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Obstetrics,

Gynaecology
and Reproductive
Medicine
Obstetrics, Gynaecology and Reproductive Medicine is a great revision guide for the MRCOG and beyond.
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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.
Visit our website at: www.obstetrics-gynaecology-journal.com for previous issues, subscription information and further details.

CASE-BASED LEARNING

Menstrual dysfunction

Menstrual dysfunction or abnormal uterine bleeding generally


can be categorised as anovulatory or ovulatory abnormal uterine
bleeding (AUB). Anovulatory AUB is caused by failure of the
corpus luteum to sustain the developing endometrium. Ovulatory cycles are predictable and patients often have an imbalance
of prostaglandin levels and increased fibrinolytic activity. Both
ovulatory and anovulatory AUB may coexist with intracavitary
lesions, including polyps or fibroids, which may cause heavy or
erratic bleeding. In all cases of dysfunctional uterine bleeding,
pregnancy, and the complications thereof should be ruled out as
a cause.
Table 1 summarizes the differential diagnosis of menstrual
dysfunction.
This review gives five scenarios which are common presentations of menstrual dysfunction.

Gail Busby

Abstract
Menstrual dysfunction is common, with approximately 9e30% of
reproductive-aged women presenting with menstrual irregularities
requiring medical evaluation. The causes are diverse and with multiple
treatment options are available. Appropriate management relies on
relevant investigation and accurate diagnosis. This article reviews
the most common causes of menstrual dysfunction using case histories for illustration. The conditions covered in this review include
menstrual dysfunction around the time of menarche, ovulatory and
anovulatory dysfunctional uterine bleeding, polycystic ovarian syndrome, uterine broids and dysfunctional bleeding around the perimenopause. Appropriate investigations and current management
strategies are also discussed.

Case 1: Abnormal uterine bleeding around the menarche


A 15 year old presents with a history of heavy, irregular periods.
Her periods started nine months before and although initially
average in flow, they increasingly became heavier and more
frequent.
Anovulation looms large in the pathogenesis of heavy, irregular bleeding around menarche. Within the first 2 years after
menarche, lack of ovulation is common due to the immaturity of
the hypothalamicepituitaryeovarian axis. The result of this is
prolonged stimulation of the endometrium by oestrogen until the
thickened endometrium is unable to be supported and sheds.
The adolescent with irregular and heavy periods should be
investigated for clotting abnormalities as the reported prevalence
of bleeding disorders in adolescents with menorrhagia varies
between 10.4% and 48%. Specifically, von Willebrands disease
and platelet disorders may present for the first time at menarche.
Pregnancy should not be forgotten as a possible cause of irregular bleeding in this age group. Appropriate investigations
include a pregnancy test, full blood count with platelets, bleeding
time, prothrombin time and partial thromboplastin time and von
Willebrands factor.
Women with clotting abnormalities should be co-managed
with a haematologist. Successful medical options for treatment
of von Willebrands disease include the combined oral contraceptive pill (COCP), desmopressin acetate, antifibrinolytic agents
and plasma-derived concentrates rich in the high-molecularweight multimers of von Willbrands factor (vWF).
If there are no haematological abnormalities, irregular cycles
can be regulated by the use of cyclical progestogens or the COCP.
These should both make the periods regular and decrease menstrual flow. If flow remains a problem, the addition of Tranexamic acid and/or Mefenamic acid during withdrawal bleeds is
frequently adequate.
This treatment can be continued indefinitely, or stopped after
1 year or so to determine if ovulatory cycles have commenced,
which should result in regular cycles of normal flow.

Keywords abnormal uterine bleeding; dysfunctional uterine bleeding;


endometrial hyperplasia; menstrual dysfunction; perimenopausal
bleeding; polycystic ovarian syndrome; uterine broids

Introduction
The majority of menstrual cycles are between 24 and 32 days and
a normal cycle is considered to be 28 days. The menstrual cycle
varies during the reproductive years, and is most regular between the ages of 20 and 40. The mean blood loss per cycle is
between 37 and 43 ml, and the upper limit for menstrual loss is
taken as 80 ml per menses. Menstrual dysfunction, or disruption
in the flow or timing of this cycle is a very common cause for
presentation to a gynaecologist. The causes are myriad, but
several common causes are reviewed here and treatment options
discussed.

The normal menstrual cycle


The first day of the menstrual cycle is the first day of menstruation, when oestrogen and progesterone are low. Ovulation occurs mid-cycle in response of high oestrogen and luteinising
hormone (LH) levels. The remaining granulosa cells then become
the corpus luteum which produces progesterone. If fertilization
does not occur, the corpus luteum degenerates and progesterone
and oestrogen levels fall.
In the uterus, endometrial cells proliferate in response to rising oestrogen levels in the follicular (preovulatory) phase of the
ovary, glands enlarge, and the endometrium becomes richly
supplied with blood vessels. The secretory phase after ovulation
is characterized by progesterone secretion by the corpus luteum,
which makes the endometrium receptive to a fertilized embryo.
In absence of pregnancy, the decrease in oestrogen and progesterone result in involution of the endometrium and menstrual
loss.

Case 2: Ovulatory abnormal uterine bleeding


A 28 year old nullipara is referred to the gynaecology clinic due
to heavy regular periods. She is in a stable relationship, but not
wishing to conceive at the moment. She uses barrier

Gail Busby MRCOG is a Consultant Gynaecologist at St. Marys


Hospital, Manchester, UK. Conicts of interest: none declared.

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COCPs
COCPs contain oestrogen and progestogen in combination.
They work on the hypothalamicepituitary axis to inhibit
ovulation and decrease fertility. They may reduce menstrual
loss by 43%, and also provide reliable contraception in the
compliant patient.

Differential diagnosis of abnormal uterine bleeding


Category

Differential diagnosis

Anovulatory

Adolescence
Diabetes mellitus uncontrolled
Eating disorder
Hyper-/hypothyroidism
Hyperprolactinaemia
Anticonvulsants
Antipsychotics
Perimenopause
Polycystic ovarian syndrome
Bleeding disorders (Haemophilia carriers)
Factor deficiency (FVII, FXI, FV FVIII, FXIII,
FV, FX, Fibrinogen deficiency)
Leukaemia
Platelet disorders (Bernard-Soulier Syndrome,
Dense granule deficiency, Glanzmanns
thrombasthenia, Alpha granule deficiency)
von Willebrands disease
Liver disease, advanced
Structural lesions- fibroids, polyps

Ovulatory

Progestogens
Oral progestogens taken solely in the luteal phase of the menstrual cycle have not been shown to be effective in reducing
heavy menstrual bleeding. Cyclical progestogens taken for 21
days of the cycle (day 5eday 26) have been shown in a small
study to reduce menstrual loss by 83%. The mechanism of action
of oral progestogens in reducing menstrual loss is unclear.
The progesterone only pill (POP) can be used to provide
reliable contraception, but has a varied effect on menstrual flow.
Twenty percent patients will be amenorrhoeic, 40% bleed regularly and 40% have erratic bleeding. This inconsistent effect on
menstruation this is not generally first-line treatment. Indeed,
altered bleeding patterns is the most common reason given by
women for stopping POPs. Injected progestogens such as Depot
Medroxyprogesterone Acetate (DMPA) provide reliable contraception and are injected every 12 weeks. Although this is not
licensed for the treatment of heavy menstrual bleeding, it is
associated with amenorrhoea rates of 12e47% after one year of
use.
The levonorgestrel-releasing intrauterine system (Mirena)
provides an effective treatment option for AUB in the patient who
is also desirous of reliable contraception. This device produces a
dramatic decline in menstrual blood loss (65e98%) within 12
months of use. The device, imbedded with 52 mg of levonorgestrel, releases 20 mg of levonorgestrel per day, causes pseudodecidualization of the endometrium with very little systemic
absorption of progesterone. It is licensed for contraception,
treatment of idiopathic menorrhagia, and as the progestogenic
arm of HRT. Its contraceptive effect lasts for 5 years.
In cases of ovulatory AUB where the patient has no further
reproductive ambitions, surgical options can be entertained such
as endometrial ablation and hysterectomy.

Table 1

contraception. Clinical examination and pelvic ultrasound scans


are normal.
The diagnosis here is AUB due to endometrial causes. This is
defined as abnormal bleeding in the absence of intracavitary or
uterine pathology, such as endometrial polyps or uterine fibroids.
The history of regular periods suggests that this is a case of
ovulatory AUB.
The need to preserve fertility in this case limits treatment
options to non-surgical, hormonal and medical non-hormonal
treatment modalities. The need for reliable contraception
should be taken into consideration in deciding upon treatment
options.
Antibrinolytics
Antifibrinolytics such as Tranexamic acid may reduce menstrual
loss by 29e58%. Tranexamic acid acts to reduce the breakdown
of fibrin in pre-formed clot. Menstrual bleeding involves the
liquefaction of clotted blood in spiral arteries within the endometrium, and tranexamic appears to work by retarding this
process. Tranexamic acid is not contraceptive. The contraindications are thromboembolic disease, fibrinolytic conditions
following disseminated intravascular coagulation and a history of
convulsions.

Endometrial ablation
Endometrial ablation refers to a host of techniques designed to
destroy the endometrium, and thereby reduce menstrual
bleeding. Initially, rollerball ablation, transcervical resection and
laser ablation were the predominant endometrial destruction
techniques performed under direct hysteroscopic vision. Over the
past decade, a second generation of techniques, which do not
require hysteroscopy have been developed which are safer,
easier to perform, involve shorter hospital stays or are performed
in the outpatient setting under local anaesthesia.
These techniques employ devices which are sited within the
uterine cavity and are activated in order to produce global
destruction of the endometrium. Various methods of destruction are used, including high-temperature fluids within a
balloon (Thermachoice and Cavaterm), Microwave energy
(Microsulis), and Bipolar radiofrequency electrical energy
(Novasure). Less commonly used ablative techniques include
free fluid at high temperature (Hydrothermablator), endometrial laser intrauterine thermotherapy (ELITT) and cryoablation

Non-steroidal anti-inammatory agents


Non-steroidal anti-inflammatory agents (NSAIDS) such as
Mefenamic acid and Naproxen have been shown to reduce
menstrual loss by 20e49%. They work by decreasing prostaglandin synthesis by the inhibition of cyclooxygenase. Prostaglandins are implicated in uterine bleeding and uterine cramps.
They also therefore have a positive effect on dysmenorrhoea.
They should not be used in heavy menstrual bleeding associated
with clotting abnormalities. NSAIDS are not contraceptive.

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endometrial instability and erratic bleeding. Prolonged unopposed oestrogenic stimulation of the endometrium can lead to
endometrial hyperplasia or carcinoma.
The most common cause of anovulation is polycystic ovarian
syndrome (PCOS). There are however, numerous other causes,
including thyroid disease, uncontrolled diabetes mellitus and
hyperprolactinaemia. Anticonvulsants and antipsychotics can
also cause anovulation.
A thorough history and examination is required to determine
the most likely cause of anovulation. A detailed clinical history
often reveals any systemic and medical conditions that cause
menstrual dysfunction. The examination should note the presence of galactorrhoea, weight gain, acanthosis nigricans, evidence of hyper- or hypo-thyroidism, hirsutism, virilization or
acne. A speculum and bimanual pelvic examination should be
performed to exclude any anatomical pathology. Should positive findings be elicited in the history or examination, appropriate investigations should be performed (e.g. serum prolactin
levels in the presence of galactorrhoea, thyroid function tests if
there is evidence of thyroid disease and a pelvic ultrasound
scan).
In this patient with irregular periods, weight gain and hirsutism, the most likely diagnosis is PCOS.

(HerOption). Other than free fluid thermal ablation, these are


blind techniques.
A recent network meta-analysis of second generation techniques produced the following results:
There was an increased rate of amenorrhoea with bipolar
radio frequency ablation (48% at 5 years) compared with thermal balloon ablation (32% at 5 years). Free fluid ablation was
associated with reduced rates of amenorrhoea and increased
rates of heavy bleeding compared with bipolar radio frequency
ablation. Microwave ablation was associated with an increased
rate of amenorrhoea (84%e87% at 5 years) compared with
thermal balloon ablation and cryoablation, and some reduction
in the rate of heavy bleeding compared with free fluid ablation.
With regard to patient satisfaction, there was some evidence
of reduced rates of dissatisfaction with bipolar radio frequency
ablation compared with thermal balloon ablation. Increased
dissatisfaction was seen with free fluid thermal ablation
compared with bipolar radio frequency. Overall rates of dissatisfaction were low (such as 0e7% for bipolar radio frequency
ablation).
The Endometrial laser intrauterine thermotherapy (ELITT) is
no longer marketed, and the microwave endometrial ablation
system from Microsulis has been withdrawn from the European
market after Hologic acquired intellectual property for this
device.
It is recommended that normal endometrial histology is
confirmed prior to the ablation procedure. Reliable contraception
is essential after endometrial ablation performed by any technique, and women should be counselled about this is an
appropriate procedure only in women with no future desire for
fertility.

PCOS
PCOS affects 7e10% women worldwide, making it the most
common endocrine disorder among reproductive-aged women.
Ascribing a diagnosis of PCOS has many implications
including an increased risk of infertility, dysfunctional uterine
bleeding, endometrial carcinoma, obesity, type 2 diabetes, dyslipidaemia, hypertension and possibly cardiovascular disease.
Therefore, this diagnosis should not be undertaken lightly, and
robust criteria used for diagnosis.
The first clinical definition of PCOS arose from the proceedings of a meeting of experts sponsored by the National
Institute of Child Health and Human Disease of the NIH in 1990.
They concluded that the major criteria for PCOS should include:
(1) Hyperandrogenism and/or hyperandrogenaemia (2) menstrual dysfunction and the (3) exclusion of other known
disorders.
An expert conference held in Rotterdam, The Netherlands in
2003 recommended that PCOS be defined when at least two of
the following three features are present: (1) oligo and/or anovulation, (2) clinical and/or biochemical signs of hyperandrogenism and (3) polycystic ovaries. These criteria also
recognize that other androgen excess or related disorders should
be excluded before assigning a diagnosis of PCOS.
More recently, in 2009, the Androgen excess and polycystic
ovary syndrome society proposed new criteria for the diagnosis
of PCOS: (1) hyperandrogenism: hirsutism and/or hyperandrogenaemia AND (2) Ovarian dysfunction: Oligo-anovulation
and/or polycystic ovaries AND (3) Exclusion of other androgen
excess or related disorders.

Hysterectomy
Hysterectomy is the only surgical technique which guarantees
amenorrhoea. It however can be associated with serious complications such as pelvic haematomas (3.9%), urinary tract
injury (1% for cystotomies and 0.1% for ureteric injuries), and
bowel injuries (0.3%). Compared with all other treatment modalities, hysterectomy is favoured for elimination of bleeding
symptoms and need for additional treatment. Hysterectomy is
also favoured over ablation techniques for pelvic pain beyond the
immediate post-operative period. However, these superior outcomes are achieved with the tradeoff of higher risks of adverse
events, and should therefore be reserved for cases in which more
conservative treatments have been unsuccessful.

Case 3: Anovulatory abnormal uterine bleeding


A 30 year old nullipara presents with a history of irregular and
heavy periods over a period of 2 years. Her periods last for 9 days
and occur every 2e3 months. Prior to this she had been on the
combined oral contraceptive pill for 10 years and had regular
periods on this. She is currently using barrier contraception as
she stopped the COCP due to significant weight gain. On direct
questioning she also reveals a history of unwanted hair growth
on her face, chest and abdomen.
When ovulation does not occur, no corpus luteum forms to
produce progesterone. The endometrium therefore undergoes
prolonged oestrogenic stimulation, excessive proliferation,

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Weight loss and physical activity


Women with PCOS have an increased prevalence of obesity,
estimated at between 40% and 60%. Obesity and insulin
resistance (IR) are closely linked to the development of PCOS
and its clinical features. Due to the potential significance of IR

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in the manifestation of PCOS, and as obesity promotes IR,


lifestyle modifications focussing on dietary weight loss and
increased physical activity is the preferred first-line treatment
for PCOS.
Modest weight loss of 5%e14% improves CVD risk factors,
hormonal profile and reproductive function in overweight and
obese women with PCOS. Improvements include reductions in
abdominal fat, blood glucose, blood lipids and IR, improvements
in menstrual cyclicity, ovulation and fertility, reductions in
testosterone levels and free androgen index and increases in sex
hormone binding globulin. There have also been demonstrated
improvements in self-esteem, depression and anxiety.

Thiazolidinediones
Thiazolidinediones act as insulin sensitizers through their
activation of the nuclear receptor PPAR-g, leading to increased
production of insulin-sensitive adipocytes and increased
glucose uptake in these cells, increased secretion of adiponectin
and decreased secretion of pro-inflammatory cytokines. Recent
data suggest that in women with PCOS, thiazolidinediones
exert additional benefit with respect to hyperandrogenism, IR,
anovulation and inflammatory mediator levels, in both lean
and obese women. The thiazolidenedione, pioglitazone, has
been shown to ameliorate the signs and symptoms of PCOS in a
cohort of women who failed a previous trial of metformin.
There have been, however concerns regarding use of these
drugs, including withdrawal from the market of the vanguard
thiazolidenedione, troglitazone, and further concerns regarding
potential adverse cardiovascular events in Type 2 diabetes
patients taking thiazolidinediones. This reinforces the need for
caution when considering use of this class of drugs. These
drugs should not be considered as first line management of
PCOS.

COCPs
COCPs are among the primary treatment options for PCOS,
particularly for those patients not wishing to become pregnant.
They produce regular menstrual periods, lower the risk of
endometrial hyperplasia and improve acne and hirsutism. COCPs
improve symptoms by increasing the production of SHBG,
resulting in a decrease in circulating free androgens, as well as
their bioavailability. They also suppress the production of FSH
and LH which in turn decreases LH-driven ovarian androgen
production. Progestogens protect the endometrium against hyperplasia induced by unopposed oestrogen stimulation. Some
progestogens, such as drospirenone and cyproterone acetate
have proven anti-androgenic effects and therefore are of added
benefit in PCOS.
Despite their potential benefits in PCOS, COCPs fail to
diminish insulin resistance in PCOS and may actually be associated with long-term metabolic derangements such as glucose
intolerance, abnormal lipid profiles and cardiovascular disease.
Further longitudinal studies in adult women with PCOS receiving
COCPs are needed.

Case 4: Abnormal uterine bleeding secondary to uterine


broids

Insulin sensitizers and insulin lowering drugs


These medications reduce insulin levels (Metformin) and increase insulin sensitivity (metformin and thiazolidinediones),
thus treating the metabolic effects associated with PCOS and
obesity.

A 35 year old multiparous woman attends the gynaecology clinic


with a history of regular, heavy, painful periods over several
years. This has been associated with gradually increasing fatigue.
On examination she has pale mucous membranes. Abdominal
and bimanual examinations reveal a 16-week sized mass arising
from the pelvis. A full blood count reveals that she is anaemic,
and a pelvic ultrasound scan reveals uterine fibroids.
Uterine fibroids are the most common benign gynaecological
tumours. Definitive management depends on the subtype of the
fibroid (ie. Submucosal, intramural or subserosal) and comprises
a choice between surgical (TCRF, hysterectomy, myomectomy)
or radiological (uterine artery embolisation) modalities. Medical
therapies, such as those discussed above (tranexamic acid,
COCP, progestogens) have been used but appear to be less
effective in women with fibroids.

Metformin
Metformin increases insulin sensitivity in the liver by reducing
gluconeogenic enzyme activities, inhibiting hepatic uptake of
lactate and alanine, increasing the conversion of pyruvate to
alanine and inhibiting glucose output. In addition, metformin
increases peripheral glucose uptake, decreases fatty acid oxidation and decreases glucose absorption from the gut. It therefore
has a positive effect on the metabolic derangements in PCOS.
The use of Metformin in PCOS has been shown to increase
menstrual cyclicity (in 50%e60%), improve percentage of
ovulatory cycles, and improve fertility.
Metformin use is associated with gastrointestinal side-effects,
which can be minimized by titration to the desired dose over a
one month period.
In adult women with PCOS, the addition of Metformin to a
COCP decreases IR, as well as androgen levels. However, the
anticipated correction of deranged lipid profiles and abdominal
obesity through metformin use appears to be blunted.

Uterine artery embolisation


Uterine artery embolisation (UAE) is a minimally invasive
radiologic procedure in which transcutaneous insertion of a
catheter through the femoral artery and subsequent occlusion of
the uterine artery with Embospheres, polyvinyl alcohol beads,
polyvinyl alcohol coils or Gelfoam causes cessation of blood flow
to the fibroid. Shortly thereafter, the fibroid necroses and
shrinks. Menorrhagia symptoms resolve in 85%e95% of patients treated in this way. Preprocedural investigations include
Magnetic Resonance Imaging of the fibroids.
UAE is associated with an increased risk of minor complications versus myomectomy or hysterectomy, but the long term
patient satisfaction is equivalent for the three procedures.
UAE is however associated with an increased risk of further
surgical procedures for up to five years after the initial procedure.
There are concerns regarding fertility after UAE due to the risk of
premature ovarian failure and there have been reports of uterine
rupture in labour with previous UAE.

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A transvaginal ultrasound scan revealed an endometrial


polyp. She underwent outpatient hysteroscopy which confirmed
the presence of a large endometrial polyp filling the uterine
cavity. She subsequently underwent an urgent hysteroscopy and
endometrial polypectomy and biopsy under general anaesthetic.
The histology revealed complex endometrial hyperplasia with
atypia. She was appropriately counselled and underwent a hysterectomy and bilateral salpingo-oophorectomy.
Patients presenting with a recent onset of abnormal uterine
bleeding around the menopause should be fully investigated to
rule out cervical and endometrial pathology. Appropriate investigation includes a cervical smear, pelvic ultrasound scan (ideally
transvaginal) and hysteroscopy with endometrial biopsy (this is
often performed as an outpatient procedure).
Endometrial biopsy alone has a sensitivity and specificity of
diagnosing endometrial cancer of 91% and 98% respectively. It
is also a good test to diagnose atypical endometrial hyperplasia
with a sensitivity of 82.3% and a specificity of 98%. It however is
very poor at diagnosing intracavitary lesions such as endometrial
polyps or submucous fibroids. Saline infusion sonography can be
used as an adjunct to transvaginal ultrasonography in order to
improve the pick up rate of intracavitary abnormalities and has a
sensitivity of 88e99% and specificity of 72e95%. This is an
improvement on TVS alone which has a sensitivity and specificity of 60e92% and 62e93% respectively. TVS also has the
advantage over hysteroscopy alone of assessing for myometrial
lesions and ovarian pathology. OPH itself has a sensitivity and
specificity of 94% and 89% of diagnosing intracavitary abnormalities, with the added benefit of allowing directed biopsy of
suspicious areas within the endometrium or excision of polyps
depending on their size and number.

Myomectomy
Myomectomy, the surgical excision of uterine fibroids, can be
performed hysteroscopically, laparoscopically or via laparotomy
depending on the number, size and position of fibroids. Submucous fibroids are amenable to hysteroscopic removal,
whereas intramural and subserosal fibroids require an abdominal approach.
Pre-operative treatment with Gonadotrophin-releasing analogues or Ulipristal acetate, a selective progesterone-receptor
modulator, decrease fibroid size and increase haemoglobin
due to causing amenorrhoea in most patients. Due to the risk of
osteoporosis, GnRH analogues should not be used for periods of
longer than six months unless concomitant oestrogen replacement is prescribed. Ulipristal acetate is approved in the European Union for pre-operative treatment of moderate to severe
symptoms of uterine fibroids in adult women of reproductive
age. It is approved for treatment periods of three months
duration or less, as the longer-term tolerability has not been
established.
In two well-conducted trials, PEARL 1 and PEARL 2, Ulipristal
acetate at a dose of 5 mg per day for 13 weeks was shown to
control excessive uterine bleeding in 90% of women with
uterine fibroids. Approximately half of the recipients were amenorrhoeic by day 10. Ulipristal acetate also resulted in a median
reduction in fibroid volume of at least 21% following 13 weeks of
treatment. These results were non-inferior to those of leuprolide
acetate.
Repeated courses of ulipristal acetate
Another trial, PEARL IV evaluated the efficacy and safety of
repeated 12-week courses of daily 5 mg or 10 mg doses of Ulipristal acetate. Amenorrhoea was achieved in 62% and 73%
respectively in the 5- and 10 mg groups. Median times to amenorrhoea was 6 days or fewer and the proportion of patients with
controlled bleeding at the end of both treatment courses were
>80%. The combined fibroid volume of the three largest fibroids
were reduced by 54% and 58% respectively after two courses.
Surgery was performed in only 3 of 230 women taking the 5 mg
does and 5 of 221 women taking the 10 mg dose. Endometrial
biopsies have not shown any increased risk of endometrial atypia
or carcinoma.
Ulipristal acetate may therefore be an alternative option to
surgery in the long-term treatment of uterine fibroids.

Management options
The finding of atypical endometrial hyperplasia conveys a risk of
progression to endometrial carcinoma of 8.2% in 4 years, 12.4%
in 9 years and 27.5% in 19 years. In addition, other studies have
shown the presence of concurrent endometrial carcinoma in
hysterectomy specimens removed for atypical hyperplasia in
43% patients. For this reason, it is recommended that hysterectomy be performed within 3 months of the diagnosis of atypical
endometrial hyperplasia.
In contrast, the finding of endometrial hyperplasia without
atypia has a very low risk of malignant transformation of 1.2% in
4 years, 1.9% in 9 years and 4.6% in 19 years. This abnormality
can be treated with cyclical progestogens with re-biopsy to
confirm regression of the hyperplasia.
In patients who have no further reproductive ambitions, total
hysterectomy with or without bilateral salpingo-oophorectomy
depending on the age group is the treatment of choice for
endometrial hyperplasia with atypia. In patients who wish to
retain their uterus for childbearing, treatment with high dose
progestogens with re-biopsy can be employed after careful
counselling.

Hysterectomy
Patients who have symptomatic uterine fibroids and have
completed their family may opt for hysterectomy, however this is
associated with increased frequency of complications compared
to hysterectomy with a normal-sized uterus.

Case 5: abnormal uterine bleeding in the perimenopause


A 48 year old attends the clinic with a 6 month history of
continuous bleeding. Her periods were previously fairly regular
lasting 5 days every 26 days. The bleeding is not excessive, but
she is getting frustrated by having to wear sanitary protection
every day. Clinical examination is normal, and speculum examination reveals a small amount of bleeding coming through
the os of a healthy-looking cervix.

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Conclusion
Abnormal uterine bleeding is the most common cause of anaemia
in the pre-menopausal woman and can have a substantial impact
on womens quality of life. Cases need to be assessed on an

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individual basis by a thorough history, clinical examination and


investigations relevant to the particular case. Pregnancy should
always be ruled out in cases of menstrual dysfunction. Other investigations vary depending on issues such as age of presentation,
co-morbidities and degree of menstrual loss.
There is a large range of available treatment options,
including medical and surgical options, and these should be
tailored to the specific case depending on the working diagnosis,
and future reproductive ambitions of the patient.
A

Matteson KA, Husam Abed MD, Wheeler II TL, et al. A systematic


review comparing hysterectomy with less-invasive treatments for
abnormal uterine bleeding. J Minim Invasive Gynecol 2012; 19:
13e28.
NICE guidance (IPG367) Uterine artery embolisation for broids Nov
2010.
NICE guidance CG44. Heavy menstrual bleeding. Jan 2007.
Peacock A, Alvi NS, Mushtaq. Period problems: disorders of
menstruation in adolescents. Arch Dis Child 2012; 97: 554e60.
Thomson RL, Buckley JD, Brinkworth GD. Exercise for the treatment
and management of overweight women with polycystic ovary
syndrome: a review of the literature. Obes Rev 2011; 12:
e202e10.

FURTHER READING
Azziz R, Carmina E, Dewailly D, et al. The Androgen Excess and PCOS
Society criteria for the polycystic ovary syndrome: the complete
task force report. Fertil Steril 2009; 91: 456e88.
Croxtall JD. Ulipristal acetate in uterine broids. Drugs 2010; 72:
1075e85.
Daniels JP, Middleton LJ, Champaneria R, et al. Second generation
endometrial ablation techniques for heavy menstrual bleeding:
network meta-analysis. BMJ 2012; 344: e2564.
Donnez J, Hudecek R, Donnez O, et al. Efcacy and safety of repeated
use of ulipristal acetate in uterine broids. Fertil Steril 2015; 103:
519e27.
Geller DH, Pacaud D, Gordon CM, Misra M. State of the art review:
emerging therapies: the use of insulin sensitizers in the treatment of
adolescents with polycystic ovary syndrome (PCOS). Int J Pediatr
Endocrinol 2011; 9.
Lacey Jr JV, Sherman ME, Rush BB, et al. Absolute risk of endometrial
carcinoma during 20 year follow up among women with endometrial hyperplasia. J Clin Oncol 2010; 28: 788e92.

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:5

Practice points
C

154

Pregnancy should be ruled out in all cases of abnormal uterine


bleeding
Appropriate management will vary with age, co-morbidities and
reproductive ambitions
There are many treatment options now available, making hysterectomy a last resort due to higher risks of complications
Menstrual dysfunction in the perimenopause should be investigated urgently due to the risk of a precancerous or cancerous
cause

2016 Published by Elsevier Ltd.

REVIEW

Modern management of
broids

undergoing assisted conception treatment and those attempting


natural conception. However some dispute this association. Evidence that fibroid removal improves fertility outcomes is more
limited as no randomised control trials exist. However evidence
from case-controls suggests that fibroid removal by myomectomy
increases pregnancy rates in those with submucosal fibroids,
however evidence to support removal of intramural fibroids is
less conclusive. Despite the conflicting evidence, since fibroids
are commonly associated with obstetric complications, this may
provide reason enough to remove fibroids preconceptually.

Amanda Jefferys
Valentine Akande

Abstract
Uterine broids are present in approximately 20% of women of reproductive age and can be associated with signicant morbidity including
menstrual disturbance, pressure symptoms and in some cases
reduced reproductive potential. Although some women remain asymptomatic any of the above presentations may be an indication for treatment. Many management options exist including conservative,
treatment with medications, radiological interventions and surgery. Interventions can be fertility sparing whereas some are contraceptive,
whilst others can result in permanent infertility. Ultimately optimal
management should be governed by presenting symptoms, size and
location of broids, as well as the desire for fertility and local expertise.

Keywords broids; hysterectomy; leiomyomas;


subfertility; uterine myomas; uterine myomectomy

Fibroid management
Fibroid management options can broadly be divided into medical, surgical and more recently radiological options. Each has its
advantages and disadvantages and will appeal to a different
subset of patients. Ultimately decisions regarding whether and
how to treat will depend on symptoms reported, size, number
and position of the fibroids, the willingness of a patient to undergo surgery, plans for future fertility and local expertise. Table
1 summarizes the indications, advantages and disadvantages of
each management option together with symptomatic effects.

menorrhagia;

Medical management
Levonorgestrel releasing intrauterine system (LNGIUS) (for heavy menstrual bleeding only)
The LNG-IUS is also well established in the management of
menorrhagia, so much so that it is now recommended as first line
treatment in the management of menorrhagia. Its effectiveness in
the context of uterine pathology such a fibroids is less clear. One
longitudinal study has reported significant reductions in menstrual blood loss and increased mean Haemoglobin concentration
within three months of insertion of the LNG-IUS, in women with
a uterine size of 12 weeks or less and one or more fibroids greater
then 1.5 cm in diameter. There was also a significant reduction in
fibroid volume within 6 months of insertion. Reductions in
menstrual blood loss were also reported by another smaller
study, with similar inclusion criteria, however at 12 months the
majority of patients with the LNG-IUS still reported symptoms of
menorrhagia, leading the authors to question the effectiveness of
the LNG-IUS in the fibroid setting. We also need to consider the
fact that fibroids are associated with increased rates of discontinuation of the LNG-IUS and difficulties at the time of fitting (e.g.
expulsion), it is also contraceptive and therefore not an option
for women wishing to conceive.

Introduction
Uterine fibroids (myomas, leiomyomas) are common. These
benign tumours of the uterine smooth muscle are thought to be
present in up to 20% of women of reproductive age (and perhaps
up to 60% of women of African descent). Uterine fibroids are
thought to result from increased mitotic divisions within the
myometrium under the influence of oestrogen and progesterone,
however, what initiates fibroid growth is unclear. Symptoms
depend on size and position of the fibroids, but it is thought that
between 20 and 50% of women are symptomatic of their fibroids. Symptoms include bleeding disturbances (often heavy,
prolonged, frequent and unpredictable bleeds) and pressure
symptoms (bladder and bowel symptoms, bloating, chronic
pelvic pain and dyspareunia). Bleeding disturbances are more
pathognomonic of submucosal or intramural fibroids which
protrude into the endometrial cavity, whereas pressure symptoms are dependent on fibroid size and the extent to which these
fibroids encroach on the peritoneal cavity and the structures
within. Importantly over 50% of fibroids are asymptomatic, and
in many symptoms are mild. As such, the majority of patients
may not require treatment.
The role of fibroids in subfertility remains controversial.
Systematic reviews have suggested reduced livebirth rates in
women with both submucosal and intramural fibroids

Gonadotrophin releasing hormone agonists (GnRH


agonists)
GnRH agonists are synthetic analogues of GNRH which compete
for GnRH receptors and, after an initial flare effect, inhibit the
hypothalamic-pituitary-ovarian axis. The resulting drop in
circulating oestrogen levels is associated with fibroid degeneration resulting in shrinkage of the fibroid. There is strong evidence
that if given 3e4 months prior to myomectomy or hysterectomy
GnRHa is associated with reduced fibroid volume, correction of
pre-operative anaemia, reductions in intraoperative blood loss,
reduced midline incisions and increased vaginal approach to
surgery where appropriate. The benefits for laparoscopic myomectomy are less clear. GnRH agonists have been used outside of

Amanda Jefferys MRCOG BMBS Subspecialty Trainee in Reproductive Medicine,


Bristol Centre for Reproductive Medicine, Southmead Hospital,
Bristol, UK. Conicts of interest: none declared.
Valentine Akande PHD MRCOG Consultant in Gynaecology and Reproductive
Medicine, Bristol Centre for Reproductive Medicine, Southmead
Hospital, Bristol, UK. Conicts of interest: none declared.

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:5

127

2016 Elsevier Ltd. All rights reserved.

REVIEW

Fibroid management options


Indication

Advantages

Disadvantages

Therapeutic effects
Menstrual
symptoms

LNG-IUS

Menorrhagia

GnRH agonists

Menorrhagia
Pressure symptoms
Pre-surgery

SPRMs

Menorrhagia
Pressure symptoms
Pre-surgery
Menorrhagia
Pressure symptoms

Uterine Artery
Embolisation

MRI focused
High intensity
ultrasound

Menorrhagia
Pressure symptoms

Reversible

May be difficult to
fit / expelled if large
fibroids.
Reduce
Hypoestrogenic
intraoperative
side effects limit
blood loss and
duration of use
midline incisions
Fibroid re-growth
shortly after
cessation of
treatment
Oestrogen levels
One month break
maintained
required between
Few side effects
each course
Quick recovery
High rates of minor
Short hospital stay complications post
procedure (pain,
post-embolisation
syndrome)
High rates of
subsequent
intervention
Quick recovery
High rates of
Short hospital stay subsequent
intervention
Not recommended
for pedunculated
fibroids or where
uterine size > 24
weeks

Open myomectomy Menorrhagia


More complete
Pressure symptoms fibroid clearance
Laparoscopic
myomectomy

Menorrhagia
Quicker recovery
Pressure symptoms times, shorter
hospital stays.
Reduced mean
blood loss.

Hysteroscopic
myomectomy

Menorrhagia

Shorter operating
times, shorter
hospital stays,
quicker recovery.
Fewer
intraoperative
complications

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:5

Long recovery time.


Longer hospital
stays.
Requires significant
skill and expertise
Less complete
fibroid removal
Not possible for
very large or
multiple (>5)
fibroids
Concerns over
morcellation and
cancer spread
Only possible for
submucosal
fibroids
Can be associated
with intrauterine
adhesion formation

128

Fibroid size

Fertility

Reduced menstrual Some possible


blood loss
reduction
Usually induces
ameneorrhoea

Contraceptive

Reduction in fibroid Inhibits HPO axis


volume after 3
-temporary
months
reduction in fertility

Reduced menstrual Reduction in fibroid


blood loss
volume after 3
months
Reduced menstrual Fibroid shrinkage
blood loss

Insufficient
evidence to confirm
safety
Insufficient
evidence of safety

Reduced menstrual Fibroid shrinkage


blood loss

Insufficiant
evidence of safety

Reduced menstrual Fibroid removal


blood loss

Livebirths reported
in literature.

Reduced menstrual Fibroid removal


blood loss

Livebirths reported
in literature.

Reduced menstrual Not appropriate for Associated with


fibroids causing
improved obstetric
blood loss
pressure symptoms outcomes despite
concerns over
adhesion formation

2016 Elsevier Ltd. All rights reserved.

REVIEW

Hysterectomy

Menorrhagia
Definitive
Pressure symptoms resolution of
symptoms.
May deal with other
pathologies

Abdominal
approach often
necessary due to
uterine size.
Long recovery time
(especially
abdominal /
vaginal.

Permanent
cessation of
menstrual blood
loss

Permanent fibroid
removal

Permanently
removes option of
future fertility

Table 1

the pre-operative setting with reductions in fibroid size and


symptomatic relief, however use of agents long-term is limited by
high rates of hypoestrogenic symptoms experienced by women
whilst on treatment and concerns over reductions in bone mineral density with long term use (>6 months). There is evidence
that within 24 weeks of cessation of GnRH agonists the fibroid
will re-grow to pre-treatment size in the majority. Add-back
oestrogen and progesterone therapy for has been found to successfully reverse hypoestrogenic effects in those on longer term
treatment without causing fibroid re-growth. This may be
particularly of benefit in peri-menopausal women wishing to
avoid surgery.

with low rates of adverse events (headaches, flushes, dizziness)


demonstrated in all studies makes it an alternative to surgery for
women symptomatic of fibroids. Although pregnancies following
Ulipristal Acetate treatment have been reported there is insufficient evidence to confirm its safety prior to pregnancy. However,
the fact that several patients conceive in cycles following the use
of high dose SPRMs for emergency contraception suggest it is
likely to be safe.
Aromatase inhibitors
Aromatase inhibitors block peripheral conversion of androgens
to oestrogens in both ovarian and peripheral tissues. Interestingly aromatase expression is increased in fibroid tissue in African women and is proposed as a mechanism by which this group
of women might be more susceptible to fibroids. Few studies
have assessed the efficacy of aromatase inhibitors in the management of fibroids. One non-RCT demonstrated a more than
50% reduction in fibroid volume with a 3 month course of
anastrozole. One RCT has demonstrated reductions in fibroid
volume with a 12 week course of letrozole comparable to that
seen with triporelin, with advantages of avoidance of the initial
flare effect of GnRH agonists and maintenance of oestrogen
levels. However, no studies have demonstrated symptomatic
improvements with aromatase inhibitors and a Cochrane Systematic Review has suggested there is insufficient evidence to
recommend their use in the management of fibroids.

Gonadotrophin releasing antagonists (GNRHantagonsists)


Although studied less the efficacy of GnRH antagonsists have
been investigated and it would appear that they result in a similar
reduction in fibroid volume. However there use is limited by the
fact that they have a shorter half life necessitating daily administration and there are few oral preparations.
Selective progesterone receptor modulators (SPRMs)
Since it was first established that progesterone receptor expression is higher within fibroid tissue than surrounding myometrial
tissue and that progesterone promotes fibroid growth, attention
has turned more recently to SPRMs to potentially alleviate the
symptoms of fibroids. SPRMs such as Ulipristal Acetate have
tissue specific agonist/antagonist effects and act on the
hypothalamo-pituitary-ovarian axis, the endometrium and
within fibroids themselves. This results in fibroid shrinkage,
reduced endometrial blood loss and amenorrhoea (secondary to
inhibition of ovulation), whilst maintaining (as FSH and LH
levels are unaffected) oestrogen levels. Results of the PEARL I
study, a double blinded placebo controlled trial, demonstrated
reductions in menstrual loss in 91% and greater than 20% reductions in fibroid volume in those taking either 5 mg or 10 mg of
ulipristal acetate for 13 weeks, making it useful in reducing
fibroid volume prior to surgery. These results were mirrored by
the PEARL II study which demonstrated Ulipristal Acetate to be
as effective as the GnRH agonist Leucoprolide in controlling
uterine bleeding and achieving fibroid shrinkage, with fewer
hypoestrogenic side effects. More recently studies have assessed
the safety and efficacy of Ulipristal Acetate for prolonged (up to
four 13 week courses) and intermittent usage, which demonstrated maintained and continued improvements in fibroid
shrinkage and symptom control with fibroid shrinkage maintained 3 months following cessation of treatment. This along

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:5

Selective estrogen receptor modulators (SERMS)


SERMs such as Tamoxifen and Raloxifene which exert tissue
specific agonist and antagonist effects on oestrogen receptors
have been proposed as a potential therapy for fibroids. Raloxifene is the most investigated of the SERMs with suggestions from
two studies of reduced fibroid volume when administered to
postmenopausal women. However this effect has not been seen
in pre-menopausal women, presumably due to the effect of the
SERMs on ovarian stimulation and therefore oestrogen levels,
limiting its use in this setting. A Cochrane Systematic Review has
suggested there is insufficient evidence to support its use in the
management of fibroids.

Radiological interventions
More recently interventional radiology has offered a more permanent solution to symptomatic fibroids for women wishing to
avoid surgery. Traditionally this has been with Uterine Artery
Embolisation, however MRI focused high intensity ultrasound
has received increasing attention recently.

129

2016 Elsevier Ltd. All rights reserved.

REVIEW

regarding pregnancy outcomes following the procedure, there


is insufficient evidence to deem the procedure safe for those
wishing to conceive.

Uterine Artery Embolisation (UAE)


In UAE occlusion of both uterine arteries is achieved by the
introduction of tiny particles of polyvinyl alcohol via the
femoral artery under fluoroscopic guidance. The fibroids shrink
as a result of ischaemic necrosis but blood supply to the uterus
is preserved via collateral vessels. The aim of the procedure is
not removal of the fibroid but elimination of fibroid related
symptoms. Because the technique aims to achieve fibroids
shrinkage rather than removal it is less effective in the case of
large fibroids associated with pressure symptoms and most
effective in the treatment of menorrhagia. A number of studies
have compared the efficacy of UAE to surgery (myomectomy
and hysterectomy), all of which have demonstrated comparable
patient satisfaction. Despite a high rate of post-procedural
minor complications including post embolization syndrome
(fever, nausea, vomiting and pain) and readmissions for pain,
UAE has been associated with shorter hospital stays, quicker
recovery and a quicker return to daily activities compared to
surgical alternatives, making UAE over a 2 year period a more
cost effective alternative to hysterectomy. However, concerns
have been raised regarding the effect UAE might have on future
reproductive functioning with suggestions of reduced ovarian
reserve, impaired placentation and post partum haemorrhage
and an increased risk of miscarriage. Reassuringly the few
studies that have assessed ovarian reserve post UAE have not
demonstrated any difference in antimullerian hormone levels
pre- and post-procedure, and similar follicle stimulating hormone levels post-procedure to those post hysterectomy. However, the only study to assess livebirth rates following UAE has
demonstrated reduced livebirth rates in those undergoing UAE
compared to myomectomy, however numbers in this study
were small. Studies have consistently demonstrated high rates
of further intervention at 2 years or more post UAE, in one
study almost a quarter of patients went on to have a hysterectomy at 2 years, calling into question the overall costeffectiveness of the procedure.

Surgical management
Surgical management often offers a more definitive solution to
uterine fibroids but are more invasive and not without complications. Surgical options for the management of fibroids can
broadly be divided into fertility-sparing and non-fertility-sparing
surgery. Fertility sparing surgery comprises removal of the fibroid(s) from the myometrium which can be approached via
laparotomy, laparoscopy or hysteroscopically. Ultimately the
most definitive option in the management of fibroids is a hysterectomy, however, for some the psychological and fertility
implications of this are too great.
Open myomectomy
First described in 1845 the open myomectomy is achieved via a
laparotomy and enucleation of the fibroid from the myometrium.
This is followed by closure of the myometrium in three layers to
close the dead space. Open myomectomy is preferably undertaken via the low transverse (Pfannensteil) approach, which is
associated with lower postoperative morbidity and quicker recovery times. For large fibroids it may be beneficial to pre-treat
for three months with GnRH agonists or SPRMs (e.g. Ulipristal
acetate) to shrink the fibroid sufficiently for a pfannensteil
approach to be used. Such pretreatment may also provide other
benefits including increasing pre- and post-operative haemoglobin and reducing intra-operative blood loss.
Although myomectomy has traditionally been associated
with excessive blood loss due to the vascular nature of fibroids,
thanks to adjuvant measures to reduce intraoperative blood loss
including mechanical clamps, and more recently intramyometrial vasopressin, intraoperative tranexamic acid, preoperative misoprostol and haemostatic sealing agents, open
myomectomy now offers low rates of conversion to hysterectomy (<1%) and a low rate of blood transfusions (8%),
together with low rates of intraoperative complications (bowel,
bladder, ureteric injury) (2%) even in the case of large fibroids.
Although in many centres the open myomectomy has been
superseded by the laparoscopic approach, in the majority of
centres the considerable technical skill and expertise will not be
available locally, meaning open myomectomy still holds a place
in the modern day management of fibroids. What is more the
open approach is associated with shorter operating times and
lesser cost than the laparoscopic approach. Even those with the
expertise in laparoscopic surgery acknowledge that for large
(>15 cm) or multiple (>5) fibroids open myomectomy offers
the safest approach and for multiple fibroids is more likely to
result in complete fibroid clearance than the laparoscopic
approach.
As with many surgical interventions there are few studies
assessing the effectiveness of myomectomy in the fertility setting.
Studies that have been undertaken have not looked at open
myomectomy independent of other approaches and have not
demonstrated a benefit in those undergoing surgery compared to
controls. However, successful livebirths have been reported
consistently in the literature.

MRI focused high intensity ultrasound


MRI Focused High Intensity Ultrasound is the newest interventional radiology technique to be used for the treatment of
symptomatic fibroids. The technique utilises MRI scanning to
locate the fibroid and focus a high intensity ultrasound beams
on to a point within the fibroid resulting in tissue heating and
subsequent necrosis. Observational studies have consistently
reported symptomatic improvement over a 6e12 month
period and fibroid shrinkage from 15 to 70% at 6 months.
Fibroids of various size and locations have been treated
although uterine size of greater than 24 weeks gestation and
pedunculated fibroids are considered relative contraindications to this treatment, it is also not useful in multifibroid
uteri. Despite the symptomatic improvements seen with this
procedure, as with UAE, there appear to be high rates of
requirement for further surgical or radiological interventions
which were more than 20% in some studies. A randomised
control trial comparing MRI focused high intensity ultrasound
with UAE (the FIRSTT trial) is currently underway. Although
there have been a number of reports of pregnancies following
MRI focused high intensity ultrasound e the largest case series consisting of 54 pregnancies, provided reassurance

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REVIEW

advantage of shorter operating times and hospital stays and


low complications rates. The technique has proven efficacy in
achieving symptomatic relief with rates of improvement in
menstrual symptoms of between 75 and 89%. Further improvements in symptoms have been reported postoperatively
following pretreatment with GnRH agonists pre-operatively,
pretreatment with GnRH agonists has also been found to
reduce operative time e which is important to limit intraoperative fluid absorption and minimise the risk of associated
hyponatraemia. Despite the apparent benefits of the technique
caution should be exercised in those wishing to conceive.
Inevitably trauma to the endometrium is necessary to achieve
fibroid resection, trauma which in contrast can be avoided via
the laparoscopic or open approach. Endometrial trauma risks
the formation of intrauterine adhesions. Rates of adhesions at
second look hysteroscopy have varied in the literature from 0%
to almost 50%. Risk factors for adhesion formation appear to
be multiple fibroids and opposing fibroids. Some have also
suggested that use of monopolar diathermy may increase the
risk, although this finding has not been consistent. Various
adjuncts have been suggested which may reduce adhesion
formation including gel adhesion barriers, which were found in
a small randomised control trial to significantly reduce adhesion formation at 3 month follow up. Others have used the
Intrauterine Contraceptive Device (IUCD) or a postoperative
course of oestradiol valerate, although to date no strong evidence of benefit has been demonstrated. Despite the concerns
over the formation of intrauterine adhesions reproductive
outcomes following hysteroscopic myomectomy appear to be
good with improvement in obstetric outcomes including reductions in miscarriage rates and increased livebirth rates in
retrospective studies, however, as with many other surgical
techniques no randomised control trials have been undertaken
to confirm a benefit.

Laparoscopic myomectomy
Laparoscopic myomectomy is achieved via laparoscopic
enucleation of the fibroid from the myometrium followed by
morcellation and removal of the fibroid with minimal extension
of the laparoscopic port site. The myometrium is then closed in
layers via laparoscopic suturing techniques. Because of the low
intraoperative complication rates (transfusion rates <0.2%,
visceral injury <0.04%), reduced postoperative febrile
morbidity, shorter recovery times and hospital stays and lower
rates of adhesion formation, at least in expert hands, the laparoscopic approach is in many centres replacing the traditional
laparotomy. Obstetric outcomes including time to pregnancy,
pregnancy rates and miscarriage rates are comparable to those
following laparoscopic myomectomy. Concerns have been
raised that rates of uterine rupture may be higher following
laparoscopic myomectomy, because of the difficulties achieving
multi-layer closure under tension. As with open myomectomy
uterine ruptures have been reported following laparoscopic
myomectomy. Risk factors for uterine rupture appear to be
breach of the endometrial cavity and the excessive use of
diathermy. Few studies have assessed the overall risk of uterine
rupture following laparoscopic myomectomy, however the
largest analysis of 145 pregnancies suggested a reassuringly low
rupture rate of 1%.
Although there appear to be many advantages of the laparoscopic approach, studies conducted so far have been undertaken in settings where there is great local expertise in
laparoscopic surgery, these outcomes may not therefore be
generalizable. Intraoperative risks and technical difficulties
with the laparoscopic technique increase with increasing size
and number of fibroids. Recurrence rates have also been reported as being higher (as high as 30%) following laparoscopic
myomectomy, higher than with the open approach, perhaps
because of reduced fibroid clearance, however others have
disputed this.
Most recently, laparoscopic myomectomy has attracted
negative attention due to concerns over possible seeding and
spread of malignancy following morcellation. Such has been the
concern that the FDA has discouraged the use of morcellation in
the treatment of uterine fibroids. In reality the prevalence of
cancer in those undergoing myomectomy is low (<0.2%) and
evidence suggests that there is no increase in sarcoma dissemination with power morcellation. However, knowing that risk of
sarcoma is increased in older women and in those whose fibroids
have grown rapidly, morcellation should perhaps be used with
caution in these groups. Women should be counselled about
these risks pre-operatively to aid decision-making. Techniques
such as undertaking morcellation within the retrieval bag may
further reduce the risk.

Hysterectomy
Hysterectomy offers definitive treatment of fibroid related
symptoms and guarantees no recurrence of disease, but at the
expense of future fertility and therefore can only be considered in
those women who have completed their family. Because of the
effect of the fibroid on uterine size, vaginal hysterectomy, which
carries the lowest risk of complications and fastest recovery time
will often not be possible, meaning an abdominal or laparoscopic
approach is necessary.

Summary
Ultimately the decision as to how to manage fibroids will depend
principally on presenting symptoms and a patients desire for
future fertility. As with the management of any condition it
seems sensible to start with conservative (medical) measures,
however for women with large fibroids and associated pressure
symptoms ultimately a radiological or surgical solution will be
necessary. Which technique is chosen will depend upon local
expertise as well as patient preference following a detailed discussion regarding risks and benefits.
A

Hysteroscopic myomectomy
Hysteroscopic myomectomy, first described in 1976, is the least
invasive option for the surgical removal of fibroids and can be
used to remove submucosal fibroids. Compared to laparoscopic
and open myomectomy the hysteroscopic approach has the

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Zhang Y, Sun L, Guo Y, et al. The impact of preoperative


gonadotropin-releasing hormone agonist treatment on women with
uterine broids: a meta-analysis. Obstet Gynecol Surv 2014; 69:
100e8.
UPDATED Laparoscopic Uterine Power Morcellation in Hysterectomy
and Myomectomy: FDA Safety Communication. November 2014,
www.fda.gov.

FURTHER READING
Donnez J, Hudecek R, Donnez O, et al. Efcacy and safety of repeated
use of ulipristal acetate in uterine broids. Fertil Steril 2015; 103:
519e27. e513.
zquez F, et al. Ulipristal acetate versus
Donnez J, Tomaszewski J, Va
leuprolide acetate for uterine broids. New Engl J Med 2012; 366:
421e32.
Donnez J, Vazquez F, Tomaszewski J, et al. Long-term treatment of
uterine broids with ulipristal acetate. Fertil Steril 2014; 101:
1565e73. e1561e1518.
Grigorieva V, Chen-Mok M, Tarasova M, Mikhailov A. Use of a
levonorgestrel-releasing intrauterine system to treat bleeding
related to uterine leiomyomas. Fertil Steril 2003; 79: 1194e8.
Gupta JK, Sinha A, Lumsden MA, Hickey M. Uterine artery embolization for symptomatic uterine broids. Cochrane Database Syst
Rev 2014. Issue. 12. Art. No.: CD005073.
Hehenkamp WJ, Volkers NA, Birnie E, Reekers JA, Ankum WM.
Symptomatic uterine broids: treatment with uterine artery embolization or hysterectomyeresults from the randomized clinical
Embolisation versus Hysterectomy (EMMY) Trial. Radiology 2008;
246: 823e32.
Jun F, Yamin L, Xinli X, et al. Uterine artery embolization versus surgery for symptomatic uterine broids: a randomized controlled trial
and a meta-analysis of the literature. Arch Gynecol Obstet 2012;
285: 1407e13.
Manyonda IT, Bratby M, Horst JS, Banu N, Gorti M, Belli AM.
Uterine artery embolization versus myomectomy: impact on quality
of lifeeresults of the FUME (Fibroids of the Uterus: myomectomy
versus Embolization) Trial. Cardiovasc Intervent Radiol 2012; 35:
530e6.
Wright JD, Tergas AI, Cui R, et al. Use of electric power morcellation
and prevalence of underlying cancer in women who undergo
myomectomy. JAMA Oncol 2015; 1: 69e77.

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:5

Practice points
C

132

Although uterine fibroids are common, the majority of women are


asymptomatic or experience mild symptoms, management may
therefore not be indicated.
Management may be indicated in those experiencing symptoms
including menorrhagia and pressure symptoms or those with
submucosal or intramural fibroids presenting in the fertility
setting.
The levonorgestrel containing intrauterine system (LNG-IUS) may
reduce menstrual blood loss in those women with small fibroids
but women should be aware of greater rates of expulsion and
fitting difficulties.
Selective progesterone receptor modulators provide an effective
short term alternative to surgery in those with menorrhagia and
pressure symptoms.
Uterine artery embolization provides effective symptomatic relief
and quicker recovery time in those wishing to avoid surgery,
however immediate post-procedural rates of pain are high and
women should be aware of the high rates of future reintervention.
Myomectomy provides an alternative for fibroid removal to hysterectomy in those women wishing to conserve their fertility. The
route of myomectomy (open, laparoscopic, hysteroscopic) will
depend on fibroid size, location, number, local expertise and
patient preference.

2016 Elsevier Ltd. All rights reserved.

ETHICS/EDUCATION

The role of bariatric


surgery on female
reproductive health

(2006) recommends that women with a BMI of more than 29 kg/


m2 should be advised that it would take longer for them to
conceive compared with women with normal BMI and that
assisted reproduction would be less successful.

Effect of obesity on pregnancy

Tahir Mahmood

Obesity is an independent risk factor for adverse obstetric outcomes and increased maternal and neonatal morbidity and
mortality. This is due to the increased risk of the following obstetric and neonatal problems:
 Congenital abnormalities (spina bifida and heart defects)
 Pre eclampsia
 Gestational diabetes
 Deep venous thrombosis
 Macrosomia
 Intrauterine foetal demise
 Induction of labour
 Infection related morbidity
 Difficult instrumental deliveries
 Caesarean section
 Postpartum haemorrhage

Omar Thanoon

Abstract
Obesity is now a critical global issue, as more than 2.1 billion people
(nearly 30% of the world population) are either overweight or obese.
It has been reported that , for every increase in body mass index of
5 kg/m2, there was a 30% overall higher mortality with a 40% increase
in vascular mortality, a >50% increase in diabetic, renal and hepatic
mortality. It has been proposed that all obese women should be
encouraged to normalise their weight before embarking on a pregnancy. The most recently published multi-centre study, The Upbeat
has concluded that a behavioural intervention addressing diet and
physical activity in women with obesity during pregnancy is not
adequate to prevent gestational diabetes, or to reduce the incidence
of large for gestational age infants. Therefore not surprisingly, there
is a huge public interest in bariatric surgery for managing morbid
obesity. However question arises whether weight loss by this route
does improve fertility potential of women without any adverse effects
on the pregnancy outcome?

What interventions can be used to improve outcomes?


Weight loss is usually modest with dieting, exercise, behavioural therapy and pharmacological interventions and weight
regain is very common. Cochrane review concluded that surgery results in greater improvement in weight loss outcomes
and weight associated comorbidities compared with nonsurgical interventions, regardless of the type of procedures
used. Bariatric surgery is therefore considered to be an effective
treatment for morbid obesity, defined as a BMI equal or more
than 40 kg/m2. Many studies have reported that weightreducing surgery is very effective in treating patients with
morbid obesity, with long-term excess weight loss of more than
60%. This is usually associated with improvement of associated
medical problems such as diabetes, hyperlipidaemia, hypertension and sleep apnoea.

Keywords body mass index; fertility; obesity; polycystic ovary


syndrome; pregnancy

Effect of obesity on fertility potential


Obesity is linked to pubertal menorrhagia and the all too common problem of polycystic ovarian syndrome leading to sub
fertility. Hyperandrogenism, hyperleptinaemia, increased levels
of luteinising hormone and insulin resistance play a pivotal role
throughout the reproductive age of obese women. Obesity per se
is an independent risk factor for anovulation related infertility, an
increased risk of early pregnancy loss and recurrent miscarriage.
Obesity is also associated with poor reproductive outcomes
regardless of the mode of conception; including natural conception, pregnancies achieved by ovulation induction, IVF-ICSI and
from ovum donation programme. It has been postulated that the
metabolic changes and inflammatory responses in obesity affect
the ovarian follicular microenvironments, and thus affects oocyte
quality.
NICEs Guidance on the Prevention, Assessment and Management of Overweight and Obesity in Adults and Children

Different types of bariatric surgery procedures


Bariatric procedures can be classified into three main groups:
1. Restrictive procedures include gastric bands and sleeve
gastrectomy,
2. Malabsorptive procedures include bilio-pancreatic diversion
and duodenal switch,
3. Combined procedures (restrictive and malabsorptive)such as
Roux en Y gastric bypass
Gastric bands involve placing a silicone band laparoscpically
around the fundus of the stomach to restrict food intake.
These bands are adjustable in order to control the size of the
stomach stoma and this can be done by injecting saline into
the inner shell of the band.
Sleeve gastrectomy can also be done laparoscpically and the
aim of the procedure is to reduce the size of the stomach by
25% by dividing the stomach vertically.
Bilio-pancreatic diversion is the least frequently used bariatric procedure and it involves performing a gastrectomy and

Tahir Mahmood MD FRCPI FRCPE FACOG FRCOG is a Consultant in


Obstetrics and Gynaecology at the Victoria Hospital, Kirkcaldy, UK.
Conicts of interest: none declared.
Omar Thanoon MRCOG is a Consultant in Obstetrics and Gynaecology
at the Victoria Hospital, Kirkcaldy, UK. Conicts of interest: none
declared.

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ETHICS/EDUCATION

to the rest of the population, and there was a higher caesarean


section rate in the bariatric surgery group.
A recent meta-analysis reported no difference in GDM between post bariatric surgery and control groups matched for
BMI. Multiple studies have reported a significant reduction in
pregnancy induced hypertension following bariatric surgery.
Several studies have found the risk of large for gestational age
infants lower (up to 50%) after bariatric surgery but the risk for
small for gestational infants higher (up to 80%). Women who
have had malabsorptive and combined bariatric procedures are
more likely to have foetal growth restriction and prematurity
compared to women who have had restrictive bariatric
procedures.
It has been recommended that women who have had bariatric
surgery should delay pregnancy until the initial weight loss phase
is over, and these patients should remain on lifelong vitamin
supplement. The American College of Obstetricians and Gynaecologists (ACOG) practice bulletin 105 advises that women who
have had bariatric surgery should wait 12e24 months before
getting pregnant.

also division of the small bowel resulting in a bilio pancreatic


limb and a gastro intestinal limb.
Roux en Y gastric bypass (RYGB) is the most commonly used
bariatric procedure; it is both restrictive and malabsorptive. It
involves creating a small gastric pouch and a gastroenterostomy
stoma that bypasses the duodenum.

Health economic benets of bariatric surgery


A recently published report by the Scottish government estimates
that by 2030, the total cost of obesity to Scottish society (direct
and indirect costs) could range from 0.9 billion to 3 billion per
annum.
The SIGN guideline has reviewed 43 studies in patients predominantly with a BMI of >35 kg/m2. The review reported that
following bariatric surgery, there was a weight loss among women
ranging between 52.5% and 77% and this weight loss was sustained at 10 years follow up following surgery in comparison with
diet alone. The observational studies also suggested that weight
loss through surgery is maintained. The RCT involving patients
with a BMI of 30e35 kg/m2 and obesity related co-morbidities, and
concluded that laparoscopic adjustable gastric banding resulted in
greater excess weight loss at 2 years compared with intensive diet,
lifestyle and medical therapy (82.7% versus 21.8%).
Three HTAs (The Canadian, New Zealand and the UK NIHR)
reported the cost per quality-adjusted life year (QALY) for bariatric surgery compared to non surgical interventions for obesity
to be within acceptable cost effectiveness thresholds and
concluded that bariatric surgery is cost effective.
Outcomes were similar between RYGB and sleeve gastrectomy, and both of these procedures had better outcomes than
adjustable gastric banding. For people with very high BMI, bilio
pancreatic diversion with duodenal switch resulted in greater
weight loss than RYGB.

Possible mechanisms of adverse effects of bariatric


surgery
It has been suggested that malabsorptive effects of sleeve and
bypass surgery may alter the absorption of oral contraceptive
medication, thereby reducing their efficacy. In most cases,
following malabsorptive types of surgery nutritional deficiencies, have been attributed to a number of near fatal/fatal
neonatal bleeding disorders due to vitamin K deficiency exacerbated by surgery. It is therefore recommended that pregnancy
be avoided during the acute weight loss phase as ketosis can
cause foetal abnormalities and patient should be advised to
maintain a healthy diet. It is important to remember that
following bariatric surgery, the mother is at increased risk of
internal hernia during pregnancy, as a loop of bowel can herniate through the defect created in the mesentery for a gastric
bypass procedure.

What is the evidence of clinical effectiveness of bariatric


surgery?
There are no randomized controlled trials comparing the effects
of bariatric surgery with conservative therapy in obese women
wishing to conceive. Most observational studies suggest a trend
to improved spontaneous pregnancy rates and most women who
achieved pregnancy had a weight loss of >5 kg/m2 independent
of the type of procedure. However the RCOG Scientific impact
paper number 17 points out that most of these studies lacked
power to establish any statistical significance. Bariatric surgery
has been shown to improve the levels of LH, FSH, luteal prenanediol, SHBG and GnRH but the levels of Mullerian-inhibiting
substance were noted to be lower in obese women.
There are conflicting data reported in two retrospective studies
as regards the effect of bariatric surgery on the risk of miscarriage;
one showed no change in the rate of miscarriage before and after
bariatric surgery, while the other one reported a reduction in the
rate of miscarriage following weight reducing surgery.
Data on obstetric outcomes from three matched cohort studies
reported a better maternal and neonatal outcome in women who
have had bariatric surgery compared to the obese women in the
control group. Whereas a large population based study reported
a similar rate of maternal and neonatal complication among
women who had bariatric surgery prior to pregnancy, compared

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:5

Conclusion
Obesity provides an imperfect environment for fertility and
pregnancy. Despite our current understanding of these abnormal
hormonal milieus, there is yet to find a perfect medical or surgical intervention to improve outcomes. The number of women
having bariatric surgery is increasing and these women should
consider the benefits and risks of surgery carefully before having
any surgical procedure.
The current available data does not support the use of bariatric surgery as a treatment method for obese women wanting to
improve their fertility and pregnancy outcome. To date there
seems to be no treatment superior to healthy weight loss through
lifestyle interventions.
A

FURTHER READING
Colquitt JL, Pickett K, Loveman E, Frampton GK. Surgery for weight
loss in adults. Cochrane Database Syst Rev 2014 Aug 8; 8. http://
dx.doi.org/10.1002/14651858.CD003641.pub4. CD003641.

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ETHICS/EDUCATION

Poston L, Bell R, Croker H, et al. Effect of a behavioural intervention in


obese pregnant women (the UPBEAT study): a multicentre, randomised controlled trial. Lancet Diabetes Endocrinol 2015; http://dx.
doi.org/10.1016/s2213-8587(15)00227-2.
Scottish Intercollegiate Guidelines Network. Management of obesity.
SIGN 115. 2010, www.sign.ac.uk/pdf/sign115.pdf.

Mahmood T, Arulkumaran S. Obesity-A ticking time bomb for reproductive health. First edn. Elsevier insight, ISBN 978-0-12-4160453; 2013.
Owers CE, Ackroyd R. In: Metwally M, Li TC, eds. Bariatric surgery (in)
reproductive surgery in assisted conception. London: SpringerVerlag, 2015; 143e50.

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Thyroid disorders and


other endocrine disorders
in pregnancy

conceive or maintain pregnancy leads to the diagnosis as anovulation and, potentially, miscarriage can be a symptom of thyroid
disease. However, if thyroid dysfunction has not been recognised
prior to conception, establishing the diagnosis during pregnancy
can be problematic as many of the symptoms of thyroid
dysfunction are comparable to those of normal pregnancy. It is
therefore important to have an overview of the physiology of the
thyroid, its impact on reproductive health and how it changes in
pregnancy.

Anja Johansen-Bibby
Joanna Girling

Thyroid physiology
The thyroid gland is controlled from the hypothalamus, which
produces thyrotropin-releasing hormone (TRH). This polypeptide stimulates thyrotroph cells in the anterior pituitary gland
to produce thyroid stimulating hormone (TSH). This glycoprotein hormone, consisting of two alpha and two beta subunits, is
released into the blood to bind to the TSH receptor on the thyroid
gland, stimulating the production of T3 and T4 from thyroglobulin and iodine. T3 and T4 use a negative feedback loop to balance production of TRH and TSH, and this stepwise production
of hormones is modulated by somatostatin, glucocorticoids as
well as excess iodine. In early pregnancy, there is conflict between TSH and the homologous human chorionic gonadotrophin
(HCG) produced by the developing placental tissue, as the alpha
sub-units are identical. HCG can stimulate TSH receptors, (much
less potently than TSH) on the thyroid gland, leading to a decline
in the production of TSH in some women, and in a smaller subset
to a biochemical picture of hyperthyroidism with elevated T4 of
women [see later, gestational thyrotoxicosis].
Normative reference ranges in cohorts of healthy pregnant
women without thyroid disease indicate that the upper limit of
normal for TSH in uncomplicated pregnancy may be higher than
outside pregnancy, and these limits may vary according to the
laboratory technique or the demographics of the population:
ideally local gestation-specific reference ranges should be used.
These changes are of importance when interpreting blood results
of pregnant women, as the reference range throughout pregnancy differs from non-pregnant women (see Table 1). Table 1
also shows a typical reference range in a multiethnic UK
population.
Maternal iodine requirements increase (by as much as 50%)
as iodine is actively transported to the developing fetus and the
maternal thyroid upregulates to absorb more iodine to allow the
total T3 and T4 production to rise. High oestrogen concentrations
extend the half-life of plasma proteins including thyroxine
binding globulin (TBG), such that the concentration increases at
least 1.5 fold by week 8 of pregnancy, and remains at this higher
level until delivery. Thus where women have a good supply of
iodine, total T4 and T3 concentrations are increased, but the
biologically-active free T3 and free T4 stay relatively stable
throughout pregnancy. In areas where women have mild iodine
deficiency, pregnancy-induced goitre can occur, together with
relative hypothyroidism due to the limitation of T4/T3 production; this can impact upon the development of the fetus.
Iodine deficiency is the commonest cause of hypothyroidism
worldwide. The WHO states that iodine deficiency is the single
most important preventable form of brain damage in children,
now referred to as neonatal cretinism. Severe iodine deficiency
also plays a role in increased perinatal mortality. This has led to

Abstract
The number of women with endocrine conditions embarking on pregnancy is growing as more choose to delay conception or require assisted reproduction techniques. It is therefore increasingly important for
clinicians to have an understanding of common endocrine disorders
and how these may impact on pregnancy and fetal development.
Over-investigation and subsequent medicalization and treatment of
sub-clinical endocrine conditions, which have uncertain clinical impact
for the fetus or mother, is a cause for concern and debate surrounding
this practice is ongoing. Vitamin D deciency is increasing in prominence due to the rise in childhood rickets; this startling reemergence has led to more work on the prevalence of vitamin D deciency and identied a higher than expected percentage of women
affected. For this reason, national advice has called for routine vitamin
D supplementation in pregnancy, and diagnosis and treatment of
those most at risk. This review also briey discusses the management
of other rarer endocrine conditions, which can lead to signicant
maternal and fetal morbidity if the diagnosis is delayed or overlooked.

Keywords Addisons disease; congenital adrenal hyperplasia;


Conns syndrome; diabetes insipidus; hypopituitarism; parathyroid;
phaeochromocytoma; pituitary adenoma; thyroid disease; vitamin D

Thyroid disease
The maternal thyroid gland is responsible for both fetal and
maternal production of thyroxine (T4) and tri-iodiothyronine
(T3) until the fetal thyroid starts functioning at the end of the
first trimester. Until then, there is good evidence that inadequate
or excessive maternal T4 can have serious long term effects on
fetal development, which can translate into cognitive neurodevelopmental problems for the child.
As thyroid disorders are common, the incidence being up to
3% of women of child-bearing age, many pregnancies will be
complicated by thyroid dysfunction. The vast majority of these
women will have a formal diagnosis prior to pregnancy, and
should be taking appropriate treatment to ensure they are
euthyroid before embarking on pregnancy. In some, inability to

Anja Johansen-Bibby BA(Hons) MRCOG is a Specialist Registrar in


Obstetrics and Gynaecology, currently working as a Clinical Teaching
Fellow at St Marys Hospital, Imperial NHS Trust, London, UK.
Conicts of interest: none declared.
Joanna Girling MA MRCP FRCOG is a Consultant Obstetrician and
Gynaecologist at the West Middlesex University Hospital, Isleworth,
UK. Conicts of interest: none declared.

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Changes in thyroid function in pregnancy


Thyroid function tests (TFT)

Non pregnant

First trimester

Second trimester

Third trimester

FT4 pmol/l
FT3 pmol/l
TSH mu/l
TSH mu/l (Endocrine Ass)
TSH mu/l (European Thyroid Ass)

9e26
2.6e5.7
0.3e4.2

10e16
3e7
0e5.5
0.1e2.5
0.1e2.5

9e15.5
3e5.5
0.5e3.5
0.2e3.0
0.1e3.0

8e14.5
2.5e5.5
0.5e4
0.3e3.0
0.2e3.5

While the literature is useful in identifying antenatal trends in thyroid parameters, the reference ranges cited are to be used as a guide to clinical practice and not an
absolute. Reference ranges may vary depending on the laboratory method used to assay the hormones. FT4 and FT3 (Cotzias C et al. Eur J Obstet Gynecol Reprod Biol.
2008 137(1):61e6).

Table 1

programmes to administer annual boluses of iodine to susceptible women and to national salt, water and flour iodinisation. The
UK population is relatively iodine replete, with dairy and fish
being the main dietary sources, and currently there is no official
UK Government advice to take an iodine supplement prior to or
during pregnancy, although, iodine requirements are 250 micrograms per day for pregnant and lactating women, compared
with 150 micrograms for non-pregnant women.

offspring of women with very high TSH, and others suggest a role
in neurocognitive problems such as attention deficit disorder.
However, there is no convincing evidence of adverse fetal effects
when maternal TSH is within the pregnancy-specific reference
range. Therefore, the ideal for hypothyroid women is to ensure
adequate thyroxine replacement at least 3 months before
conception, to avoid the potential adverse effects of untreated or
under-treated hypothyroidism on the conceptus.
Although rarely seen in the UK, overt symptomatic untreated
hypothyroidism is also associated with an increase in miscarriage, gestational hypertension, preterm delivery, post-partum
haemorrhage together with fetal growth restriction. There has
also been a suggestion that hypothyroidism is associated with
gestational diabetes mellitus, with almost double the number of
women on levothyroxine replacement having this diagnosis
compared with background population.
There are several schools of thought regarding the need for
women with autoimmune hypothyroidism to increase thyroxine
replacement dose during pregnancy. The American Thyroid
Association (ATA) has advocated an empirical increase in levothyroxine at the diagnosis of pregnancy by 25% with the aim
of an upper limit of TSH at 2.5 mU/L. The British Thyroid Association propose an increase of 25e50 micrograms at the
beginning of pregnancy to ensure TSH levels are maintained
within the normal range, and free T4 are in the upper range of
normal. Neither group provide robust evidence to support these
statements. Observational data suggest that women with preconception TSH less than 1.2 mU/L do not require any increase
in thyroxine replacement, but no indication that this is required
for optimal outcome. Others argue that changes in thyroxine
replacement should be guided by pregnancy-specific reference
ranges. There are many reasons for these differing opinions,
and it is important to recall the gestation at which hypothyroidism could have a direct fetal effect, and that the important
end point of neurocognitive function in the offspring is dependent on many different variables; no studies of sufficient size
have prospectively addressed the impact of first trimester
maternal TSH nor shown whether altering thyroxine dose to
achieve a predetermined low TSH is beneficial [or harmful] to
the fetus [or mother]. In addition, there is some evidence that,
at least theoretically, excess circulating T4, as may result from
empirical increases in thyroxine dose, may be associated with
miscarriage.

Hypothyroidism
Overt hypothyroidism [high TSH, low fT4] affects approximately
20,000 pregnant women a year in the UK. Most of these women
have a diagnosis prior to pregnancy, and should aim to conceive
when they are euthyroid taking levothyroxine replacement.
Some women will enter pregnancy on an inadequate dose of
thyroxine, and these women should have their thyroxine dose
adjusted according to pregnancy-specific reference ranges. There
is ongoing discussion about whether thyroxine replacement
should be increased empirically during pregnancy; the evidence
for this appears to depend on the reason underlying the hypothyroid status.
The majority of women have an underlying diagnosis of
Hashimotos thyroiditis, an autoimmune condition where the
thyroid gland is damaged by auto-antibodies to thyroid peroxidase or thyroglobulin. This condition often co-exists with other
auto-immune diseases, particularly Type I diabetes mellitus,
rheumatoid arthritis and systemic lupus erythematosus, which
may be of greater importance to the mother and fetus than the
thyroid dysfunction itself. Other women are hypothyroid
following surgical thyroidectomy for treatment of malignancy,
goitre or thyrotoxicosis, or following radio-active iodine treatment. These women with total thyroidectomy have no ability to
produce thyroxine and are more likely to need an increasing dose
of levothyroxine replacement throughout pregnancy, as they
have no residual thyroid to enable any production; this is
particularly so when complete TSH suppression is required as
part of the management of thyroid cancer.
Fetal brain development relies on maternal supply of
thyroxine and iodine [as TSH and fT3 cannot cross the placenta]
until the fetal thyroid becomes functional, around 12e16 weeks
of gestation. Before this gestation, impairment in neurocognitive
development can occur without adequate thyroxine replacement.
Some studies have demonstrated a reduction in IQ score in the

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We recommend that all healthcare professionals involved in


the management of hypothyroidism ensure that women of
reproductive age know that thyroxine is safe to take in pregnancy
and lactation, that it should not be taken within 4 hours of iron or
calcium supplements [which may reduce absorption] and that
optimal control with thyroid function tests within reference range
should be achieved before contraception is discontinued. If this
guidance is followed, reduced thyroxine absorption due to nausea
and vomiting in the first trimester is minimized, and first trimester
thyroid function tests [TFT] at booking are still within pregnancyspecific range; in this situation, no changes in thyroxine dose are
needed, no additional antenatal care is required, and women can
have midwifery led care, with TFT measurement with late 2nd
trimester routine blood samples [at which gestation, maternal
thyroid hormones do not cross the placenta and do not directly
affect fetal wellbeing]. If thyroxine dose increments have been
initiated because of the pregnancy and not because of suboptimal
control prior to conception, then the pre-pregnancy dose should
be resumed around 2 weeks postpartum. It is good practice to aim
to check TFT at 6 weeks postpartum, not least because symptoms
of inadvertent undertreatment may be particularly hard to
tolerate when caring for an infant.
Further controversy exists surrounding the management of
women who have subclinical hypothyroidism [high TSH, normal
T4], possibly reflecting early auto-immune destruction of the
thyroid gland, which may become clinically apparent in the
future. If universal thyroid function testing were introduced, up
to 3.5% of pregnant women would be diagnosed with subclinical
hypothyroidism using local pregnancy-specific TSH limits, or
28% in some populations if a TSH threshold of 2.5 mU/L is
applied. However, there is evidence from a prospective randomized trial that diagnosis and treatment of subclinical hypothyroidism following universal testing of thyroid function at the
end of the first trimester does not improve childhood neurocognitive outcome [NEJM Lazarus 2012]. A recent Cochrane review concluded that whilst universal testing does identify more
women with subclinical hypothyroidism, there is insufficient
evidence that treatment improves maternal, fetal, neonatal or
childhood outcomes. The American College of Obstetrics and
Gynaecology advises against treatment of subclinical hypothyroidism in pregnancy due to a lack of benefit and that universal
testing should not be introduced. The Endocrine Society does
recommend treatment [evidence categorised as fair or poor] for
those women found to have subclinical hypothyroidism in early
pregnancy, using TSH of 2.5 mU/L. However, we consider that
there is insufficient evidence to support treatment of women with
subclinical hypothyroidism whose TSH falls within the
pregnancy-specific reference range and do not recommend it; for
women whose TSH is above the range there is still little evidence
of harm or that thyroxine therapy improves outcome so whilst
some experts suggest thyroxine therapy with monitoring to
ensure avoidance of iatrogenic thyrotoxicosis, we would again
suggest caution and careful discussion before embarking on this
course [particularly beyond the first trimester when fetal benefits
are even more improbable].
There is some evidence that thyroid autoantibodies found in
up to 15% of women of child-bearing age may play a role in
miscarriage or premature delivery, possibly by inhibiting HCG
binding on the corpus luteum, or as markers which correlate

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with adverse outcomes. Currently two double blind randomized


controlled studies, TABLET and T4-LIFE are investigating
whether low dose thyroxine may improve pregnancy outcome in
euthyroid women with thyroid autoantibodies and a history of
one or at least two [respectively] miscarriages. Until these results
are available, there is no place for testing or treating women at
risk of miscarriage for thyroid autoantibodies.
Hyperthyroidism
Overt hyperthyroidism is less common than hypothyroidism,
affecting up to 0.5% pregnancies. Similar to hypothyroidism,
most cases are known prior to pregnancy and making a new
diagnosis of hyperthyroidism during pregnancy is difficult
without a high degree of suspicion since the non-specific symptoms of hyperthyroidism [such as amenorrhoea, heat intolerance, anxiety, tachycardia] are common in normal pregnancy.
Overt hyperthyroidism is defined as a serum TSH below the
trimester e specific level, with an elevated T3 or T4. After
gestational thyrotoxicosis (see below), the most common cause
of hyperthyroidism is Graves disease, an auto-immune condition
which, like many other auto-immune conditions, improves in
pregnancy allowing a reduction in dose of medication. Other
causes include iatrogenic over-treatment of hypothyroidism,
toxic nodule(s) and de Quervains thyroiditis, which is associated
with an acute viral illness. These are generally rare in pregnancy.
Uncontrolled hyperthyroidism is associated with adverse
maternal and fetal outcomes, including miscarriage, preeclampsia, prematurity and fetal growth restriction, and if severe, a thyroid storm with severe maternal left ventricular
dysfunction and heart failure.
Subclinical hyperthyroidism, [low TSH normal T3 and T4] is
not considered of clinical importance in pregnancy and in the
absence of any previous thyroid condition does not need
treatment.
Gestational thyrotoxicosis
This is the most common cause of biochemical hyperthyroidism
in the first trimester, and occurs in up to 45% of cases of
hyperemesis gravidarum [HG]. This condition is associated with
very high levels of HCG seen in the first trimester; the identical
alpha sub-units of TSH and HCG mean that the HCG can bind to
the TSH receptor on the thyroid, stimulating T3 and T4 release
and suppressing TSH production. This is typically seen in situations where HCG is highest, for example molar or multiple
pregnancies. Symptoms of hyperemesis, whilst similar to thyrotoxicosis (including severe vomiting, associated with dehydration, and weight loss), are a consequence of pregnancy
hormones, rather than thyroid dysfunction and therefore no antithyroid medication is required. The symptoms tend to subside
with the decrease of HCG towards the second trimester. Women
with HG should always have thyroid function measured as part
of a full workup, and if biochemical hyperthyroidism is present,
the history and examination should be repeated to ensure that
undiagnosed Graves disease has not been overlooked: a history
of symptoms antedating conception or of previous thyrotoxicosis, presence of goitre, thyroid eye disease [such as exophthalmos, proptosis, lid lag or retraction] or pre-tibial myxedema
make Graves disease more likely and testing for TSH receptor
antibodies should be carried out.

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pregnancy progresses, the dose of medication can be reduced and


some can discontinue their medication in the third trimester.
All anti-thyroid medications cross the placenta and can suppress fetal thyroid function, however they rarely causes fetal
hypothyroidism, not least because of the stimulatory effect of
maternally-derived TRAbs. Indeed, in women who are off
medication and euthyroid [following previous radioactive iodine
or thyroid surgery] TSH- receptor stimulating antibodies can
persist, and especially if the titre is high, can cause fetal thyrotoxicosis, with potential for fetal tachycardia, intrauterine growth
restriction or fetal goitre [possibly with associated polyhydramnios due to neck compression, or head extension and
associated delivery difficulties]. Most units advocate that women
with high titres should have an ultrasound to assess for growth
restriction and the presence of goitre, and the fetal heart rate
should be recorded each visit, with further ultrasonography if
fetal tachycardia becomes evident. The paediatricians should be
made aware of any mothers with TRAbs as there is a small
chance of neonatal hyperthyroidism. This often presents after
discharge from hospital as the maternal antibodies persist in the
neonates circulation longer than the anti-thyroid medication and
therefore families should also be warned to look out for signs of
failure to thrive and irritability.

Graves disease
This is the most common cause of hyperthyroidism in pregnant
women. Graves disease is an auto-immune condition characterised by suppressed TSH, high T4/T3 and the presence of TSH
receptor stimulating antibodies (TRAb). During pregnancy, disease control is usually achieved by using medication to block
thyroid hormone synthesis, such as propylthiouracil (PTU),
carbimazole (CBZ) and in the US methimazole, combined with
beta-blockers, if required, for symptomatic relief. It can be
particularly active in the first trimester due to the stimulatory
effect of HCG which can often worsen symptoms; this is often
followed by an improvement as the immunomodulating effects of
pregnancy result in a lower titre of TRAb, and medication can
often be discontinued. Total or partial thyroidectomy can be
carried out in pregnancy, usually the second trimester, but is
mainly reserved for women intolerant of or resistant to oral
medication, with goitre compromising the airway or when malignancy is suspected. Radio-active iodine is contraindicated in
pregnancy, as it would render the fetus athyrotic; if required it
should occur at least six months before conception; if considered
in the postnatal period, careful counselling is needed as it will
require a period of separation of mother and baby after administration of the radioactive medicine, and a longer period of
abstinence from breastfeeding.
It is essential for maternal and fetal wellbeing that optimal
control of thyrotoxicosis is maintained, with the lowest effective
dose of medication. Abrupt or inappropriate cessation of therapy is likely to result in a worse outcome than its continuation.
Both PTU and CBZ are associated with mild maternal side effects, and a small chance of agranulocytosis. Carbimazole is
associated with an embryopathy in less than 2% of exposed
infants, which may include feature such as aplasia cutis, choanal atresia, trachea-oesophagael fistula, facial dymorphism and
cognitive development delay, and thus PTU may be preferred in
the first trimester since the link with congenital anomalies
seems weaker. However, PTU can cause hepatotoxicity, and
cases of maternal fulminating hepatotoxicity associated with
PTU in late pregnancy have occurred. Due to these potential
repercussions, some consider that conceiving on PTU and
changing to CBZ from the 2nd trimester onwards is optimal.
Changing medication risks new maternal symptoms, however,
with possible loss of thyroid control and fetal exposure to two
medications. In addition, not all pregnancies are planned, and if
conception (and therefore fetal exposure) has occurred on CBZ,
there may be an argument for continuing this therapy. These
issues should be discussed with the woman, ideally when
medical management of hyperthyroidism is first initiated, and
an individual plan made. Conception should be deferred at least
until biochemical euthyroidism is well established; women who
conceive when control is poor are more likely to have an
adverse pregnancy outcome than those whose condition is well
controlled by antithyroid medication.
The medication dosage should be the lowest possible to
ensure that free T4 level remains at the upper end of the
pregnancy-specific normal range. TSH levels change more
slowly, and may not reflect current thyroid status, so are not
used for medication titration. Women on anti-thyroid medication
should have their thyroid function checked every 6 weeks after a
change of medication, and each trimester if stable. As the

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Vitamin D deciency in pregnancy


Traditionally, vitamin D has been associated with bone health
and calcium homeostasis, however, numerous studies are now
detailing the myriad of other areas where vitamin D appears to
play a role. There has been much interest in the immunomodulatory role of vitamin D, together with its potential to influence
cell proliferation and differentiation in many organs including the
brain, pancreas and heart. In pregnancy, there has been some
controversy surrounding what constitutes a normal level of
vitamin D, with the Endocrine Society suggesting a level of over
75 nmol/L, and the Institute of Medicine initially proposing 50
nmol/L. Despite this debate, it is still recognised that both
vitamin D deficiency (VDD) [<25 nmol/l] and vitamin D insufficiency [25e50 nmol/l] in pregnancy are widespread within the
UK, with up to 15% being deficient and up to 50% with insufficiency. Dark-skinned women, teenagers, women with BMI over
30 [due to loss of VD into adipose tissue], housebound women,
women taking anti-epileptic medication or with renal or liver
dysfunction and those who adopt a completely covered dress
style are particularly at risk. In one study 64% of Middle Eastern
women were found to be deficient.
The major source of vitamin D is the endogenous synthesis of
cholecalciferol from a precursor in the skin under the influence of
sunlight, with only 10% being from diet. Since 2008, NICE have
recommended all pregnant women take a vitamin D supplement
of 10 mg/day (400 IU), and the RCOG have recently published a
recommendation for high risk women to take up to 1000 IU/day;
the Endocrine Society advise to 2000 IU/day particularly in
populations where VDD is prevalent. Treatment of diagnosed
VDD [level <25 nmol/l] is usually with oral supplements of
20,000 IU every 3 days for 2 months. As universal screening for
VDD is currently not recommended, some women will be inadequately treated with the routine 400 IU/day. There is a theoretical risk of over-dosing on vitamin D with concern regarding

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The parathyroid glands secrete parathyroid hormone in


response to low calcium levels to maintain calcium homeostasis.
In pregnancy, however, calcium levels are already lowered by
combination of hypoalbuminaemia and increased renal clearance, as well as placental transfer to the fetus. This means that
the clinical hypercalcaemia due to hyperparathyroidism only
occurs in pregnancy in severe cases; in other cases with mild
hypercalcaemia, clinically significant effects are unlikely and so
the diagnosis may not be made until after pregnancy.
Symptoms of elevated calcium include vomiting, muscle
weakness, fatigue, all of which may be attributed to normal
pregnancy. When the calcium level is severely elevated, this can
lead to renal stones, pancreatitis, cardiac arrhythmia and hypertension. Measurement of serum calcium should be considered
in women with these symptoms. Mildly raised calcium levels are
unlikely to have any significant effects on fetal development and
pregnancy outcomes, although there has been conflicting evidence whether primary hyperparathyroidism leads to increased
miscarriage. Poor outcomes are most likely with higher calcium
levels: including development of hypertension and or preeclampsia and for the fetus, reciprocal fetal growth restriction,
and potential neonatal hypoparathyroidism with hypocalcaemic
tetany.
The mainstay of treatment is surgical removal of the parathyroid adenoma or parathyroidectomy in hyperplasia or carcinoma, usually reserved for severe cases and carried out in the
second trimester. The majority of cases in pregnancy respond to
a low calcium diet and good hydration.

maternal hypercalcaemia and hypercalciuria, however, some


studies have used up to 10,000 IU/day achieving a serum 25(OH)
D over 80 nmol/L, without any evidence of toxicity.
Two active forms of vitamin D exist, calciferol (ergocalciferol), obtained from plants, and cholecalciferol from animal
products. Vitamin D is hydroxylated twice to form the active
compound, first in the liver and then the kidneys. The parathyroid, calcium and phosphate levels combine to regulate the
hydroxylation process to ensure tight control of the maternal
calcium level.
The re-appearance of rickets in children and a surge in cases
of osteomalacia have focused more attention on VDD in pregnancy. Severe VDD can lead to multiple adverse effects in pregnancy for mother and fetus, and some of these translate in
neonatal effects. Studies initially demonstrated VDD affecting
bone health with the appearance of neonatal rickets and neonatal
craniotabes (a softening of fetal bones), however, hypocalcaemic
tetany and fitting has also been reported as well as osteomalacia
in pregnant women. Continuing from this, studies are now
demonstrating that the role of vitamin D is much wider than
initially anticipated and that VDD is associated with many conditions of pregnancy. There is literature available detailing the
association [but not necessarily causality] of low vitamin D with
development of impaired glucose tolerance, suggesting that those
with VDD are at higher risk of gestational diabetes mellitus.
There is now widespread agreement that VDD can affect the
development of pre-eclampsia, although not all studies have
confirmed a causative link. The RCOG advocates that those
women at high risk of pre-eclampsia should receive a supplementation of at least 800 IU/day throughout pregnancy with
calcium. In association with pre-eclampsia comes evidence that
VDD is associated with lower birth weights, and fetal growth
restriction, with some studies reporting reduced fetal bone
growth in pregnancy if women are vitamin D deficient. There
have also been discussions regarding increase risk of premature
labour, and bacterial vaginosis. Those women severely deficient
are more likely to have anaemia and deliver by Caesarean section; the explanations for this at the moment are speculative.
With many conditions, the in utero environment impacts on
neonatal and childhood growth and has implications in adult
health. Children whose mother had VDD appear more likely to
develop eczema, and lower respiratory tract infections with
associated wheeze. Those neonates who suffer from hypocalcaemia at birth have been found to be at increased risk of poor
bone growth as children and osteoporotic fracture later in life.
With this rationale, vitamin D deficiency should be corrected
prior to conception or supplementation should start as early as
possible in pregnancy, and only cease once the deficiency is
completely treated and breastfeeding is complete. For many
women, supplementation may need to be long-term if the risk
factors for VDD are permanent.

Hypoparathyroidism
The low calcium status of women with hypoparathyroidism can
have significant effects on pregnancy and fetal development.
Women can develop muscle cramps, paraesthesia and seizures if
untreated, with a reduction in fetal growth occurring due to poor
bone development, and increased likelihood of developing
rickets. These situations, however, are rare in pregnancy, as
most women who have had thyroid surgery, the most common
cause of hypoparathyroidism, have been fully informed of the
need for calcium and vitamin D supplementation. Serum calcium
can be measured through pregnancy to ensure sufficient supplementation and it is rare for this to become a problem in
pregnancy.

Pituitary disorders
The pituitary gland orchestrates many hormonal axes within the
body, the majority of which are activated and functional during
pregnancy. The notable exception is the gonadotrophin axis
(hypothalmic e pituitary- ovarian axis) which is inhibited due to
the high levels of oestrogen and progesterone. Due to the
increased production of mainly prolactin from the anterior pituitary lactotrophs, the pituitary gland increases in size by up to
three fold secondary to hyperplasia as well as hypertrophy. Some
pituitary-like hormones are also produced by the placenta,
namely adrenocorticotrophin (ACTH) and growth hormone
(GH); despite increased pituitary production, the placenta supports pituitary production to ensure the necessary levels of
cortisol are achieved.

Parathyroid dysfunction
Primary hyperparathyroidism
Primary hyperparathyroidism is a common endocrine condition in
adults, however, is uncommonly seen in pregnancy and due to the
changes of pregnancy, rarely causes significant complications.

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Prolactinomas
Prolactinomas are the most common benign pituitary adenomas
in pregnancy, and have usually been diagnosed and treated prior
to conception. Outside of pregnancy, symptoms commonly
include amenorrhoea, anovulation, galactorrhoea and infertility.
Prolactin secretion is under negative feedback control from
dopamine, and hence the dopamine agonists bromocryptine and
more recently cabergoline form the mainstay of management
outside pregnancy. Management during pregnancy depends on
the size of the adenoma; micro adenomas less than 10 mm in size
rarely causing a problem, whereas those which are greater than
10 mm [macroprolactinoma] may require more careful
management.

Acromegaly
Oversecretion of growth hormone from pituitary somatotrophs is
rarely encountered in pregnancy, as most women with acromegaly do not ovulate. 40% also present with hyperprolactinaemia, with or without a macroadenoma. Concerns are
similar to those with prolactinomas regarding growth of the adenoma and pressure on the optic chiasm. Other co-morbidities of
acromegaly, such as high blood pressure, insulin resistance or
diabetes mellitus and cardiac disease can also impact pregnancy
and these must be optimised prior to conception.
Treatment of acromegaly is primarily surgical, however, some
women require medical treatment with a dopamine agonist, somatostatin receptor ligands (such as octreotide) and the new
growth hormone receptor antagonist, pegvisomant. Women
considering pregnancy who have not had surgery should ideally
discuss their management options before conception. There are
some reassuring safety data emerging regarding pegvisomant use
in pregnancy, and it is in FDA category B [no risk identified from
animal studies; no adequate data in humans], however, this is
not recommended unless absolutely necessary, and is usually
discontinued prior to pregnancy or at conception; short acting
octreotide can be used if required.
Women can be reassured that acromegaly appears not to
affect the developing fetus. They should have serial visual fields
testing in pregnancy, and education regarding potential symptoms as well as be considered at high risk of developing gestational diabetes. If symptoms deteriorate an MRI is required to
assess tumour expansion; growth hormone or insulin-like growth
factor-1 levels are not helpful in pregnancy. Medical treatment
may need to be reinstated.

Microprolactinomas
Only 3% of women with a microadenoma will experience
symptomatic enlargement of their adenoma during pregnancy,
mainly consisting of headaches, and visual disturbances secondary to the adenoma encroaching on the optic chiasm. Due to
this low incidence, women usually stop dopamine agonist
medication when they confirm pregnancy. Women need to be
educated to seek advice should they develop symptoms, and
visual fields should be formally tested every trimester, ideally
with a pre-pregnancy baseline. Prolactin levels should not be
measured, as they are elevated during normal pregnancy and
therefore are not useful for management, however, women
should have testing after delivery or after cessation of breastfeeding. Should prolonged periods of breastfeeding be desired, an
MRI should be considered to ensure no significant enlargement
of the prolactinoma. Interestingly, in up to 65% of women with
microprolactinomas, remission occurs after pregnancy; although
the mechanism is unknown, auto-infarction of the tumour has
been proposed.

Cushings syndrome
The classical Cushings disease is caused by a pituitary adenoma
leading to excessive adrenal production of cortisol, however, the
eponym Cushings syndrome is used for any condition leading to
hypercortisolaemia. The condition itself leads to sub fertility and
therefore is rarely encountered in pregnancy, however, when
seen, 40e50% are due to an adrenal adenoma, 15% due to adrenal carcinoma and the remaining from a pituitary adenoma. In
normal pregnancy, ACTH levels significantly increase which
contributes to normal physiological changes of weight gain,
water and salt retention and striae; other symptoms of impaired
glucose tolerance, and high blood pressure can also be attributed
to pregnancy and an alternative diagnosis may not be sought.
Thus diagnosing Cushings syndrome presenting for the first time
in pregnancy can be a significant challenge. High dose dexamethasone suppression test, or loss of circadian variation in
salivary cortisol can be diagnostically helpful, but imaging,
initially ultrasound of the adrenals and then MRI of both the
adrenal and pituitary are required. A multidisciplinary approach
is essential.
A state of excessive hypercortisolaemia has significant
impact on maternal and fetal wellbeing. Pregnancies complicated by this condition have a high chance (70%) of hypertension, together with pre-eclampsia in up to 15%, gestational
diabetes (up to 25%), and a risk of cardiac failure if untreated.
There is increased risk of premature delivery with the subsequent neonatal morbidity, due to the high cortisol levels triggering labour, and resultant hypocortisolaemia in the neonate.

Macroprolactinomas
These are less common than microadenomas, but are more likely
to have a significant impact on management in pregnancy.
Symptomatic enlargement is reported in up to 30% of pregnant
women with macroprolactinoma. The ideal is to have an MRI
prior to commencing pregnancy, to determine the extent of the
adenoma and whether definitive treatment with transphenoidal
surgery or radiotherapy should be pursued prior to pregnancy,
although with careful discussion regarding the potential for hypopituitarism and implications of this as a consequence of
treatment. For those with a large tumour which abuts the optic
chiasm, a dopamine agonist should be continued throughout
pregnancy and if this fails to stop enlargement, surgical treatment
may be needed in the second trimester. For those with a
macroadenoma which is not encroaching the chiasm, discontinuation of dopamine agonist can be considered, however,
formal visual field testing is needed each trimester, and should
any symptoms occur, an MRI performed and cabergoline restarted. Similarly to microprolactinomas, prolactin measurements are unhelpful during pregnancy and not required.
Cabergoline is not licensed in pregnancy, however it has a
good safety profile and minimal adverse side effects. Long term
use (over 1 year) has been associated with heart valve fibrosis
and surveillance with echocardiography is advisable if long term
treatment is being considered.

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There is also a higher risk of fetal growth restriction and intrauterine death. Outside of pregnancy, surgical treatment is the
first line option, and if possible this could take place in the
second trimester, or delivery should be considered if the fetus is
sufficiently mature. In pregnancy there is limited experience of
using metyrapone to block cortisol production, although there
have been reports of an increase in hypertensive related
morbidity.

Diabetes insipidus (DI)


This is a rare condition leading to polyuria and polydipsia with
subsequent dehydration if water deprived; it can, most
commonly, be from the reduced production of anti-diuretic
hormone (ADH, vasopressin) from the hypothalamus, released
by the posterior pituitary (cranial diabetes insipidus) or a genetic
condition where the kidney is insensitive to ADH, nephrogenic
diabetes insipidus. The incidence of affected pregnancies is
around 1 in 30,000. Reports of transient DI have described in
pregnancy, gestational DI, as a consequence of placental production of vasopressinase and in cases of severe pre-eclampsia,
acute fatty liver and HELLP syndrome (Haemolysis, Elevated
liver function, Low Platelets). These cases, unlike other forms of
DI, usually resolve after delivery and do not need formal treatment other than strict fluid balance.
For those women with underlying DI, the treatment consists
of replacement with desmopressin, delivered either orally, sublingually or by nasal spray; the dose of which may need to be
increased due to the normal action of placental vasopressinase
and increased renal filtration. Women often monitor their condition by observing water intake and urine output.
Some women will have subclinical DI unmasked by pregnancy. The condition is difficult to diagnose during pregnancy, as
the water deprivation test, which monitors the increase in serum
osmolality due to developing dehydration and associated failure
to increase urine osmolality, is considered inappropriate in
pregnancy. Most clinicians would consider treating with desmopressin empirically if symptoms are consistent, and delay
formal testing until after pregnancy. Although desmopressin has
a similar structure to oxytocin, premature labour is not
increased, the fetus is not affected and it is not contra-indicated
in pregnancy. Carbamazepine has been used in nephrogenic
DI, however, there is a small increased risk of teratogenesis when
used in the first trimester, which should be discussed with
women.

Hypopituitarism
Most obstetricians have some appreciation of hypopituitarism
secondary to Sheehans syndrome, that is pituitary infarction
secondary to massive postpartum haemorrhage. Other causes of
hypopituitarism include previous pituitary surgery or radiotherapy, infarction of a pituitary adenoma, and auto-immune
lymphocytic hypophysitis. Each case needs assessment
regarding the extent of the hypopituitarism, some will have only
partial disturbance of the pituitary function, whereas other
women will have panhypopituitarism, involving all pituitary
hormones. Over time most women will gradually lose complete
function and will develop panhypopituitarism. The condition is
rare in pregnancy as gonadotrophin axis appears most fragile,
and impairment leads to anovulation, however, there are now
more pregnancies in women conceived using gonadotrophin
replacement. These women are usually given progesterone supplementation to support the corpus luteum, as the low luteinising
hormone levels have been suggested to be one of the causal
factors in the higher miscarriage rates in these women. Those
women who conceive will need careful monitoring of the
replacement hormones throughout pregnancy, which usually
include levothyroxine and glucocorticoid replacement, with hydrocortisone, specifically to avoid an Addisonian crisis (see
below). Some women will also have growth hormone replacement, however, if pregnancy is achieved, the placenta will
overcome this particular maternal deficiency and this can be
discontinued after the first trimester.

Adrenal disease

Pituitary apoplexy
This condition is a set of symptoms and signs which occur with
abrupt haemorrhage or infarction classically into a pituitary adenoma, leading to rapid expansion of the pituitary out of the sella
turcica. The major symptom is severe headache, however, the
situation can deteriorate rapidly with subarachnoid haemorrhage, meningism, visual and neurological deficit, including
cranial nerve palsies and reduced consciousness. This condition
is rare in pregnancy, with only 12 case reports to date. Those
describe patients complaining of sudden onset headache, sometimes with associated nausea and vomiting. Imaging via MRI will
determine the extent of the expansion and whether the optic
chasm has been compromised. Hormone replacement is
mandatory particularly with steroids, otherwise an Addisonian
crisis can develop; the other pituitary controlled hormones,
namely thyroxine, should be checked and adequate dose prescribed. Non-tumourous apoplexy is seen in Sheehans syndrome, when postpartum haemorrhage changes the blood supply
via the single pituitary artery, leading to infarction and necrosis.
Typically, this will present with failure of lactation and persistent
amenorrhea, which should then alert clinicians to the need to
ensure functioning of other pituitary axes.

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Primary adrenal insufciency (Addisons disease)


The adrenal gland is responsible for steroid hormone production
including glucocorticoid and mineralocorticoid release, to maintain fluid and electrolyte balance, and aids glucose homeostasis.
Acute Addisons disease is potentially life-threatening if not
recognised and treated, due to hyponatraemia, loss of blood
pressure maintenance and hypoglycaemia. This condition is rare
in pregnancy and most women have a pre-conception diagnosis
of adrenal insufficiency. Sometimes, however, the condition is
insidious, and develops with non-specific symptoms of lethargy,
weight loss and skin pigmentation. As these overlap with the
symptoms of normal pregnancy, a high clinical suspicion should
be afforded especially to those women with other auto-immune
conditions. Outside of pregnancy, diagnosis is suggested by the
finding of hyponatraemia, hyperkalaemia, low 9 am cortisol, and
poor response to synthetic ACTH (the synacthen test). These
tests are not as easy to interpret during pregnancy, however, a
short synacthen test would be the most appropriate together with
measurement of salivary cortisol if this is available locally.
Maintenance treatment includes replacement of glucocorticoids, with hydrocortisone, and mineralocorticoids with

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If the diagnosis is suspected, further investigations with ultrasound and MRI of the adrenals are recommended. Outside
pregnancy, meta-iodo-benzylguanidine [MIBG] scintiscan is used
to locate tumours, but it is contra-indicated in pregnancy due to
the use of radioactive iodine.
Management is based around blood pressure control and then
surgical removal. Hypertensive crises can be precipitated by labour, delivery and general anaesthetic. Blood pressure control
should be with alpha blockade [usually intravenous phenoxybenzamine] initially and beta blockade [usually propranolol] to
control the tachycardia. There has been a recommendation to
deliver women with phaechromocytoma by elective Caesarean
section [due to the history of maternal deaths during labour and
vaginal delivery, secondary to malignant hypertension], either
combined with removal of the phaeochromocytoa or with the
latter as an interval procedure, potentially laparoscopically.
There have, however, been recent reports of successful vaginal
delivery with regional analgesia and close monitoring. There
have also been reports of successful pregnancy following early
second trimester surgery.

fludrocortisone. Often these medications will need to increase


during pregnancy and careful monitoring of capillary blood
glucose and electrolyte balance is required. During pregnancy,
women need educating to increase their doses at times of stress
where normally the output of the adrenal would be stimulated,
for example, during severe vomiting, or infection. Labour should
be covered with intravenous hydrocortisone 50e100 mg 6-hourly
to prevent hypotension and hypoglycaemia. These treatments are
safe in pregnancy, with minimal effect to the developing fetal
adrenals, however, pregnancies complicated by adrenal insufficiency appear to have an increased risk of premature labour, and
fetal growth restriction, and increased surveillance is required.
Primary hyperaldosteronism (Conns syndrome)
Primary hyperaldosteronism, presenting with hypertension and
hypokalaemia, is extremely rare in pregnancy despite being a
common cause of secondary high blood pressure. Hypertension
in pregnancy is a common finding, and secondary causes other
than pregnancy induced hypertension or pre-eclampsia should
always be considered, especially if blood pressure is hard to
control or there are atypical features. All women with hypertension should have serum electrolytes checked: the finding of
hypokalemia is rare and should not be attributed to pregnancyrelated increases in circulating aldosterone. Hypokalaemia with
hypertension should provoke a high degree of clinical suspicion,
and warrant further investigations for adrenal adenoma, adrenal
hyperplasia or rarely adrenal carcinoma.
Antenatally, women often develop pre-eclampsia and consequent fetal growth restriction with potential of preterm delivery
and placental abruption. In some cases the diagnosis is first
considered postpartum; in pregnancy, high progesterone concentrations compete with and diminish the effect of high aldosterone, however, after delivery as the aldosterone levels are still
elevated, symptoms do not resolve and may deteriorate.
Treatment consists of potassium supplementation with
potassium-sparing diuretics, such as amiloride, or certain
mineralocorticoid receptor antagonists such as eplerenone,
however, spironolactone should be avoided in pregnancy due to
the anti-androgenic effects and under-virilisation of a male fetus.
Should definitive surgical treatment be needed in pregnancy,
laparoscopic removal can be considered in the second trimester.

Congenital adrenal hyperplasia (CAH)


CAH is an autosomal recessive condition due to one of several
genetic mutations in the enzyme chain producing steroid hormones; the most common one leads to 21-hydroxylase deficiency. They all result in the underproduction of cortisol from the
adrenal. In turn, this leads to the loss of the negative feedback
regulation of the hypothalamic-pituitary axis, allowing the
continued release of ACTH driving further steroid hormone
production and leading to adrenal gland hyperplasia. This culminates in the production of excess androgens, which dependent
on the sub-type of CAH, can start to affect in utero development,
or can present later in puberty.
There are two forms recognised at birth, those infants who,
without swift treatment with glucocorticoid and mineralocorticoid replacement, have a salt-wasting crisis, with hypotension,
hypovolaemia, and hypoglyaemia and electrolytes disturbance.
Other female infants are diagnosed with a less acute form with
ambiguous genitalia, clitoromegaly and scrotalisation of labial
folds.
Due to improved treatment, more women with CAH are now
negotiating pregnancy. The effect of CAH on pregnancy is minimal, although there are reports of a small increased risk of
miscarriage and pre-eclampsia. Outside pregnancy, women are
usually treated with either dexamethasone or prednisolone, to
correct the cortisol deficiency, and to suppress ACTH and
androgen production. During pregnancy, dexamethasone is not
usually used as it crosses the placenta [unless fetal benefits are
sought: see below]; doses do not need to be changed routinely.
Any excess maternal serum androgens in pregnancy are converted to oestrogen by placental aromatase and therefore the
fetus is protected from exposure to them, although there have
been rare case reports of masculinization of unaffected female
fetuses. Increased steroid cover is required in times of stress, for
example during labour and delivery and if infection is suspected,
in order to avoid Addisonian type collapse. There should be extra
antenatal surveillance due to the increased rates of gestational
diabetes, and pre-eclampsia.

Phaeochromocytoma
This condition is another secondary cause of high blood pressure
which can be overlooked in pregnancy if it is not considered.
Missed diagnoses can potentially be fatal due to the paroxysmal
bursts of extreme blood pressure; maternal mortality is up to
15%. This condition often mimics pre-eclampsia, however, is
associated with much higher fetal mortality. The initial key to
diagnosis is to consider it as a diagnosis, and then to review the
history: typical symptoms include palpitations, excessive
sweating, and labile blood pressure causing postural hypotension, then significant hypertension and the key finding is the
presence of elevated urine catecholamines and their metabolites
specifically vanillylmandelic acid. These findings are caused by
the sporadic release of excessive catecholamines from the
tumour, which may be in the adrenal medulla or elsewhere along
the sympathetic chain.

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When the fetus is at risk of having CAH [mother affected by


CAH and father a carrier, or both partners carriers] early antenatal care is vital as fetal adrenocortical function begins at 7
weeks of gestation and virilisation of an affected female starts
from 9 weeks gestation. Women should be advised that as soon
as a viable intrauterine pregnancy is confirmed, virilisation can
be prevented by starting dexamethasone. This crosses the
placenta and acts as negative feedback to the fetal hypothalamicpituitary adrenal axis to prevent excessive androgen production.
With the advent of noninvasive prenatal testing [NIPT] using cell
free e fetal DNA in maternal serum, the sex of the fetus can be
determined from an early gestation, and therefore women with a
male fetus can discontinue dexamethasone, as the excess fetal
androgens do not cause virilisation. With a female fetus, the
mother needs to continue to take dexamethasone until a chorionic villus sample genetically determines whether the female
fetus has inherited CAH; in the near future NIPT may be available for the most common forms of CAH. As for any prolonged
use of steroid in pregnancy, monitoring for maternal hyperglycaemia is required. All affected neonates need to review by
the paediatric team for monitoring for salt-wasting crisis if
glucocorticoid replacement is not instigated.

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Conclusion
This review summarises the management of common endocrine
conditions, gives an overview of the rarer conditions and covers
important fetal and neonatal issues which need to be considered
during pregnancy.
A knowledge of endocrine conditions is important for the
obstetrician as they are increasingly common, particularly with
the advent of women delaying pregnancy and with increased
assisted reproduction therapy. Ideally, pre-conceptual advice
should be given regarding the pertinent issues, and all healthcare
professionals in primary and secondary care have a role to play
in this. In pregnancy, some women will be managed with minimal change to their routine antenatal care and unnecessary
medicalization can be avoided; others will require a full multidisciplinary approach, with endocrinologists, anaesthetists, paediatricians and surgeons involved, preferably led by an expert in
Obstetric Medicine. A high degree of clinical suspicion is needed
as apparently common symptoms can rarely be due to important
endocrine disorders.
A

Practice points
C

FURTHER READING
Almalki MH, Alzahrani S, Alshahrani F, et al. Managing prolactinomas
during pregnancy. Front Endocrinol (Lausanne) 2015 May 26; 6: 85.
Bhattacharyya R, Mukherjee K, Das A, Biswas MR, Mukherjee A. Antithyroid peroxidase antibody positivity during early pregnancy is
associated with pregnancy complications and maternal morbidity
in later life. J Nat Sci Biol Med 2015 Jul-Dec; 6: 402e5.
Chan S, Boelaert K. Optimal management of hypothyroidism, hypothyroxinaemia and euthyroid TPO antibody positivity preconception and in pregnancy. Clin Endocrinol (Oxf) 2015 Mar; 82: 313e26.
De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid
dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012; 97:
2543e65.

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:5

148

Ideally all women with known endocrine conditions will be


counselled prior to pregnancy to ensure their treatment is optimised prior to conception, and implications of pregnancy are
understood.
Thyroid disease is the most common endocrine problem after
diabetes mellitus, and whilst there is controversy regarding subclinical conditions, ensuring the patient remains euthyroid
throughout pregnancy is key.
Those women at high risk of vitamin D deficiency should have
replacement through pregnancy, and all women should be
advised to have 400 IU/day.
Microprolactinomas are the most common pituitary condition
encountered in pregnancy; women with a macroprolactinoma
need increased surveillance with visual field testing. All women
with a pituitary adenoma need to be educated regarding symptoms of headache as expansion can compromise the optic
chiasm.
Secondary causes of high blood pressure must be considered in
women who do not respond to regular treatment. A high clinical
suspicion is needed to ensure cases of Cushings syndrome,
phaeochromocytoma and Conns syndrome are not overlooked, in
order to optimize management and minimize adverse maternal
and fetal effects.

2016 Elsevier Ltd. All rights reserved.

REVIEW

Venous
thromboembolism in
pregnancy

syndrome and deep venous insufficiency, which cause leg


swelling, varicose veins, atrophic changes, and skin ulceration.
These changes affect up to 70% of women with previous DVT
within 5 years.
Pulmonary embolism is a major cause of maternal mortality.
Whilst earlier Confidential Enquiries into maternal deaths in the
United Kingdom showed a reduction in maternal death rates
associated with VTE, the most recent confidential enquiry
(published by MBRRACE-UK, 2009e2013) showed a reversal
of the pattern of maternal deaths to that seen before the 2006
e2008 report, with thrombosis and thromboembolism as the
leading cause of direct deaths. There were 30 deaths from
thrombosis and thromboembolism in the triennium of 2009
e2011, giving a maternal mortality rate of 1.26 per 100,000
maternities compared with a rate of 1.08 per 100,000 maternities in the previous triennium (although this was not statistically significant). This trend has been attributed to obesity,
and the rising rates of obesity in the pregnant population. This
trend is also noted in other developed countries like Australia.
The most recent report on maternal deaths in Australia (2008
e2012) noted 10 deaths related to VTE, all of whom died of
pulmonary embolism. This constituted a maternal mortality rate
of 0.7 cases per 100,000 women giving birth to a baby of at least
20 weeks gestation or at least 400 g birth weight. Thromboembolism comprised 9.5% of all maternal deaths in the report.
The association with a rising trend in obesity was noted as an
important factor.

Annabel Lim
Anushika Samarage
Boon H Lim

Abstract
Venous thromboembolism (VTE) is a leading cause of maternal
morbidity and mortality in the developed world. The term includes
deep vein thrombosis (DVT) and pulmonary embolism (PE). Women
are at least ve times more likely to develop VTE during pregnancy
compared to when they are not pregnant. The symptoms of acute
VTE can be non-specic. Strategies should be put in place during
the antenatal period to identify women at increased risk of thromboembolic disease. When an acute event thromboembolic is suspected
in high risk women during pregnancy, therapy may be commenced
empirically whilst investigations are commenced to conrm the
diagnosis.

Keywords deep vein thrombosis; pregnancy; pulmonary embolism;


venous thromboembolism

Introduction

Pathophysiology of venous thromboembolism in


pregnancy
The increased risk of developing VTE during pregnancy relates to
physiological changes that occur as the body adapts to cope with
the haemostatic demands of pregnancy and delivery. In pregnancy there are increased concentrations of factors VII, VIII, X,
von Willebrand factor, and fibrinogen, all of which tend to increase the propensity to form clots. Furthermore, concentrations
of active free Protein S decrease, resulting in a hypercoagulable
state. There are five-fold increased levels of plasminogen activator inhibitor type 1 (PAI-1), which reduce fibrinolysis. PAI-2,
which has the same activity, is markedly increased in the third
trimester as it is produced by the placenta. Factors II, V and IX
remain unchanged.
A higher level of haemostatic activity during pregnancy is
indicated by raised concentrations of coagulation markers
such as prothrombin F1 & 2, D-dimer and thrombinantithrombin (TAT) complexes, which remain elevated in
the postpartum period and may take more than 8 weeks to
return to baseline.
Anatomical factors of pregnancy also contribute to increased
risk of thrombosis. Venous dilatation (with turbulent flow in
dilated vessels), mechanical obstruction to venous return, and
decreased mobility cause a reduction in venous flow and promote stasis. Endothelial injury, the final component of Virchows
triad, occurs during labour and Caesarean section.
These changes collectively result in the 6e10 fold increased
risk of VTE compared to the non-pregnant situation. The frequency of VTE is similar in all three trimesters, but the highest
risk per day is during the postpartum period.

The increased risk of developing venous thromboembolism


(VTE) during pregnancy is a consequence of physiological adaptations that mitigate the haemostatic demands of delivery and
the puerperium. The risk increases throughout gestation,
reaching a peak immediately after delivery and remains elevated
for at least 6 weeks postpartum. The overall incidence of VTE,
which includes deep venous thrombosis (DVT) and pulmonary
embolism (PE), is approximately 1 in 1000 pregnancies. Understanding the pathophysiology, preventative, and treatment
strategies are key to improving outcomes for the pregnant
woman.

Maternal morbidity and mortality


The most serious maternal morbidity associated with VTE arises
when pulmonary embolism occurs. However morbidity may also
occur secondary to DVT. Such morbidities include post-phlebitic

Annabel Lim BA Hons. (Cantab.) MD is a Resident Medical Ofcer,


Lyell McEwin Hospital, Adelaide, Australia. Conict of interest: none
declared.
Anushika Samarage MBBS is a Registrar in the Department of
Obstetrics and Gynaecology, Royal Hobart Hospital, Hobart,
Australia. Conict of interest: none declared.
Boon H Lim MBBS FRCOG FRANZCOG is Clinical Director, Department of
Obstetrics and Gynaecology, Centenary Hospital for Women and
Children, Canberra, Australia. Conict of interest: none declared.

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:5

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Fondaparinux, a synthetic pentasaccharide that selectively


inhibits factor Xa, can also be considered as alternative therapy
in cases of heparin intolerance. Fondaparinux is currently classified as Food and Drug Authority (FDA) Pregnancy Category B.
While there is limited clinical experience of its use during pregnancy, case reports have described successful use and the Pregnancy and Thrombosis Working Group has recommended
fondaparinux as an alternative to LMWH for cases of Heparin
Induced Thrombocytopenia (HIT). Other agents that are
currently not licensed for use in pregnancy but have been
described in case reports are direct thrombin inhibitors such as
argatroban and r-hirudin.
The new oral anticoagulants have been studied for thromboprophylaxis and treatment of VTE in non-pregnant populations,
in whom they are increasingly favoured due to their quick onset
of action, reliable pharmacokinetics and lack of requirement for
monitoring. However, their use in animal studies found significant adverse effects during pregnancy including teratogenicity,
haemorrhagic changes, and placental abnormalities. Therefore
the new oral anticoagulants have not been studied in pregnant or
breast-feeding human populations. Patients who are prescribed
new oral anticoagulants off-license should be warned of the data
from animal studies suggesting that there may be adverse effects
during pregnancy. More data is needed before these drugs can be
used routinely in clinical practice.

Prevention of venous thromboembolism in pregnancy


Identication of risk factors
As well the physiological changes of pregnancy outlined above,
some women will have additional risk factors predisposing them to
VTE. Epidemiological studies show that a high proportion of
women with pregnancy-associated VTE (70e90% of those with
PE) have identifiable risk factors. Significant risk factors include
thrombophilia and previous VTE, maternal age >35 years, obesity,
and operative delivery (including Caesarean section and
rotational/mid-cavity instrumental delivery), which are increasing
in prevalence. Notably, admission to hospital during pregnancy is
associated with an 18-fold increased risk of first VTE compared
with time outside hospital. In the 28 days after discharge, the risk
remains increased up to 6-fold higher, with higher risk in the third
trimester and in women over 35 years old (Table 1).
Thromboprophylaxis during pregnancy
An individual assessment of thrombotic risk should be undertaken at booking, and repeated at each hospital admission
thereafter. Early assessment is important in view of the increased
thrombotic risks associated with first trimester complications
such as hyperemesis gravidarum (due to the additional risk
factor of dehydration).
Thromboprophylaxis can be either by pharmacological i.e.
using subcutaneous injection of low molecular weight heparin
(LMWH) or mechanical means with graduated elastic compression
stockings (GCS). Low molecular weight heparin does not cross the
placenta and is the first-line choice for antenatal and postnatal
thromboprophylaxis. There is no evidence to support the use of
aspirin for thromboprophylaxis in obstetric patients. The use of
GCS is recommended for women with a previous history of VTE or
thrombophilia during the pregnancy and for 6e12 weeks postpartum. They should be fitted for each individual woman.
Women with previous VTE should be offered thromboprophylaxis with LMWH as they are at increased risk of recurrence
during pregnancy and the postpartum period (relative risk 3.5).
Dosing of LMWH is based on the booking or most recent weight,
and given from as early as possible in the antenatal period until 6
weeks postpartum.
As women with a past history of VTE should be offered
thromboprophylaxis, testing for thrombophilia in these patients
is not routinely required as it will not alter clinical management.
However, patients with anti-thrombin deficiency or antiphospholipid syndrome (not simply the presence of antibodies)
may require higher doses of LMWH. Screening can be considered
for these conditions if there is a suspicion of these conditions
based on strong personal and family history, especially of
unprovoked VTE.

Management of thromboprophylaxis for delivery


It is important to discuss the implications of LMWH for regional
analgesia with woman prior to delivery, and to make a cohesive
delivery plan. The highest risk of a thrombotic event is in the
early postpartum period. Women are generally advised to discontinue LMWH should they experience any vaginal bleeding, at
the onset of labour, or prior to planned delivery so as to minimize the risk of epidural haematoma when regional analgesia or
anaesthesia is used. Regional techniques should ideally be
avoided until at least 12 hours after the previous prophylactic
dose of LMWH. If elective Caesarean section is planned, the last
dose before surgery should be given on the day before planned
delivery. LMWH should not be given for 4 hours after use of
spinal anaesthesia or after removal of an epidural catheter, and
the catheter should not be removed within 12 hours of the most
recent LMWH injection. There should be discussion with a senior
anaesthetist regarding the timing of re-initiation of LMWH after
regional anaesthesia.
In some women, particularly those on high-dose prophylactic
LMWH, there may be an indication for induction of labour to
help plan thromboprophylaxis around delivery. This enables a
24-hour window between the last dose of LMWH and regional
analgesia to be organized. If LMWH has been administered too
recently for safe use of regional techniques (e.g. the woman who
presents in spontaneous labour within 12 hours of taking a
LMWH dose), alternatives such as opiate-based intravenous
patient-controlled analgesia can be offered.

Alternatives to low molecular weight heparin


Allergic delayed-type hypersensitivity reactions to LMWH in
pregnancy are not uncommon, with a reported incidence of 20%
in an observational study (median time of onset 50.5 days). A
third of patients with hypersensitivity also displayed crossreactivity to other heparins. For patients with intolerance to
heparin, evidence from case reports has shown danaparoid, a
heparinoid, to be an effective and safe alternative anticoagulant
in pregnancy.

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:5

Postpartum thromboprophylaxis
All women should have a further risk reassessment of VTE in
labour and the postnatal period. Appropriate arrangements and
education for self-administration of LMWH should be instituted
before discharge.

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surgery in the puerperium, thromboprophylaxis should be


extended for up to 6 weeks or until the additional risk factors
are no longer present.
After Caesarean section, thromboprophylaxis with LMWH for
10 days should be considered for emergency cases or in elective
patients with additional risk factors. Women with class 3 obesity
(BMI greater than or equal to 40 kg/m2) and no additional risk
factors should be considered for prophylactic LMWH for 10 days
after delivery.
Properly fitted and applied graduated compression stockings
reduce venous stasis by compressing the superficial and common
femoral veins and increasing blood blow. They are useful adjuncts
to thromboprophylaxis with LMWH for women who are postCaesarean delivery and who are considered high risk (previous
VTE, >4 risk factors antenatally or >2 risk factors postnatally).

Risk factors for venous thromboembolism in pregnancy


and the puerperium
Previous venous thromboembolism
Thrombophilia
Heritable
C
Anti-thrombin deficiency
C
Protein C deficiency
C
Protein S deficiency
C
Factor V Leiden
C
Prothrombin gene G20210A
Acquired
C
Antiphospholipid syndrome
C
Persistent lupus anticoagulant
C
Persistent moderate/high-titre anticardiolipin antibodies or b2
glycoprotein 1 antibodies
Medical comorbidities
e.g. heart or lung disease, systemic lupus erythematosus, cancer,
inflammatory conditions (inflammatory bowel disease or inflammatory, polyarthropathy, nephrotic syndrome (proteinuria >3 g/
day), sickle cell disease, b thalassaemia major, intravenous drug
user
Age >35
Obesity (BMI >30 kg/m2) either pre-pregnancy or in early
pregnancy
Parity 3
Smoking
Gross varicose veins (symptomatic or above knee or with
associated phlebitis, oedema/skin changes)
Paraplegia
Obstetric risk factors
C
Multiple pregnancy
C
Assisted reproductive therapy
C
Pre-eclampsia
C
Caesarean section
C
Postpartum haemorrhage (>1 L) requiring transfusion
C
Prolonged labour
C
Mid-cavity rotational operative delivery
New-onset/transient risk factors (Potentially reversible and may
develop in later gestation)
C
Surgical procedures in pregnancy or puerperium (e.g. evacuation
of products of conception, appendectomy, postpartum
sterilization)
C
Hyperemesis gravidarum, dehydration
C
Ovarian hyperstimulation syndrome
C
Systemic infection requiring antibiotics or admission to hospital
(e.g. pneumonia, pyelonephritis, postpartum wound infection)
C
Long distance travel (>4 hours)

Practice points
C

Acute venous thromboembolism in pregnancy


Signs and symptoms
VTE should be suspected in patients presenting with symptoms
and signs such as leg pain and swelling, dyspnoea, tachypnoea,
tachycardia, chest pain, haemoptysis, or collapse. The presentation of isolated iliac thrombosis may range from a completely
asymptomatic patient to one with abdominal pain, back pain, or
entire leg swelling. Diagnosis based on clinical presentation
alone is therefore unreliable. As the potential consequences of
VTE are significant, including a risk of sudden death, patients
should be promptly investigated. Empirical treatment should also
be given until VTE is ruled out by objective testing.
The standard approach to VTE diagnosis in non-pregnant
patients using structured pre-test clinical probability assessment such as Wells criteria have not been validated in pregnancy. The value of D-dimer assay in aiding diagnosis is
controversial because D-dimer levels physiologically increase
throughout pregnancy. While a negative D-dimer may be of
value in reducing the likelihood that VTE has occurred, a positive
D-dimer is of very little value. The future development of
pregnancy-specific D-dimer thresholds may increase validity of
the test but further study is currently required before use of the
assay can be recommended.

Source: RCOG Green-top Guideline No.37a, 2015.

Table 1

Thromboprophylaxis should be continued for 6 weeks in


high risk women (e.g. those with a previous VTE) and for 10
days in intermediate-risk women. In women who have additional persistent (lasting more than 10 days postpartum) risk
factors, such as prolonged admission, wound infection or

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:5

Pregnancy is a hypercoagulable state that increases the risk of


venous thromboembolism. The early postpartum period is the
time of highest risk
All women should undergo a documented assessment of risk
factors for VTE early in pregnancy or before pregnancy. This
assessment should be repeated if the woman is admitted to
hospital for any reason or develops inter-current problems.
Identification of at-risk women and the use of thromboprophylaxis save lives

Initial investigations (Figure 1)


When PE is suspected, electrocardiogram (ECG) and chest X-ray
are recommended as initial investigations. While ECG is of

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limited value in the diagnosis of PE, ECG abnormalities occur in


41% of women in pregnancy and the puerperium with symptomatic acute PE. The most common findings were T wave
inversion (21%), S1Q3T3 (15%), and right bundle branch block
(18% during pregnancy and 4% in puerperium).
Chest X-ray (CXR) is normal in over half of patients with
objectively proven PE but is helpful in identifying other differential
diagnoses for chest symptoms such as pneumonia or pneumothorax. The fetal radiation dose is negligible (<0.01 mSv).
Abnormal radiographic findings in PE include pleural effusion,
lung infarction, atelectasis, infiltrate, cardiomegaly, focal opacities, regional oligaemia, and rarely pulmonary oedema.

radiation dose (up to 20 mGy). This is much larger (20e100


times) than the dose provided by VQ scan. There is wide variation in estimates of the increased risk of breast cancer due to lack
of data and based on extrapolation and modelling. Radiation
exposure of 10 mGy to a womans breasts when aged under 35
years is associated with a 13.6% increased lifetime risk of
developing breast cancer above her background risk. It has been
suggested that VQ scan should be chosen over CTPA in young
women with a family history of breast cancer or who have
already previously undergone chest CT. Bismuth shields can be
used to decrease breast radiation exposure by 20e40%.
New imaging techniques
Ventilation and perfusion single-photon emission computed tomography (V/QSPECT) is a new modality that provides multiple
3D images with better quality, speed, improved sensitivity and
specificity than traditional planar V/Q imaging. The European
Association of Nuclear Medicine recommends that V/QSPECT
should be the gold standard for the diagnosis of PE in all patients.
However, it is not widely available and has yet to be fully evaluated in pregnancy. Other new imaging techniques include
magnetic resonance pulmonary angiogram and digital subtraction angiography; these require further evaluation of safety,
sensitivity and specificity in pregnancy.

Duplex ultrasound
Bilateral compression duplex leg ultrasound should be performed
in all pregnant women suspected to have deep vein thrombosis
(DVT). The higher incidence of isolated iliac vein DVT in pregnancy may lead to increased risk of false negatives. If ultrasound
does not identify DVT, and PE is suspected, further imaging is
required. However, if DVT is diagnosed, then accompanying
chest symptoms may be assumed as the result of PE and further
imaging for PE can be omitted as therapeutic treatment is similar
in both situations.
If ultrasound is negative and there is a low level of clinical
suspicion for DVT, anticoagulant treatment can be ceased. If
ultrasound is negative and a high level of clinical suspicion remains, anticoagulant treatment should be discontinued but the
ultrasound should be repeated on days 3 and 7.

Baseline investigations
Full blood count, coagulation studies, urea, electrolytes and liver
function tests should be performed as baseline blood investigations to check renal and hepatic function before starting
anticoagulant treatment. Thrombophilia screening during acute
VTE is not routinely indicated because coagulation parameters
are altered in pregnancy and testing will not alter immediate
management.

Denitive imaging
Ventilation perfusion (V/Q) scan or computed tomography pulmonary angiogram (CTPA) can be used to provide definitive
diagnosis of PE. If CXR is abnormal, CTPA should be performed.
If CXR is normal, then the choice of scan should be made with
consideration of local availability, sensitivity, maternal and fetal
risks, and discussion with a radiologist. Hospitals should have a
local protocol in place with a diagnostic pathway for suspected
PE in pregnancy. Advantages of CTPA over V/Q scan include
better availability (found in more hospitals, often operated 24
hours a day) and the ability to identify other pathology including
pneumonia (5e7%), pulmonary oedema (2e6%) and rarely
aortic dissection.
CTPA and V/Q scan are associated with similar amounts of
fetal radiation exposure. The exposure is considered low dose
and well below the threshold for teratogenicity, fetal growth restriction and fetal death. The concern associated with this level of
fetal radiation exposure relates to a small increased risk of
childhood cancer (1:280,000 with V/Q scans vs. 1:1,000,000 with
CTPA). The increased risk of fatal childhood cancer to the age of
15 following in utero radiation exposure has been estimated by
the International Commission on Radiological Protection as
0.006% per mGy. Despite the wide variation in estimates of fetal
radiation exposure from CTPA and VQ scans (0.06e0.66 mGy)
the overall risks of radiation to the fetus can be considered low.
When performing a V/Q scan in pregnancy, the ventilation
component can often be omitted, further minimizing the fetal
radiation exposure.
The maternal radiation risk from CTPA is more significant.
CTPA exposes the maternal breast tissue to a relatively high

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:5

First-line treatment
Low molecular weight heparin (LMWH) is the treatment of
choice for VTE in both pregnant and non-pregnant populations.
LMWH are safe, easy to administer, and women can be taught to
inject themselves. They do not cross the placenta and can be
used throughout pregnancy.
Warfarin crosses the placenta and is teratogenic in the first
trimester, with a 6% risk of embryopathy if taken between 6 and
12 weeks gestation. Complications such as miscarriage and
stillbirth are more common. Furthermore, the incidence of fetal
intracerebral haemorrhage is increased when warfarin is used in
the third trimester. Warfarin is rarely recommended in pregnancy except in women with prosthetic (mechanical) heart
valves; it is more commonly used in women with metallic mitral
valves who are at the highest risk of thrombotic complications,
but even then should only be continued under specialist maternal
medicine care jointly with a cardiologist.
A Cochrane review of 22 studies of patients with VTE showed
that LMWH treatment was superior to unfractionated heparin (UH)
with lower rates of VTE recurrence or extension, less major haemorrhage during initial treatment, and overall lower mortality.
Knol et al (2012) found that LMWH therapy is associated with an
increased risk of postpartum haemorrhage (30% after vaginal delivery compared to 18% in the control group; 12% after Caesarean
section compared to 4% in the control group) but there was no

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Investigation and initial management of suspected pulmonary


embolism in pregnancy and the puerperium
Suspected PE:
clinical assessment
perform CXR and ECG
test FBC, U&E, LFTs
commence LMWH (unless treatment is contraindicated)

Symptoms and signs of DVT

YES

NO

Perform compression
duplex ultrasound

Compression ultrasound

NO

Is the CXR normal?

YES

YES

Continue therapeutic
doses of LMWH

Perform V/Q scan

NO

If the clinical suspicion of PE is low, discontinue


LMWH and consider alternative diagnoses
If the clinical suspicion of PE is high, consider
alternative or repeat testing and continue LMWH

NO

Perform CTPA

YES

Continue therapeutic
doses of LMWH

Reproduced from: Royal College of Obstetricians and Gynaecologists.Thromboembolic


Disease in Pregnancy and the Puerperium: Acute Management. Green-top Guideline
No. 37b. London: RCOG; 2015, with the permission of the Royal College of
Obstetricians and Gynaecologists
Figure 1

association with an increased risk of clinically relevant severe


postpartum haemorrhage. Compared to UH, LMWH are also associated with a lower risk of heparin-induced thrombocytopenia and
heparin-induced osteoporosis (0% and 0.04% respectively in a
systematic review including 2777 pregnancies).

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:5

The dose of LMWH is calculated using the patients booking


or early pregnancy weight (RCOG recommends enoxaparin 1
mg/kg twice daily) and given via the subcutaneous route. In
pregnancy, the half-life of LMWH is shortened due to increased
renal excretion as well as increased plasma volume, which

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anticoagulant for the duration of pregnancy; at least 6 weeks


postnatally and with a total treatment time of at least 3 months.
Women with DVT in pregnancy should be advised that prolonged use of LMWH (more than 12 weeks) is associated with a
significantly lower chance of developing post-thrombotic syndrome (PTS), characterized by chronic persistent leg swelling,
pain, a feeling of heaviness, dependant cyanosis, telangiectasia,
chronic pigmentation, eczema, associated varicose veins and in
the most severe cases, venous ulceration. Following a DVT,
graduated elastic compression stockings should be worn on the
affected leg to reduce pain and swelling. Compression stockings
may also help to reduce the incidence of post-thrombotic
syndrome.

reduces the peak drug concentration. The requirement for twice


daily dosing is based on these pharmacokinetic changes in
pregnancy. In practice, clinicians have opted for once-daily
dosing to simplify the regimen for patients and there remains
no clear evidence to favour once or twice daily regimes.
Routine anti-Xa monitoring is not required, but could be
considered in patients with low body weight (<50 kg), morbid
obesity, or renal impairment, with a target peak anti-Xa activity
of 0.5e1.2 u/ml (3 hours post-injection). Routine platelet count
monitoring is not required as the risk of HIT is low.
The placement of a temporary inferior vena cava filter should
be considered (in conjunction with a haematologist who has a
special interest in obstetric haematology) in the peripartum
period for patients with iliac vein to reduce the risk of PE, or in
patients with proven DVT who have recurrent emboli despite
adequate anticoagulation.
In the initial management of DVT, the leg should be elevated
and a graduated elastic compression stocking applied to reduce
oedema. Mobilization with graduated elastic compression
stockings should be encouraged.
Danaparoid or fondaparinux may be used in women who
have intolerance to heparin or LMWH, or in those with HIT (see
earlier).

Management of labour and delivery


LMWH should be stopped as soon as the patient is in labour, or
24 hours before a planned delivery. Regional anaesthesia should
not be given until 24 hours after the last dose of therapeutic
LMWH. Following elective Caesarean section, a prophylactic
dose of LMWH should be given after 4 hours after removal of an
epidural catheter, if placed. Therapeutic LMWH should then be
recommenced 8e12 hours later.
If a patient is receiving UH, this should be discontinued
(subcutaneous UH 12 hours, intravenous UH 6 hours) before
induction of labour or regional anaesthesia. If Caesarean section
is performed, wound drains should be considered and skin
incision closed with interrupted sutures to allow for drainage of
any haematoma as there is an increased incidence of wound
complications.

Haemodynamic instability
Patients with massive PE may present with shock, hypoxaemia or
right ventricular dysfunction. In massive life-threatening PE with
cardiovascular compromise, UH is the preferred treatment due to
its rapid effect, reversibility and widespread clinical experience of
its use in this scenario. A multi-disciplinary approach with input
from senior physicians, haematologists, obstetricians and radiologists should be adopted, following local protocol to guide weightbased administration of intravenous UH.
When UH is given, APTT must be measured 4e6 hours after
the loading dose, 6 hours after any dose change, and daily when
in therapeutic range. However, it is noted that in late pregnancy,
increased fibrinogen and factor VIII affect the APTT, which can
lead to the use of higher than necessary doses of heparin and
consequent bleeding problems. Senior haematology advice should
be sought and the anti-Xa level may be used as a measure of
heparin dose. Platelets should also be monitored every 2e3 days
from day 4e14 or until UH is stopped, due to the risk of HIT.
If there is haemodynamic compromise, thrombolysis should
be considered. Randomized trials have provided evidence that
thrombolysis in addition to anticoagulation aids more rapid
dissolution of emboli, helping to restore pulmonary circulation,
but without any beneficial effect on mortality. Case reports of
thrombolysis during pregnancy (most commonly using streptokinase, urokinase and recombinant tissue plasminogen activator) have been published, with complications including fetal
death (1.7%), non-fatal maternal bleeding (2.9%), placental
abruption, and preterm labour. If thrombolysis is contraindicated, thoracotomy and surgical embolectomy can be
considered.

Postnatal treatment
Following delivery, women may choose to convert to warfarin or
remain on LMWH. Women on LMWH or warfarin may continue
to breastfeed as only minimal amounts are found in the
breastmilk.
Postnatally, therapeutic anticoagulant should be continued for
at least 6 weeks, with total therapy duration of at least 3 months.
If continuing anticoagulation with LMWH, the previous antenatal
dose can be continued or changed to the manufacturers recommended dose for non-pregnant patients (1.5 mg/kg enoxaparin daily). If warfarin is selected for continuation of
anticoagulation, it should be started no sooner than day 5 postpartum (longer if there is a risk of PPH), with bridging LMWH in
the interim and daily international normalized ratio (INR)
monitoring during titration to initialize her dose. Both warfarin
and LMWH are suitable for continuation during breast-feeding.
Patients should be ideally followed up at outpatient clinic with
physician or haematology input to assess post-thrombotic venous
damage and plan for thromboprophylaxis in future pregnancies.
Thrombophilia screening should only performed after anticoagulant therapy is ceased and in cases where results would
affect future management plans.

Conclusion
The most recent confidential enquiry into maternal deaths report
from MBRRACE-UK has shown that the pattern of direct maternal
deaths has reverted to that seen prior to 2006e2008, with
thrombosis and thromboembolism as the leading cause of direct

Maintenance treatment
Women receiving therapeutic LMWH for treatment of VTE
should be taught to self-administer injections and can be
managed as outpatients. They should receive therapeutic

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REVIEW

deaths. More women are obese at the start of pregnancy, and


many delay childbearing and consequently require fertility
treatment. All these are independent risk factors for VTE in
pregnancy. National guidelines are now available to manage VTE
risk. Maternity units are adopting the required assessment tools
to stratify individual risk so that appropriate preventive strategies
can be put in place. Health professionals need to be aware that
the risk of VTE rises above baseline non-pregnant risk for all
women throughout pregnancy and the puerperium. Symptoms of
DVT and PE may be non-specific and subtle. A high index of
suspicion should be maintained whenever any pregnant or recent
postpartum woman presents with suggestive signs or symptoms.
In situations where VTE is suspected, there should be no hesitation to institute therapy whilst waiting for confirmatory
tests.
A

Royal College of Obstetricians and Gynaecologists. Reducing the


risk of venous thromboembolism during pregnancy and the
puerperium. Green-top guideline No. 37a. London: RCOG,
2015.
Royal College of Obstetricians and Gynaecologists. Thromboembolic disease in pregnancy and the puerperium: acute
management. Green-top guideline No. 37b. London: RCOG,
2015.
Tooher R, Gates S, Dowswell T, Davis LJ. Prophylaxis for venous
thromboembolic disease in pregnancy and the early postnatal
period. Cochrane Database Syst Rev 2010. Issue 5. Art. No.:
CD001689.

Practice points
C

FURTHER READING
Cutts BA, Dasgupta D, Hunt BJ. New directions in the diagnosis and
treatment of pulmonary embolism in pregnancy. Am J Obstet
Gynecol 2013 Feb; 208: 102e8.
Leung AN, Bull TM, Jaeschke R, et al. ATS/STR Committee on
Pulmonary Embolism in Pregnancy. An ofcial American
Thoracic Society/Society of Thoracic Radiology clinical
practice guideline: evaluation of suspected pulmonary embolism in pregnancy. Am J Respir Crit Care Med 2011; 184:
1200e8.

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:5

139

When a diagnosis of deep vein thrombosis or pulmonary embolism is suspected, there should be no hesitation in commencing
therapeutic doses of low molecular weight heparin whilst waiting
for confirmatory tests
All institutions should have clear guidelines for repeated
assessment of women for VTE risk during pregnancy and postpartum, as well as for the diagnosis and treatment of confirmed
VTE
Appropriate doses of LMWH should be instituted based on the
booking or early pregnancy weight

2016 Elsevier Ltd. All rights reserved.

SELF-ASSESSMENT

Self-assessment questions
Questions

D. She should wear graduated compression stockings


throughout pregnancy and then commence on low molecular weight heparin for 6 weeks postpartum.
E. No thromboprophylaxis will be required if she has a
normal delivery as her BMI is within normal limits.

Question 1 (SBA)
A 42 year old woman with pressure symptoms and heavy
menstrual bleeding leading to iron deficiency anaemia is found
to have two large uterine fibroids on ultrasound. You discuss
medical management options first, in detail. Which one of the
following pieces of information is correct regarding selective
progesterone receptor modulators (SPRMs)?
A. Safety prior to pregnancy has been demonstrated
B. They can be used continuously for 6 months
C. The duration of use is limited by hypoestrogenic side
effects
D. Fibroid shrinkage is maintained for at least 3 months
following cessation
E. They are contraindicated in those at risk of thrombosis

Question 4 (SBA)
A 28-year old para 1 was delivered by emergency caesarean
section for obstructed labour 48 hours ago. Her booking BMI
was 35 (booking weight 90 kg) and she was commenced on
prophylactic low molecular weight heparin 40 mg subcutaneously daily immediately after her operation. Although she
remained afebrile, her pulse rate has remained persistently
elevated at 100 per minute. Her haemoglobin level was 10 g/
dL and her white cell count normal. Her ECG showed sinus
tachycardia and chest X-ray was normal. She is keen to
breastfeed. Her oxygen saturation in air is 92% and she is
slightly breathless.
What advice would you give her and how would you
manage her?
A. Order a D-Dimer and get a duplex leg ultrasound scan after
discussing with the medical team on call.
B. Commence enoxaparin 100 mg twice daily and arrange for
a chest X-ray followed by a CTPA or Ventilation/Perfusion
(VQ) scan.
C. Organize a CTPA and advise her that this will increase the
risk of her child getting childhood cancer, so she should
avoid breastfeeding.
D. Commence warfarin and warn her that her baby could be
at risk of developing haemorrhagic complications if she
continues to breastfeed.
E. Investigate with V/Q scan and avoid CTPA because it will
increase her lifetime breast cancer risk by 25%.

Question 2 (SBA)
The same patient, as in question 1, decides that a surgical
management option will suit her better. Which of the
following is true with regards to open myomectomy compared
with laparoscopic management?
A. Longer operating times
B. More complete fibroid clearance
C. Reduced blood loss
D. Reduced rates of fibroid recurrence
E. Shorter recovery times
Question 3 (SBA)
A 36 year old woman presents at 12 weeks gestation for her
antenatal booking visit. She had three previous first trimester
miscarriages prior to this pregnancy. She was fully investigated and was found to be heterozygous for Factor V Leiden
mutation. She smokes 10 cigarettes a day and has no significant past medical or family history. Examination showed her
booking BMI to be 25 kg/m2. Her BP is 120/70 mmHg and no
abnormality is found on examination. What would you advise
her regarding her Factor V Leiden status?
A. She is at significant risk of venous thromboembolism and
should commence on low dose aspirin plus low molecular
weight heparin as soon as possible.
B. She should stop smoking and commence low dose aspirin
immediately. She should undergo duplex ultrasound of her
legs as a screen for deep vein thrombosis.
C. She should be advised to commence on low molecular
weight heparin from 28 weeks gestation and continue with
thromboprophylaxis for 10 days postpartum in the absence
of any additional risk factor after delivery.

Question 5 (SBA)
A 25 year old woman with a BMI of 37 has been trying to
conceive and has been told that reducing her weight might
help. She has normal glucose tolerance and wishes to discuss
weight loss surgery. Which of the following pieces of advice is
incorrect?
A. Surgery is more effective in achieving weight loss than
lifestyle interventions
B. Weight loss surgery would be supported by NICE guidance
in her case
C. Fetal growth restriction is more likely following weight loss
surgery
D. Evidence shows that fertility and miscarriage rates are
favourably affected by weight loss surgery
E. Hypertensive complications of pregnancy are reduced in
women who have undergone weight loss surgery
Question 6 (SBA)
A 28-year old woman attends the antenatal clinic in her first
pregnancy. She is concerned as she has a past history of

Alec McEwan MRCOG is a Consultant in Fetal and Maternal


Medicine at the Division of Obstetrics and Gynaecology, Queens
Medical Centre, Nottingham, UK.

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2016 Published by Elsevier Ltd.

SELF-ASSESSMENT

D.
E.
F.
G.
H.

hypothyroidism. Which one of the following complications of


pregnancy is not associated with untreated hypothyroidism.
A. Miscarriage
B. Gestational diabetes
C. Preterm, pre-labour rupture of membrane
D. Pregnancy induced hypertension
E. Caesarean section

I. A 16-year girl who has recently become sexually active


with her boyfriend suffers from migraines and heavy,
painful periods.
II. A 52-year old woman with a BMI of 42 who is no longer
sexually active suffers from heavy, regular periods. An
ultrasound reveals a thick, regular endometrium and a
hysteroscopic biopsy is normal.
III. A 34-year para 2 woman presents with a 1 year of heavy,
irregular menstrual bleeding. An ultrasound scan demonstrates a 3 cm fibroid indenting the uterine cavity.

Question 7 (SBA)
A 40-year old woman in her third pregnancy is diagnosed with
a prolactinoma at 32 weeks gestation after suffering from
increasing headaches. Which one of the following is true
regarding prolactinomas in pregnancy?
A. Headache, nausea and vomiting can be a sign of enlargement in all trimesters
B. Dopamine agonists are recommended throughout pregnancy for microprolactinomas
C. Visual fields studies should only be performed in women
with known macroprolactinoma who develop symptoms
D. Women are advised not to breastfeed
E. Transphenoidal surgery is mainstay of therapy for
asymptomatic microprolactinoma

Answers
Answer 1
D
Although pregnancies have been reported after treatment
with SPRMs there is insufficient evidence to confirm safety.
Recommendations state that although repeated courses can
be used, there should be a 1 month break between each 12
week course of treatment. Oestrogen levels are maintained in
those taking SPRMs as FSH and LH levels are unaffected by
treatment. Fibroid shrinkage is maintained for at least 3
months following treatment. As SPRMs do not result in
raised oestrogen levels, previous thrombosis is not a
contraindication.

Question 8 (SBA)
A 35-year old woman with a BMI of 32 is referred to the
menstrual dysfunction clinic and, after investigation, receives
a diagnosis of PCOS. She would like to know about the potential health benefits of weight loss. Which one of the
following is not likely to be improved by a 5e10% weight
loss?
A. Anxiety
B. Insulin resistance
C. Cardiovascular risk factors
D. Hypothyroidism
E. Free androgen index

Answer 2
D
Laparoscopic myomectomy is associated with longer
operating times than open myomectomy, however the laparoscopic approach has been associated with reduced operative
blood loss and higher post-operative haemoglobin concentrations. Additionally, duration of hospital stay and recovery
times are reduced with the laparoscopic approach. As more
complete fibroid removal is possible with the open approach,
rates of fibroid recurrence are greater following a laparoscopic
myomectomy.

Question 9 (SBA)
A 51-year old university professor suffers from heavy regular
periods and has opted to have a Mirena IUS fitted in an
attempt to improve these. She has some detailed questions
about how the Mirena will work and how it will treat her
menorrhagia. Which one of the following is not true regarding
the Mirena IUS?
A. She can expect at least a 60% reduction in menstrual blood
loss within a year of use
B. The Mirena IUS is not licensed for this particular indication
C. The contraceptive effect of a Mirena has a duration of 5
years
D. The primary mechanism of action is pseudodecidualization
of the endometrium
E. The Mirena will release 20 mg of levonorgestrel per day

Answer 3
C
There is no evidence that aspirin has any benefit in the
prevention of venous thromboembolism. Heterozygosity for
factor V Leiden, prothrombin gene mutation or antiphospholipid antibodies are considered to be risk factors for
thrombosis in asymptomatic women. In this case, the risk
factors in addition to the womans Factor V Leiden status are
her age of 36 years and her smoking, giving her two additional
risk factors. With three risk factors in total for VTE, thromboprophylaxis should be considered from 28 weeks.
Should another risk factor occur e.g. if she is delivered by
caesarean section, she should be considered for thromboprophylaxis for 6 weeks postpartum.

Question 10 (EMQ)
For each of the cases below (ieiii) choose the most suitable
first line therapy (AeH) for the menstrual dysfunction case
described:
A. Tranexamic acid
B. Oral contraceptive pills
C. Naproxen

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Total abdominal hysterectomy


Endometrial ablation
Uterine artery embolization
Transcervical resection of fibroid polyp
Depot Medroxyprogesterone Acetate

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2016 Published by Elsevier Ltd.

SELF-ASSESSMENT

Answer 4
C
Whenever there is a suspicion of deep vein thrombosis or
pulmonary embolism, therapeutic doses of LMWH should be
commenced whilst investigative tests are being arranged. DDimer is elevated in pregnancy and is not a useful test to
order. Symptoms of pulmonary embolism can be non-specific
and should be suspected when a woman has unexplained
tachycardia. CTPA will provide definitive diagnosis and can
also reveal the presence of other lung pathology. The correct
dose of enoxaparin is 1.0 mg/kg of the booking weight twice
daily or 1.5 mg/kg daily, as she is post-natal. Estimates of the
increased risk of breast cancer associated with CTPA in
pregnancy vary considerably and are based on modelling or
extrapolated data. The delivery of 10 mGy of radiation to a
womans breast has been estimated to increase her lifetime
risk of developing breast cancer by 13.6% above her background risk and this figure has been cited widely. There is no
contraindication to breastfeeding with either LMWH or
warfarin as minimal amounts of these medications are found
in breast milk.

Answer 7
A
Prolactinomas are the most common benign pituitary adenomas in pregnancy. Management during pregnancy depends on the size of the adenoma; micro adenomas less than
10 mm in size rarely cause a problem, whereas those which
are greater than 10 mm [macroprolactinoma] may require
more careful management.
Answer 8
D
Modest weight loss of 5e14% improves CVD risk factors,
hormonal profile and reproductive function in overweight and
obese women with PCOS. Improvements include reductions in
abdominal fat, blood glucose, blood lipids and IR, improvements in menstrual cyclicity, ovulation and fertility, reductions in testosterone levels and free androgen index and
increases in sex hormone binding globulin. There have also
been demonstrated improvements in self-esteem, depression
and anxiety. Although treatment of hypothyroidism is likely to
result in weight loss, the opposite is not true.
Answer 9
B
The levonorgestrel-releasing intrauterine system (Mirena)
produces a dramatic decline in menstrual blood loss (65
e98%) within 12 months of use. The device, imbedded with
52 mg of levonorgestrel, releases 20 mg of levonorgestrel per
day, causing pseudodecidualization of the endometrium with
very little systemic absorption of progesterone. The Mirena is
licensed for treatment of idiopathic menorrhagia. Its contraceptive effect lasts for 5 years.

Answer 5
B
Good evidence shows that bariatric surgery is more effective at bringing about weight loss than lifestyle interventions.
NICE guidance supports use of bariatric surgery for individuals
with a BMI 40 kg/m2. It only supports weight loss surgery at
lower BMIs if there are other co-morbidities such as type 2
diabetes. There is no randomized controlled evidence to show
that it increases conception rates, or reduces miscarriage risk,
although there are plausible biological explanations for why
this might be the case. Evidence so far does suggest that hypertensive disorders of pregnancy are less frequent in the
treated group, perhaps at the expense of an increased risk of
fetal growth restriction, particularly in the women who have
had malabsorptive procedures.

Answer 10
I. H
This girl needs a reliable method of contraception as well
as a treatment to reduce menstrual blood loss. She should not
be prescribed oestrogens as she suffers from migraines.
II. E
This woman would be suitable for endometrial ablation.
This would avoid the high surgical risks of hysterectomy in
view of her high BMI.
III. G
Resecting this fibroid polyp transcervically should cure
her menstrual dysfunction and retain her future fertility. As
no information is given regarding her future fertility intentions, it should be assumed that this should preserved if
possible.

Answer 6
C
Although rarely seen in the UK, overt symptomatic untreated hypothyroidism is also associated with an increase in
miscarriage, gestational hypertension, preterm delivery, postpartum haemorrhage and fetal growth restriction. There has
also been a suggestion that hypothyroidism is associated with
gestational diabetes mellitus, with almost double the number
of women on levothyroxine replacement having this diagnosis
compared with the background population.

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