselling?
A) The most likely karyotype in Turners syndrome is 45 XO
B) The incidence of Turners syndrome varies between 1 in
200 and 1 in 500
C) Characteristic features include shield chest and widely
spaced nipples
D) Growth hormone is recommended in children and
adolescents
124
SELF-ASSESSMENT
Answer 3
D
Although pre-pregnancy symptoms attributable to cardiac
disease are a poor prognosticator for pregnancy outcome, their
absence does not guarantee a straightforward pregnancy. The
end of the second trimester, and third stage, are particularly
stressful times and cardiac decompensation will often occur at
these times, rather than earlier in the pregnancy, potentially
even in someone who was symptom free prior to pregnancy.
Fetal loss rates may be extremely high in uncorrected
congenital heart disease, particularly if there is associated
pulmonary hypertension, but that is not the case here. Indeed,
the prognosis for mother and baby is not so poor as to
recommend termination. However, she does need to understand that the pregnancy could cause more rapid deterioration
in right sided cardiac function which may not be completely
reversible after the birth.
Behcets syndrome is a chronic autoimmune disease, characterized by small vessel vasculitis. The pattern of symptoms
described here is typical and requires management in
conjunction with a specialist rheumatologist.
iii. F
Psoriasis
Psoriasis is typically characterized by well-demarcated pink
lesions, which do not have the characteristic of scale psoriasis
elsewhere when affecting vulval area. It is often associated
with other autoimmune conditions (in this case type 1
diabetes).
Answer 8
B
Idiopathic hypogonadotrophic hypogonadism is characterized
by an isolated defect in the secretion of GnRH from the hypothalamus or defective GnRH action on the pituitary, with
otherwise normal hormonal testing and imaging of the anterior pituitary. Kallmanns syndrome is one possible variant.
Answer 4
C
The uterus would not be present in androgen insensitivity
syndrome (karyotypical males with receptor insensitivity to
androgens) or Mullerian agenesis. The gonadotrophin levels
would not be high in outflow disorders, or with constitutional
delay, although the uterus would be present in both these
diagnoses. In monosomy X (Turner syndrome) the uterus is
present (although small) and FSH and LH levels are high
because of absent/rudimentary ovaries failing to produce sex
hormones which would normally suppress gonadotrophin
levels. There are likely to be other phenotypic features of
Turner syndrome, such as short stature.
Answer 9
B
The incidence of Turners syndrome varies between 1 in 2000
and 1 in 5000. Turners syndrome is most frequently caused
by meiotic errors in the father leading to an absent or
abnormal X chromosome.
Answer 10
i. A
Complete Androgen Insensitivity Syndrome
This girl has an XY karyotype with female phenotype. Due to
lack of binding with androgen receptors, these individuals
may have no androgenization, however there is peripheral
aromatization of testosterone to oestrogen which helps in the
development of female secondary sexual characters such as
breast development.
ii. E
Pelvic irradiation
Treatment for Wilms tumour is very likely to have included
radiation to the pelvis, which affects the developing ovaries
and reduces the available germline cells. It is a recognized
cause of acquired ovarian failure. More thought is being given
to fertility preservation programmes for such young adults
with a provision of oocytes or ovarian tissue preservation
becoming available.
iii. F
Mullerian agenesis
The clue here is pain on intercourse. These patients usually
have absent upper vagina and hypoplastic/aplastic uterus. The
ovarian development and function, which is separate to the
Mullerian system, remains normal. This condition is also called
MayereRokitanskyeKustereHauser syndrome. The mainstay
of treatment is aimed at restoration of sexual function.
Answer 5
D
Vascular disease and atherosclerosis is not usually linked to
vulval pruritis, although they may cause so-called venous
eczema and itching of the lower leg. The other conditions are
all linked to vulval pruritis, with iron deficiency being
particularly common in the older population.
Answer 6
D
The risk of malignant transformation of lichen sclerosis to
squamous cell carcinoma of the vulva is approximately 5%.
Hence, treatment and surveillance should be initiated.
Answer 7
i. B
Atrophic vaginitis
This is mainly a result of low oestrogen levels in postmenopausal women. The recommended treatment is topical
or intravaginal oestrogens and review after three months.
ii. I
Behcets syndrome
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Obstetrics,

Tahir A Mahmood MD FRCOG FRCPI MBA FACOG(Hon)

Philip N Baker FRCOG, FMedSci

Fiona Reid MD MRCOG

Shreelata Datta BSc(Hons) MBBS MRCOG LLM

Mahmood I Shafi MB BCh MD DA FRCOG

Causes of pruritus vulvae in different age groups:

Keywords lichen sclerosus; pruritus vulvae; vulval dermatoses;

Prepubertal girls: poor hygiene, Streptococcal infection,

vulval eczema; vulval intraepithelial neoplasia; vulval itch

Young women in reproductive age: vaginitis, allergic contact

Pruritus in Latin means itch. Vulvae in Latin mean the external

Postmenopausal women: atrophic vaginitis, lichen sclerosus,

Etiological classification of pruritus vulvae:

Gomathy Gopal MRCOG is an ST5 in Obstetrics and Gynaecology at

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:4

2016 Elsevier Ltd. All rights reserved.

Secondary referral is advised for expert opinion for further

The correlation between clinical appearance of vulval

Atopic, allergic, irritant dermatitis

Pemphigoid (cicatricial type), linear

new symptoms may evolve with the passage of time. Such

Common clinical presentation in pruritus vulvae and possible clinical diagnosis

Percentage of clinical work load

Itch, soreness, excoriation, ulceration, skin

Psoriasis, leucoderma, lichen sclerous/planus,

Allergic dermatitis to soaps, deodorants,

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:4

2016 Elsevier Ltd. All rights reserved.

yeast) and, rarely, Trichosporon spp. Candida is a normal

Use soap substitute

Gently dab vulval area

Sleep without underwear

Wash with plain water. Use

NB: maintenance therapy with triazole is unlicensed. Treatment

hazard. Itching and scratching can lead to skin breakdown and

Specic conditions and management

Topical imiquimod cream (an immune

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:4

2016 Elsevier Ltd. All rights reserved.

Severe itch at night. Figure of eight

1st line e 0.5% clobetasol propionate

Lichen simplex chronicus

HaileyeHailey disease (Familial benign chronic

Dariers disease (very rare)

Well demarcated border, absence of scale

FoxeFoydyce disease (very rare)

Itchy rash in high stress or emotional

0.025% betamethasone valerate cream/

General care of vulva, emollients, soap

Symptoms can resolve in 1/3rd as they grow

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:4

2016 Elsevier Ltd. All rights reserved.

Localized urticaria triggered by a direct firm

Avoid triggers, self resolution in 5 years.

Intense itching around anal opening, which

Burrows alongside of fingers and front of

Pain predominant itching, smear shows

Frothy green-white discharge. Direct

Gardnerella vaginalis (BV)

Fishy smell in discharge. Wet mount shows

Plasma cell (Zoons vulvitis)

Extra mammary Pagets disease

Recurrent ulcers. Cervix and vagina can be