REVIEW
Current management of
gestational trophoblastic
disease
Ka Yu Tse
Karen KL Chan
Kar Fai Tam
Hextan YS Ngan
Abstract
Gestational trophoblastic disease is a rare pregnancy-related disorder. It
comprises of partial mole, complete mole, choriocarcinoma, placental
site trophoblastic tumour and epithelioid trophoblastic tumour. Novel
immunohistochemical technologies have helped in the diagnosis of the
disease and some of the genes may also serve as prognostic markers.
Partial and complete moles can be treated by suction evacuation and
most patients do not require further treatment. However, 10e20% of
them may develop gestational trophoblastic neoplasia. The International
Federation of Obstetrics and Gynaecology has adopted a staging system
with incorporation of the modified World Health Organization scoring sys-
tem. Low-risk disease is treated by single-agent chemotherapy while high-
risk disease is treated by multi-agent chemotherapy. The overall cure rate
is more than 90% and most patients can preserve fertility and anticipate
normal pregnancy outcomes. Nevertheless, the disease can recur. Referral
to a specialist centre is important to ensure proper monitoring and
management.
Keywords choriocarcinoma; gestational trophoblastic disease; gesta-
tional trophoblastic neoplasia; hydatidiform mole; management
Introduction
Gestational trophoblastic disease (GTD) consists of a spectrum of
pregnancy-related disorders ranging from benign hydatidiform
mole to malignant conditions. In the report by the International
Federation of Obstetrics and Gynaecology (FIGO) in 2012,
gestational trophoblastic neoplasia (GTN) replaces the terms
including chorioadenoma destruens, metastasizing mole, and
choriocarcinoma, though a histological verification is still
Ka Yu Tse MRCOG MMedSc FHKCOG is at the Department of Obstetrics and
Gynaecology, University of Hong Kong, Queen Mary Hospital, Hong
Kong. Conflicts of interest: none declared.
Karen K L Chan FRCOG FHKCOG is at the Department of Obstetrics and
Gynaecology, University of Hong Kong, Queen Mary Hospital, Hong
Kong. Conflicts of interest: none declared.
Kar Fai Tam FRCOG FHKCOG is at the Department of Obstetrics and Gy-
naecology, University of Hong Kong, Queen Mary Hospital, Hong Kong.
Conflicts of interest: none declared.
Hextan Y S Ngan MD FRCOG FHKCOG is at the Department of Obstetrics and
Gynaecology, University of Hong Kong, Queen Mary Hospital, Hong
Kong. Conflicts of interest: none declared.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
desirable. GTN also represents a condition when there is a
plateau comprising of at least four persistently elevated human
chorionic gonadatrophic (hCG) levels (day 1, 7, 14 and 21), or
sequential rise of hCG for two weeks (day 1, 7 and 14) or longer,
or lung metastases diagnosed by chest X-ray. Non-metastatic
trophoblastic neoplasia refers to diseases localised within the
uterus, while metastatic GTN refers to diseases spreading to
other sites such as vagina, lungs, liver and brain. Placental-site
trophoblastic tumour (PSTT) and epithelioid trophoblastic
tumour (ETT) have distinct pathological and clinical presentation
and should be classified separately. GTD was once a fatal dis-
ease. But with the advances in the disease diagnosis, better hCG
assay, availability of effective chemotherapy, >90% patients can
be treated successfully without the need of surgery even in the
presence of metastatic diseases.
Hydatidiform mole
Epidemiology
Hydatidiform mole can be classified into complete (CHM) and
partial (PHM) moles. Molar pregnancy is rare, and its incidence
varies from 11.5 per 1000 deliveries in Indonesia to less than one
per 1000 deliveries in the United States. In the United Kingdom,
the incidence of CHM is 1e3 in 1000 pregnancies and that of
PHM is 3 in 1000 pregnancy. The accuracy of these epidemio-
logical data depends on reliability of the diagnostic techniques
and the availability of a vigilant registry system. Besides, the
incidence of molar pregnancy may be under-estimated if the
tissue masses are not saved for histological examination after
miscarriage or termination of pregnancy.
Molar pregnancy is more common at the extremes of ages.
The risk of recurrent molar pregnancy increased to 1e1.8% after
one molar pregnancy and to 15e20% after two molar pregnan-
cies. Recent genetic studies also showed that mutation in NLRP7
(formerly known as NALP7) gene on chromosome 19q13 and
rarely KHDC3L on chromosome 6, is associated with familial
recurrent hydatidiform mole which is an autosomal recessive
disorder causing CHM of diploid and biparental in origin. In
addition, the use of oral contraceptive pills had been implicated
to lead to an increased risk of molar pregnancy and such risk
appears to increase with the duration of the use of the pills. On
the other hand, the relationship of vitamin A precursor carotene
deficiency, late menarache, light menstrual flow, parity, blood
group, paternal age, smoking and alcohol consumption with
molar pregnancy remains unclear.
Pathology
Cytogenetic studies have shown that CHM has a diploid karyo-
type and is paternal in origin. 80e90% of CHM are the result of
fertilisation of an empty ovum by a haploid sperm which then
duplicates its chromosomes. Hence, the karyotype configuration
of the CHM zygote is 46, XX. In the remaining cases, an empty
ovum is fertilised by two haploid sperms resulting in 46, XX or
XY. In PHM, a haploid ovum is fertilised by two sperms. The
zygote, therefore, becomes triploid containing 69, XXY, XXX and
rarely XYY.
Although less conspicuous in early gestation, CHM is char-
acterised by gross villous vesicles, diffuse hydropic villi and
trophoblastic hyperplasia with stromal hypercellularity and
12 2014 Elsevier Ltd. All rights reserved.
 REVIEW
karyorrhoectic debris. The cytotrophoblasts may show nuclear
pleomorphism. In contrast, gross villous vesicles are only occa-
sionally seen in PHM and the hydropic villi tend to be smaller
and less numerous compared with CHM. Trophoblastic hyper-
plasia is less obvious and there may be scalloping of chorionic
villi and trophoblastic stromal pseudo-inclusion. Normal gesta-
tional products like gestational sac, embryo, foetus, foetal
erythrocyte or placenta may be present. p57 (KIP2) is a pater-
nally imprinted gene and is maternally expressed. CHM is
composed of paternal DNA and so there is absence of p57 (KIP2)
nuclear staining in the cytotrophoblasts and villous stromal cells.
On the other hand, since PHM and hydropic abortion contain
maternal DNA, p57 (KIP2) is positive. Ploidy analysis using in
situ hybridisation, flow cytolmetry or short tandem repeat gen-
otyping can determine the paternal or maternal origin of the
polymorphic alleles. Thus, it is possible to distinguish between
androgenetic diploidy, diandrogenic triploidy and biparental
diploidy in the diagnsosis of CHM, PHM and non-molar
pregnancy.
Presentation
The most common presentation of molar pregnancy is vaginal
bleeding complicating pregnancy. Some may also have passage
of vesicles and the uterus may be larger than date on examina-
tion. With more popular use of early ultrasound and hCG mea-
surement, molar pregnancy can be diagnosed earlier. Therefore,
florid symptoms like hyperemesis gravidarum, hyperthyroidism,
early-onset pre-eclampsia, thromboembolism, large ovarian
theca lutein cysts and neurological and chest symptoms due to
brain and lung metastasis are rarely seen nowadays.
Investigation
Ultrasound, especially transvaginal scan with Doppler flow, may
help to detect molar pregnancy. CHM may be diagnosed by
features such as anembryonic pregnancy, delayed miscarriage
and snow-storm appearance. The suspicion of PHM may be
raised when soft markers like cystic spaces in placenta, ratio of
transverse to antero-posterior diameters of the gestational sac
more than 1.5 are present. In general, the detection rate of molar
pregnancy by ultrasound is poor. In one retrospective study
involving more than 1000 patients, the sensitivity, specificity,
positive predictive value and negative predictive value of ultra-
sound in detecting hydatidiform mole were 44%, 74%, 88% and
23%, respectively. Therefore, the diagnosis of GTD can only be
reliably made with histological examination and it should be
performed after every non-viable pregnancy.
Human chorionic gonadotrophin
hCG is a glycoprotein produced by syncytiotrophoblasts con-
taining a and b subunits joined by non-covalent bonds. In
normal pregnancy, most hCG is intact. In GTD, there is a higher
proportion of b-hCG compared with that in normal pregnancy.
Various forms of b-hCG exist in GTD, including free-b, b-core,
nicked free-b and carboxyl-terminal fragments. Therefore, an
ideal hCG assay for GTD should detect all portions of b-hCG,
particularly the free beta subunit, hyperglycosylated hCG (hCG-
H), nicked hCG, and hCG missing the terminal carboxyl segment.
False-positive and false-negative results can occur. Phantom hCG
(pseudohypergonadotropinemia) is a result of the presence of
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
heterophilic antibodies in serum that react with the animal-
derived antigens used in commercial hCG immunoassay kits
giving rise to a falsely elevated hCG. Heterophilic antibodies may
be present in approximately 3.4% of healthy individuals. If there
is discrepancy with the clinical presentation, hCG levels should
be rechecked with a different immunoassay. The other easy
alternative is to measure the urine hCG or its derivatives (free-b
subunit or b-core fragment) either quantitatively or qualitatively
because heterophilic antibodies have a large molecular size and
are not excreted into the urine. So if the serum hCG is persistently
positive while the urine hCG is negative, it implies the presence
of interference with the serum hCG immunoassay. The lack of
linear parallelism with serial serum dilutions can also help to
corroborate the presence of false-positive hCG, as heterophilic
antibodies react with reagents in the immunoassay and not hCG.
Serum can also be pre-absorbed to eliminate the heterophilic
antibodies. If the serum hCG returns to negative after the pre-
absorption, inference with the immunoassay is confirmed. Low
level of pituitary-derived hCG may also be detected in serum in
1.3% peri-menopausal and 6.7% post-menopausal women due
to the lack of oestrogen and progesterone negative feedback on
the luteinizing hormone and follicle-stimulating hormone (FSH)
production. Interpretation of the concurrent FSH level and the
use of oral contraceptive pills to suppress the pituitary may be
useful to determine the origin of the hCG production.
On the other hand, high dose hook effect can occur with a
falsely low serum hCG level. When the serum hCG level is too
high, there are not enough antibodies in the solution to bind the
hCG molecules and hence much of them are being washed away
without being measured. If a very high hCG level is suspected,
the laboratory should be informed and the serum should be
diluted before measurement.
In a retrospective study on 153 patients, 46% of the patients
with CHM had hCG level over 100,000 IU/l before evacuation.
However, a cut-off level for diagnosing pregnancy is not known,
though some studies showed that molar pregnancy was likely if
the hCG level was higher than two multiples of the median or
more than 80,000 mIU/ml.
Treatment
Suction evacuation of the uterus can aid histological diagnosis
and treatment. Cervical priming immediately before uterine
evacuation does not increase the need of subsequent chemo-
therapy. Medical induction is not recommended for molar
pregnancy because of the theoretical risk of myometrial
contraction and tumour embolism through the venous system.
Besides, medical induction might incur higher risk of incomplete
abortion and hence the need of subsequent chemotherapy.
Nevertheless, medical abortion may be considered in PHM at
second trimester because the foetal parts may obstruct the
evacuation and the risk of persistent trophoblastic disease after
the procedure is low. Because the uterus is usually vascular and
bigger than date, uterine evacuation should be performed by an
experienced gynaecologist. If the gestation is more than 16
weeks, the evacuation should be performed in a trophoblastic
disease centre. In case of heavy bleeding during the procedure,
oxytocic agents can be given, preferably after the evacuation has
been completed. Anti-D prophylaxis should be given where
appropriate.
13 2014 Elsevier Ltd. All rights reserved.
 REVIEW
Up to date, there is still no strong evidence about the role of
prophylactic chemotherapy. A meta-analysis including three
randomised trials of 613 patients showed that prophylactic
chemotherapy might reduce the risk of progression from CHM to
GTN. However, two of the three studies had problems with the
methodology. Besides, the prophylactic chemotherapy might
delay the diagnosis of GTN and these patients appeared to
require more courses of chemotherapy if GTN is subsequently
diagnosed. Prophylactic chemotherapy might only be restricted
to patients who cannot be followed and the decision should be
made after discussion with experts in treating GTD.
Mole in multiple pregnancy
Hydatidiform mole can co-exist with a live foetus. An option of
continuing the pregnancy can be given to the patient after
informing the risks of miscarriage (40%), pre-term delivery
(36%), pre-eclampsia (20%) and rarely pulmonary embolism.
The patient should be referred to a maternalefoetal medicine
unit for close antenatal check-up and the chance of achieving a
live baby is 25e40%. There is no increased risk of persistent
GTD. Hydatidiform mole has also been reported in triplet and
quadruplet pregnancies. However, the risk of foetal loss is more
than 90% and selective feticide might have to be considered.
Follow-up
According to the FIGO recommendation, patients with molar
pregnancy should be followed up with weekly hCG until normal
and then two more weekly specimens should be checked. After
that, the hCG should be monitored monthly for six months and
then every two months for six more months. In the UK, all pa-
tients with GTD should be registered in one of three specialist
centres for follow-up: Weston Park Hospital (Sheffield), Nine-
wells Hospital (Dundee) or Charing Cross Hospital (London). A
retrospective study involving 6701 patients showed that among
the 422 patients (6%) who developed persistent GTN, 412 (98%)
presented within 6 months after evacuation and only one woman
was detected by routine extended follow-up. The current UK
practice is to ask the patients to send their serum and urine
samples for hCG assay every 2 weeks until the hCG levels return
to normal. If the hCG levels return to normal within 56 days after
evacuation, urine hCG will be checked monthly for 6 months
from the date of evacuation. If the hCG levels return to normal
more than 56 days after evacuation, urine hCG will be checked
monthly for 6 months after the date when the levels drop to
normal.
The patients should practice reliable contraception for at least
6 months after the hCG levels become normal, because raised
hCG levels during pregnancy will confuse the clinical picture. A
longer delay of subsequent pregnancy may be necessary if the
decline of hCG is slow. A summary of the United Kingdom
Medical Eligibility of Contraceptive Use (UKMEC) recommenda-
tions of the use of different contraceptive methods is illustrated
in Table 1. Although it suggests that hormonal methods can be
safely used even when the hCG level is persistently elevated or in
the presence of malignant disease, it is generally advised to defer
their use until the hCG level becomes normal. Similarly, intra-
uterine contraceptive devices are not recommended when hCG is
high because of the risk of abnormal vaginal bleeding and uterine
perforation. If the patient happens to get pregnant within 6
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
months, the pregnancy may be allowed to continue because the
risk of foetal abnormality or persistent trophoblastic disease is
minimal.
Patient should notify the screening centres after each preg-
nancy regardless of the outcomes, and the serum and urine hCG
level should be measured at 6 weeks and 10 weeks after the
pregnancy until undetectable.
A summary of the management of hydatidiform mole is
shown in Table 2.
GTN
Similar to molar pregnancy, GTN is more common in Southeast
Asia than the West. The incidence in India and Indonesia varies
from 15e19 per 1000 pregnancies and that in the West is 0.2e0.7
per 1000 pregnancies. 25% of it is associated with antecedent
miscarriage or abortion, 5% with ectopic pregnancy, 20% with
full-term pregnancy and 50% with hydatidiform mole. About 0.5
e1% of PHM and 15% CHM patients progress to GTN necessi-
tating chemotherapy. Retrospective studies have shown that
maternal age, previous history of molar pregnancy and elevated
post-evacuation hCG levels were associated with higher risk of
GTN. Recently, there were several studies showing that the
regression rate of serum and urine hCG might be a predictor for
the development of GTN.
Staging and scoring
There are few staging systems for GTN such as the ones devel-
oped in the Charing Cross Hospital and by Hammond. In 2000,
the FIGO Gynaecological Oncology Committee recommended a
clinical and anatomical staging system and accepted the incor-
poration of the WHO scoring system based on the prognostic
factors modified from the one devised by Bagshawe. Each patient
with GTN should be allotted with a stage (IeIV) and a score
separated by a colon (e.g. stage I: 3). The staging and scoring
systems are shown in Table 3.
The overall 5-year survival for patients with GTN is estimated
to be 92.7%, and is 97.3%, 85.7%, 82.8% and 61.9% for stage I,
II, III and IV patients respectively. Using 6 as the cut-off as rati-
fied by the FIGO in June 2002, the 5-year survival for low-risk
patients is similar to stage I patients, while that for high-risk
patients is 79.5% overall (84% for those with score 7e12 and
68% for those with score >12).
Pre-chemotherapy work-up
The usual indications for chemotherapy used in the UK are listed
in Table 4. In the past, raised hCG level 6 months after evacua-
tion was an indication for chemotherapy even if it was falling.
However, in a large review of 13,960 patients with molar preg-
nancy, only 76 patients (<1%) had persistently raised hCG of >5
IU/L six months after evacuation. 66 of them did not receive
chemotherapy and the hCG of 65 patients returned to normal
spontaneously. Therefore, this indication has been omitted in the
recent FIGO and UK guidelines. In general, it is recommended
that low-risk disease should be treated by single-agent chemo-
therapy while high-risk disease and choriocarcinoma by combi-
nation chemotherapy.
Physical examination is carried out to check if there is any
systematic involvement, to assess the uterine size and look for
14 2014 Elsevier Ltd. All rights reserved.
 REVIEW

Recommendations from the UKMEC 2009

CHC POP DMPA/NET-EN IMP Cu-IUD LNG-IUD Barrier Female
methods sterilisation

Decreasing/undetectable b-hCG level 1 1 1 1 1 1 1 A

Persistently elevated b-hCG level or 1 1 1 1 4 4 1 D
malignant disease

UKMEC, United Kingdom Medical Eligibility of Contraceptive Use; CHC, combined hormonal contraception; POP, progestogen-only pills; DMPA, depot medroxyprogester-
one acetate; NET-EN, norethisterone enanthate; IMP, progestogen-only implant; Cu-IUD, copper-bearing intrauterine device; LNG-IUD, levonorgestrel-releasing IUD; hCG,
human chorionic gonadotrophin; Category 1, a condition for which there is no restriction for the use of the contraceptive method; Category 2, a condition where the
advantages of using the method generally outweigh the theoretical or proven risks; Category 3, a condition where the theoretical or proven risks usually outweigh
the advantages of using the method; Category 4, a condition which represents an unacceptable health risk if the contraceptive health risk if the contraceptive method
is used; Category A, there is no medical reason to deny sterilisation to a person with this condition; Category D, the procedure is delayed until the condition is evaluated
and/or changes. Alternative temporary methods of contraception should be provided.

Table 1

any vaginal metastasis or adnexal mass. Full blood count, clot-
ting profile, liver function test, urea and electrolytes are taken to
assess the general condition of the patients. Thyroid function test
has to be checked when indicated. The serum hCG level is taken
as a baseline for subsequent monitoring of the response to
chemotherapy. Doppler ultrasound of the pelvis is needed to
exclude any pregnancy or retained products of conception that
might otherwise cause a rise of hCG, and to measure the uterine
volume and the size of any intrauterine lesion. There is also
emerging evidence that pulsatility index of the uterine artery can
predict the resistance to methotrexate especially for those at
WHO score 5e6. Chest X-ray is crucial in looking for pulmonary
metastasis and the role of routine chest computed tomography
(CT) is still controversial, because micro-metastases can occur up
to 40% and replacing chest X-ray by CT scan does not alter the
Management of hydatidiform mole
Investigation
Serum and urine hCG
Full blood count
Clotting profile
Liver function test, urea, creatinine and electrolytes
Group and saver
Thyroid function test
HIV and HBV serology
Chest X-ray
Ultrasound Doppler of pelvis
Treatment
Uterine evacuation (avoid cervical priming, and use
oxytocic agent after completion of uterine evacuation
if there is heavy vaginal bleeding)
Follow-up
Check serum and urine hCG assay every 2 weeks until
the hCG levels normalise and then urine hCG every month
for 6 months
Practice contraception for at least 6 months
hCG, human chorionic gonadotrophin.
Table 2
outcomes. Besides, lesions <2 cm may regress spontaneously. In
UK, chest CT would be performed if there are inconclusive
findings or >1 cm metastasis on chest X-ray. Ultrasound or CT is
used to look for liver metastasis. The FIGO also recommends
whole-body CT scan in the presence of lung metastasis. CT or
magnetic resonance imaging (MRI) of the brain is not routinely
performed unless the patients have neurological symptoms or
lung metastasis. If the imaging does not show any brain metas-
tasis but there is clinical suspicion, cerebrospinal fluid (CSF) can
be aspirated to measure the hCG level. A CSF: serum hCG ratio of
greater than 1:60 suggests central nervous system metastasis.
Positron emission tomography (PET)-CT, tagging fluo-
rodeoxyglucose with a positron-emitting isotope of fluorine (18F),
could detect neoplastic tissues that have high metabolic rate and
glucose uptake. In a recent retrospective study, it showed that
PET-CT did not have additional value comparing to conventional
imaging. However, it may be useful in locating the primary
source of unexplained high hCG level that may not be detected
by conventional imaging tools. It might also be potentially useful
in mapping the metastatic sites and monitoring the treatment
response.
Treatment
Low-risk GTN: second uterine evacuation is usually unnecessary
unless in selected patients who are symptomatic with retained
products of conception, or when the hCG level is below 5000 IU/
L and the tumour is confined in the endometrium. This has to be
balanced against the risk of bleeding and uterine perforation and
so the decision of repeated evacuation should only be made after
being reviewed in specialist centres. Hysterectomy may be
considered for those who have no fertility wish or have life-
threatening haemorrhage. Hysterectomy can provide permanent
sterilization and prevent local myometrial invasion, but it cannot
obviate the risk of metastasis and the need of chemotherapy.
Patients at stage IeIII with WHO score <7 are treated with
single agent. Methotrexate (MTX) is the traditional first-line
agent. One common regimen used in the UK is 50 mg MTX
intramuscular injection on days 1, 3, 5 and 7, with 0.1 mg/kg or
15 mg oral folinic acid 24e30 h after MTX on days 2, 4, 6 and 8,
repeated every 2 weeks for four courses. Serum and urine hCG
levels should be checked at least once per week to monitor the
response. As a normal hCG value implies that there are still <105

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1 15 2014 Elsevier Ltd. All rights reserved.
 REVIEW

FIGO staging and classification

FIGO staging and classification
Stage I Disease confined to the uterus
Stage II GTN extends outside of the uterus, but is limited to the genital structures (adnexal, vagina, broad ligament)
Stage III GTN extends to the lungs, with or without known genital tract involvement
Stage IV All other metastatic sites
Modified WHO prognostic scoring system as adapted by FIGO
Scores 0 1 2 4
Age <40 40 e e
Antecedent pregnancy mole abortion term e
Interval months from index pregnancy <4 4e<7 7e<13
Pre-treatment serum hCG (IU/l) <103 103e<104 103e<104 105
Largest tumour size (including uterus) e 3e<5 cm 5 cm e
Site of metastases lung spleen, kidney gastro- intestinal liver, brain
Number of metastases e 1e4 5e8 >8
Previous failed chemotherapy e e single drug 2 drugs

FIGO, Federation of Obstetrics and Gynaecology; GTN, gestational trophoblastic neoplasia; WHO, World Health Organization; hCG, human chorionic gonadotrophin.

Table 3

tumour cells in the body, at least one and preferably three more
courses of chemotherapy should be given for consolidation after
hCG normalisation in order to eliminate any residual tropho-
blastic cells and reduce the chance of relapse. The complete
response rate is 72% with 20e25% primary failure rate. Less
than 5% of patients develop grade III/IV toxicity including
mucositis, stomatitis, pleuritic chest pain, thrombocytopaenia,
uterine bleeding, abdominal pain, liver derangement, rash and
pericardial effusion. Other regimens of MTX have also been re-
ported, for example, 0.4 mg/kg MTX intramuscularly for 5 days
and repeated every 2 weeks where the primary failure rate is 11
e15% for non-metastatic diseases and 27e33% for metastatic
diseases, and weekly intramuscular MTX 50 mg/m2 where the
primary failure rate is 30%. Direct comparison of these regimens
is difficult because there are no randomised controlled trials and
the indications of chemotherapy and scoring systems are
different in different centres. Some may also administer
Indications for chemotherapy after GTD
Rising hCG of 10% in two consecutive serum samples
over at least 2 weeks (days 1, 7 and 14)
hCG plateau in four or more consecutive serum samples
after evacuation over at lest 3 weeks (days 1, 7, 14 and 21)
Serum hCG 20,000 IU/l more than 4 weeks after evacuation
Brain, liver, gastrointestinal or lung metastases >2 cm
on chest X-ray
Histological evidence of choriocarcinoma
Heavy vaginal bleeding or gastrointestinal/intraperitoneal
bleeding
Pulmonary, vulval or vaginal metastases, unless the hCG
level is falling
hCG, human chorionic gonadotrophin.
Table 4
intrathecal methotrexate (12.5 mg) prophylaxis every 2 weeks for
three doses for those low-risk women with pulmonary but not
central nervous system metastasis, although this practice is still
being questioned.
Actinomycin-D is also widely used. It can be given as an
intravenous bolus of 1.25 mg/m2 or an intravenous infusion of
0.5 mg for 5 days every 2 weeks until documented complete
response. About 75e80% of patients resistant to methotrexate
attained complete response with minimal toxicity. Using as
first-line treatment, the response rate was even up to 90%. A
recent randomized controlled trial comparing weekly intra-
muscular methotrexate 30 mg/m2 and biweekly intravenous
actinomycin D 1.25 mg/m2 showed a better response in the
latter group (complete response rate 53% Vs 70%, p 0.01)
with modest toxicity. A Cochrane review including 513 patients
in 5 randomized controlled trials showed that actinomycin D
appeared to be superior to methotrexate (risk ratio [RR] 0.64,
95% confidence interval [CI] 0.54e0.76), and methotrexate
was associated with significantly more treatment failure than
actinomycin D (RR 3.81, 95% CI 1.64e8.86). However, caution
should be taken in interpreting the results as the review
included different regimens and direct comparison was diffi-
cult. In the past, 5-fluorouracil and etoposide were also used to
treat low-risk GTN but they are now seldom used alone because
of toxicity.
It has been demonstrated that only about 30% of patients with
score 5e6 or hCG between 100,000e400,000 IU/L would
respond to single agent chemotherapy. For those whose initial
hCG is >400,000 IU/L, single agent is unlikely to be effective and
therefore combined chemotherapy is recommended.
In a retrospective study on 328 low-risk post-molar GTN pa-
tients, the median time to remission was 46 days (28e77 days).
The diagnosis of CHM, presence of metastatic disease, the use of
multi-agent therapy and FIGO score were independently associ-
ated with longer time to remission. And each one-point increase
in the WHO score would lead a 17-day increase in time to achieve

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1 16 2014 Elsevier Ltd. All rights reserved.
 REVIEW
hCG remission. The role of uterine artery pulsatility index, hCG
normogram and hCG kinetic models in predicting resistance to
MTX needs to be further evaluated.
High-risk GTN: patients in stage IeIII with WHO score 7 or
stage IV are treated with combined chemotherapy. The most
popular regimen used nowadays is the EMA-CO (Table 5). The
complete remission rate was about 85% and the 5-year overall
survival rate was 75e90%. However, cause-specific survival was
only 68% for those with liver metastasis. The overall survival
was 50e70% with brain metastasis, and was worse for those
with symptoms compared to those without symptoms (41% Vs
100%, p 0.0005). If both brain and liver metastases are pre-
sent, the 5-year survival is only 10%. The major side effects
include mucositis, pleuritis, alopecia, liver derangement, mye-
losuppression and vincristine-associated peripheral neuropathy.
One health questionnaire study conducted in the UK showed that
combined chemotherapy containing etoposide was associated
with a slight increased risk of secondary malignancy (RR 1.5;
95% CI 1.1e2.1) with the greatest risk in myeloid leukaemia (RR
16.6; 95% CI 5.4e38.9), colon (RR 4.6; 95% CI 1.5e10.7), and
breast cancer when the survival exceeded 25 years (RR 5.8; 95%
CI 1.2e16.9). Some centres lower the dosage of etoposide after
normalization of the hCG level to minimise the risk of secondary
malignancies.
Examples of other regimens include MEA (methotrexate,
etoposide and actinomycin-D); MAC (methotrexate,
actinomycin-D and cyclophosphamide or chlorambucil); CHA-
MOMA (cyclophosphamide, hydroxyurea, actinomycin-D,
methotrexate with folinic acid, vincristine, melphalan and
doxorubicin); and CHAMOC (cyclophosphamide, hydroxyurea,
actinomycin-D, methotrexate with folinic acid, vincristine). Used
as primary treatment, the response rate was around 60e80%.
Although some studies attempted to compare the response rate
and toxicity of different regimens, a Cochrane review failed to
draw any conclusion because only one randomised controlled
trial comparing MAC and CHAMOCA was identified and there
was no randomised controlled trial comparing EMA-CO with
other regimens.
Those patients presenting at very advanced stage involving
organs like the lungs, brain, and/or liver, might be commenced
on reduced-dose chemotherapy, such as etoposide 100 mg/m2
and cisplatin 20 mg/m2 on days 1 and 2 and repeated weekly for
1e3 weeks before returning to the usual chemotherapy regimen,
to avoid life-threatening complications such as pulmonary, ce-
rebral, or liver decompensation from tumour oedema or
haemorrhage.
A review containing 22 patients with MTX-resistant GTN and
24 patients with primary high-risk diseases using EMA-CO
showed that half of each group would be able to achieve hCG
remission before the 3rd and 6th course, respectively. The 90th
percentile was below the normal before the start of the 4th cycle
for those MTX-resistant patients and before the start of the 8th
cycle for those primary high-risk patients. Such normogram
might potentially be useful in predicting resistance to EMA-CO
but further validation is needed.
Resistant or relapsed high-risk GTN: Chemo-resistance is
featured by a plateau or a rise in hCG level with or without new
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
metastasis while the patient is receiving chemotherapy, and
relapse is defined by >2 consecutive rise of hCG not related to
pregnancy after complete remission from primary treatment. The
relapse rate is about 3% in low-risk GTN, and 7e10% and up to
25% in some case series in high-risk GTN. Although 20e30% of
these patients eventually fail to respond to treatment and prog-
ress, the rest are salvageable by further chemotherapy with or
without surgery. Those who are resistant to chemotherapy have
worse prognosis than those who relapse. The overall 5-year
survival for patients with relapsed GTN is more than 90%
(nearly 100% for low-risk GTN and around 85% for high-risk
GTN).
In the United Kingdom, in case of resistance to methotrexate
or relapse in low-risk GTN, actinomycin-D will replace metho-
trexate if the hCG level is less than 300 IU/l and combined
chemotherapy like EMA-CO will be given if hCG is higher than
300 IU/l. For those high-risk patients who are resistant to first-
line chemotherapy or have relapse, salvage combined chemo-
therapy can be given. The most commonly used regimen in this
scenario is EP-EMA (etoposide, cisplatin, etoposide, metho-
trexate and actinomycin-D), which has been shown to have 66
e75% complete remission rate and 88% survival rate. EP may be
replaced by doxorubicin and cisplatin in selected cases. Another
regimen consisting of TP/TE (paclitaxel, cisplatin/paclitaxel,
etoposide) is also gaining favour, which has a response rate of
50% and survival rate of 44% in those who failed previous
chemotherapy and the side effects are tolerable. The survival rate
increases to 70% for those who had not exposed to platinum-
based chemotherapy before. Other alternative regimens include
MBE (methotrexate, bleomycin and etoposide), FA (5-
fluorouracil, dactinomycin), BEP (bleomycin, etoposide and
cisplatin), FAEV (floxuridine, dactinomycin, etoposide, and
vincristine), VIP or ICE (etoposide, ifosfamide, and cisplatin or
carboplatin) and capecitabine. Myelosuppression remains the
dose-limiting factor and granulocyte-colony stimulating factor
may be needed. Some authors have also used high-dose
chemotherapy and autologous stem cell support as salvage
treatment though this practice has not been evaluated in clinical
trials. The Cochrance review published in 2012 could not identify
any randomised control study and so no conclusion could be
drawn to suggest the most optimal therapy.
Quiescent GTD: it has been suggested that hyperglycosylated
hCG (hCG-H), produced by extra-villous cytotrophoblast cells,
can enhance trophoblast invasion in choriocarcinoma, and
trigger cytotrophoblast growth and placental implantation during
pregnancy. It is elevated in GTN. In the recent decades, a con-
dition called quiescent GTD has been described. It is thought to
be an inactive form of GTD which can be diagnosed by
persistently low hCG, usually in the range of 50e100 IU/l and
typically below 207 IU/l, for at least three consecutive months. It
is postulated that the low level of hCG is due to the presence of
differentiated syncytiotrophoblasts which produce a small
amount of hCG. Because there is no significant amount of cyto-
trophoblast cells, the hCG-H level is negligible. Chemotherapy is
not needed and the condition usually will disappear within 6
months. It has been estimated that approximately 20% of women
with quiescent hCG will have a rise in hCG months to years later
when the hCG-H constitutes a large proportion of the total hCG
17 2014 Elsevier Ltd. All rights reserved.
 REVIEW
EMA-CO chemotherapy
Regimen 1
Day 1
Etoposide
Actinomycin-D
Methotrexate
Day 2
Etoposide
Actinomycin-D
Folinic acid rescue
Regimen 2
Day 8
Vincristine
Cyclophosphamide
The two regimens alternate each week
EMA-CO chemotherapy, etoposide, methotrexate, actinomycin-D, cyclophosphamide and vincristine with folinic acid rescue.
Table 5
and treatment should then be initiated. However, whether
quiescent GTD is a new disease entity and whether it is reliable to
utilise hCG-H in managing this condition are still under debate.
Role of surgery
About 50% of high-risk GTN patients may require surgery during
the course of their treatment. Surgery may be indicated to
remove resistant or persistent disease in the uterus or metastatic
sites, decrease the uterine tumour load in case of limited
metastasis, control profuse tumour haemorrhage, and relieve
symptoms like bowel or urinary obstruction due to the large
tumour bulk.
Uterine evacuation only benefits a limited number of patients
with low-risk GTN but may be useful in those who do not require
immediate chemotherapy and where urinary hCG is <1500 IU/l.
Surgical bleeder plication and arterial ligation may be necessary in
case of torrential bleeding from the tumours. Ovarian cystectomy
or salpingo-oophorectomy may be required if the patients
complain of sudden abdominal pain related to ovarian theca lutein
cyst complications. About 1 in 140 patients require hysterectomy
for GTN. About one-third of them are performed as primary
treatment, one-third are because of resistance to chemotherapy,
and another third because of heavy bleeding. The remission rate of
patients undergoing hysterectomy is around 75e90%. Metastatic
lesions outside lungs and pelvis, the number of metastases,
chemo-resistance especially to combination chemotherapy and the
use of  2 regimens, appear to adversely affect the therapeutic
response after hysterectomy in high-risk patients.
Residual lung lesions after completion of chemotherapy may
not need to be resected. Besides, it was postulated that the
radiological finding of tumour regression lagged behind the
decline of hCG and many patients still had a persistent chest
lesion for years despite clinical remission. However, if the
chemo-resistance is due to the pulmonary metastasis and the
lung lesion is amenable to operation, lung resection may be
justified. A remission rate of up to 90% has been reported.
Craniotomy is usually performed when there is acute cerebral
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
100 mg/m2 intravenous infusion over 30 min
0.5 mg intravenous bolus
300 mg/m2 intravenous infusion over 12 h
100 mg/m2 intravenous infusion over 30 min
0.5 mg intravenous bolus
15 mg intramuscularly or orally every 12 h for four doses
(starting 24 h after beginning the methotrexate infusion)
1 mg/m2 intravenous bolus (maximum 2 mg)
600 mg/m2 intravenous infusion over 30 min
haemorrhage or other neurological complications requiring
emergency decompression, or when there are multiple metasta-
ses where early removal of solitary superficial tumour can sta-
bilise the patients before contemplating further treatment. A
retrospective study showed that all chemo-resistant patients
having treatment failure after salvage surgery had 2 out of the 4
risk factors: age older than 35, antecedent non-molar pregnancy,
metastasis outside lungs and pre-operative b-hCG level >10 IU/l.
Role of selective arterial embolization
Selective arterial embolization using modified Seldinger tech-
nique with gelfoam particles has been used to control intractable
bleeding in uterine, vaginal, hepatic metastasis. There has also
been a case report describing the use of embolization to control
bleeding and disease in a patient with low-risk GTN, eliminating
the need of subsequent chemotherapy. This technique is an
attractive alternative to surgery because it is non-invasive and
can be done under conscious sedation. Pregnancy has been re-
ported after this treatment. However, complications can arise,
including post-embolization syndrome like malaise, fever, pelvic
pain and leucocytosis. If iliac vessels are embolized, severe
complications such as perineal skin sloughing, recto-vesico-
vaginal fistulae and neurological deficits in the lower limbs can
occur.
Role of radiotherapy
Radiotherapy is rarely needed in the treatment of GTN but it has
a pivotal role in preventing unexpected bleeding in brain me-
tastases. When whole brain irradiation is given concurrently
with combined chemotherapy, the overall survival rate is around
40e90%. A retrospective study found that the survival rate of
patients receiving chemotherapy and irradiation, chemotherapy
alone and no treatment was 50%, 24% and 0%, respectively. A
total of 58% and 74% of the second and third groups died of
central nervous causes. Patients with neurological symptoms,
prior treatment and brain metastasis during treatment had poor
prognosis. The dosage of irradiation is also important. One study
18 2014 Elsevier Ltd. All rights reserved.
 REVIEW

Management of gestational trophoblastic neoplasia

Investigation
Clinical examination (watch for vaginal metastasis)
Weekly serum  urine hCG
Complete blood count, clotting profile, liver and renal function tests, group and save
Thyroid function test when indicated
(HIV and HBV serology)
Ultrasound Doppler of pelvis
Chest X-ray (Chest CT if chest X-ray is inconclusive or shows metastasis of >1 cm)
Ultrasound of liver or CT abdomen
Whole body CT if there is lung metastasis
CT or MRI brain if there are neurological symptoms or lung metastasis
Curettage should be performed if there is uterine bleeding
Biopsies may be obtained from accessible sites with balance of risk of haemorrhage
Selective scanning using anti-hCG antibody linked to radioactive iodine or indium may be done if there is persistent disease resistant to
chemotherapy
Treatment
Low-risk: single agent chemotherapy like methotrexate
High-risk: multi-agent chemotherapy like EMA-CO
Surgery, selective arterial embolisation and radiotherapy are used in selected cases
Follow-up
Serum and urine hCG are taken twice weekly during treatment
After treatment stops, serum and urine hCG are measured weekly for 6 weeks
At the 6th week, perform USS Doppler of pelvis, CXR or CT/MRI if they are abnormal at presentation
Year 1 e Two-weekly serum and urine hCG at 2e6 months, and then two-weekly urine hCG at 7e12 months
Year 2 e Monthly urine hCG
Year 3 e Two-monthly urine hCG
Year 4 e Three-monthly urine hCG
Year 5 e Four-monthly urine hCG
Year 6 and life-long e Six-monthly urine hCG
Practice contraception for at least 12 months

hCG, human chorionic gonadotrophin; CT, computed tomography; MRI, magnetic resonance imaging; CSF, cerebrospinal fluid, EMA-CO, etoposide, methotrexate,
actinomycin-D, cyclophosphamide and vincristine with folinic acid rescue.

Table 6

showed that the 5-year overall survival rate for those receiving
less than 2200 cGy was 39%, whereas for those receiving more
than 2200 cGy the survival rate was 100% ( p 0.03). In general,
the usual dosage is 2000e4000 cGy given in 10e20 fractions of
200e300 cGy each and the radiotherapy is usually given under
steroid cover to reduce cerebral oedema.
Radiotherapy has also been used in patients with liver
metastasis to avoid haemorrhagic complications. Whole-liver
irradiation is usually delivered at around 2000 cGy concur-
rently with chemotherapy over 2 weeks in an attempt to reduce
the risk of radiation-induced hepatitis. However, the prognosis of
these patients is poor with an overall 5-year survival rate less
than 30%. Radiotherapy to liver probably does not provide any
survival benefit and it is seldom given nowadays.
Follow-up
Recurrence usually occurs within 1 year. There is no recom-
mendation for the best schedule of follow-up. The follow-up
protocol used in the Charing Cross Hospital is shown in Table
6. As it is unclear when it is safe to stop the surveillance, the
monitoring is life-long.
Fertility
Most patients with GTN belong to the reproductive age group
and fertility is an important issue. There is concern that sexual
performance, ovarian function and foetal outcomes may be
affected after the completion of chemotherapy. A questionnaire
survey involving 47 patients receiving chemotherapy and/or
surgery for GTN showed that 70% experienced absent or low
sexual desire, 42% had dyspareunia, 45% had lubrication
problems and 53% had changes in the relationship with their
partners within the first year after remission. This indicated that
sexual dysfunction was a rather common phenomenon after
treatment for GTN, which could be overlooked by clinicians. This
problem could be partly attributed to the anxiety about disease
recurrence and future pregnancy outcomes. Thorough counsel-
ling about the nature of the disease, care about the psychosocial
aspect of patients, early detection of any distress in patients and
the involvement of a multidisciplinary team are definitely
needed.
On the other hand, another retrospective controlled survey
compared the age of menopause between patients treated with
and without chemotherapy. Although the former group

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1 19 2014 Elsevier Ltd. All rights reserved.
 REVIEW
(median 50, range 25e56 years) had menopause 3 years earlier
than the latter group (median 53, range 40e57 years) (log-rank
Chi2 test 12.6, p 0.0004), there was no evidence of pre-
mature ovarian failure and the difference did not have
great clinical significance. In addition, even if assisted repro-
ductive technique is contemplated, there is no evidence of
increased risk of recurrent GTD in spite of a small number of
case reports.
As for the pregnancy outcomes of patients receiving single
and multiple agents, the overall fertility rate is more than 80%. A
review article summarising the data from 10 different interna-
tional centres showed that patients with persistent GTN,
regardless of the risk scores and the chemotherapy regimens
used, had favourable pregnancy outcomes. The live birth rate
was 76.4% and the term delivery rate was 71.5%, while the rate
of premature deliveries, stillbirth, miscarriage and congenital
abnormalities was only 5.0%, 1.3%, 14.0% and 1.3% respec-
tively. But if patients conceive within 6 months of chemotherapy,
the incidence of abnormal pregnancies, including miscarriage,
stillbirth and repeated molar pregnancy, is significantly higher
than those who conceive more than 12 months later (37.5% Vs
10.5%, p 0.14). Besides, the growth of primordial Graafian
follicles is estimated to take more than six months. By waiting for
one year, this may allow damaged DNA to be repaired. There-
fore, patients should be advised to refrain from pregnancy for at
least 1 year in order to avoid any misinterpretation of hCG results
and possible harmful effects of chemotherapy on the ovarian
function and foetal outcome. Nonetheless, if patients happen to
conceive within 1 year, they can be reassured that the overall
outcome is favourable and termination of pregnancy is not
required.
A summary of the management of GTN is shown in Table 6.
Choriocarcinoma
In Europe and USA, the estimated number of choriocarcinoma
is 1 in 50,000 pregnancies whereas in South East Asia and
Japan it is 9.2 and 3.3 respectively. 25% of choriocarcinoma
occurred after miscarriage, 25% after term pregnancy and the
rest after molar pregnancy. It shows no chorionic villi, and
abnormal cytotrophoblastic and syntiotrophoblast with hae-
morrhage and necrosis invading myometrium and vessels are
often seen.
Heamatological spread is common. Unless developed
following molar pregnancy, it is difficult to reach the diagnosis of
choriocarcinoma and is usually made when there is an unex-
plained high hCG level and the presence of tumour in the lung,
brain or liver on imaging. Some patients present with neurolog-
ical or pulmonary symptoms and diagnosis is made histologically
after removal of the tumour. A delay in diagnosis resulting in a
delay in starting chemotherapy is a major cause of early death in
patients with brain or liver metastasis.
The management of choriocarcinoma is similar to that of high-
risk GTN.
Tumours of intermediate trophoblast
PSTT
PSTT was first described in 1976 by Kurman et al. and is a rare
neoplasm arising from the implantation site intermediate
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
trophoblast. It constitutes 0.1e2% of all GTN. Most cases of
PSTT are at least focally infiltrative and myometrial smooth
muscle cells are found in between the clusters or sheets of
tumour cells. Unlike choriocarcinoma which is immunoreactive
for hCG and has a high Ki-67 proliferative index, PSTT is only
focally and weakly immunoreactive for hCG and the mean Ki-67
is around 15%. PSTT can be preceded by normal pregnancy,
miscarriage or abortion, and less commonly molar pregnancy
and ectopic pregnancy. Most patients present with vaginal
bleeding, amenorrhoea and uterine enlargement. Rarely, pa-
tients may present with nephritic syndrome related to immu-
noglobulin deposits in the glomerular membranes, and
virilisation due to ovarian stromal hyperthecosis and paraneo-
plastic syndromes.
About half and up to 90% of patients are diagnosed at early
stage. Serum hCG may be high and 79% of patients have levels
less than 1000 IU/l and 58% less than 500 IU/l. Serum human
placental lactogen may be raised and this can be used as a
tumour marker. Ultrasound may show an intra-uterine cystic or
heterogeneous mass with various degree of vascular signal. The
definite diagnosis is often made in the hysterectomy or curettage
samples.
Age over 35, interval from preceding pregnancy over 24
months, deep myometrial invasion, advanced stage, maximum
hCG level >1000 IU/l, mitotic count more than 5 per 10 high
power fields, extensive coagulative necrosis and presence of
clear cytoplasm have been suggested to carry a poor prognostic
effect. However, a recent review showed that the only indepen-
dent predictor of overall and recurrence-free survival was the
interval from its antecedent pregnancy using 48 months as cut-
off. On the other hand, another recent case series consisting of
17 PSTT patients showed that patients with FIGO stage IV had
worse overall survival than those with stage IeIII diseases ( p
0.009).
The cornerstone treatment method is hysterectomy because
PSTT is less sensitive to chemotherapy. However, conservative
management like uterine curettage, hysteroscopic resection and
chemotherapy may be considered provided that the patient has
a strong desire of fertility, the lesion is localised in the uterus,
the mitotic count is low, there is no uterine enlargement and
close monitoring is feasible. It has been suggested that stage I
diseases can be treated by surgery alone, while stage IIeIV
diseases have to be treated by surgery and chemotherapy, and
the most commonly used regimen is EMA-EP and the alterna-
tive is TE/TP. In Charing Cross Hospital, adjuvant chemo-
therapy is also given to stage I patients after surgery if risk
factors like interval from preceding pregnancy >4 years are
present.
ETT
ETT is derived from the chorionic-type intermediate tropho-
blast and was first described in 1998. The tumour is charac-
terised by uniform nests and cords of mononucleated
intermediate trophoblastic cells surrounded by extensive ne-
crosis and associated with an eosinophilic hyaline-like matrix
creating a geographical pattern. Because about half of the
tumours are found in the lower uterine segment or endocervix,
they are often mistaken for squamous cell carcinoma of the
20 2014 Elsevier Ltd. All rights reserved.
 REVIEW
cervix. Rarely, ETT can coexist with choriocarcinoma or PSTT.
The majority of ETT occurs in the reproductive age group.
Patients often have symptoms resembling those in PSTT and
about 70% of them have abnormal vaginal bleeding. The
serum hCG level is usually mildly elevated. Similar to PSTT,
ETT is not chemo-sensitive and it is mainly treated by
operation. A GTD. The clinical presentation has, therefore, changed in the past
FURTHER READING
Committee on Gynecologic Practice. The American College of Obstetri-
cians and Gynecologist. ACOG. Committee opinion: number 278.
Avoiding inappropriate clinical decisions based on false-positive
human chorionic gonadotropin test results. Obstet Gynecol 2002
November; 2002: 1057e9.
Lurain JR. Gestational trophoblastic disease II: classification and man-
agement of gestational trophoblastic neoplasia. Am J Obstet Gynecol
2011; 204: 11e8.
Lurain JR. Gestational trophoblastic disease I: epidemiology, pathology,
clinical presentation and diagnosis of gestational trophoblastic dis-
ease, and management of hydatidiform mole. Am J Obstet Gynecol
2010; 203: 531e9.
Ngan HY, Kohorn EI, Cole LA, et al. Trophoblastic disease. Int J Gynaecol
Obstet 2012; 119(suppl 2): S130e6.
Osborne RJ, Filiaci V, Schink JC, et al. Phase III trial of weekly methotrexate
or pulsed dactinomycin for low-risk gestational trophoblastic
neoplasia: a gynecologic oncology group study. J Clin Oncol 2011; 29:
825e31.
Royal College of Obstetricians and Gynaecologists. The management of
gestational trophoblastic neoplasia. Guideline No. 38. London: RCOG
Press, 2010.
Schmid P, Nagai Y, Agarwal R, et al. Prognostic markers and long-term
outcome of placental-site trophoblastic tumours: a retrospective
observational study. Lancet 2009; 374: 48e55.
Seckl MJ, Sebire NJ, Berkowitz RS. Gestational trophoblastic disease.
Lancet 2010; 376: 717e29.
Seckl MJ, Sebire NJ, Fisher RA, Golfier F, Massuger L, Sessa C. ESMO
guidelines working group. Gestational trophoblastic disease: ESMO
clinical practice guidelines for diagnosis, treatment and follow-up. Ann
Oncol 2013 Oct; 24(suppl 6): vi39e50.
The Faculty of Family Planning and Reproductive Health Care, Royal Col-
lege of Obstetricians and Gynaecologists. UK medical eligibility criteria
for contraceptive use (UKMEC 2009). 2009. The Faculty of Family
Planning and Reproductive Health Care. Available at: http://www.fsrh.
org/pdfs/UKMEC2009.pdf.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
Practice points
C GTD is a spectrum of benign and malignant pregnancy-related
conditions and is more common in Asia and Latin America.
C The common use of ultrasound has led to earlier diagnosis of
few decades. Florid symptoms of hyperthyroidism, thromboem-
bolism, pre-eclampsia and neurological symptoms are rarely seen
nowadays.
C All patients should be referred to a specialist centre for subse-
quent management.
C Suction evacuation is the main treatment for molar pregnancy and
most often no further treatment is required.
C Specimens should be examined by experienced pathologists.
Ancillary tests with the use of paternally imprinted genes help to
differentiate partial mole from complete mole.
C Serum and urine hCG should be monitored to detect any persis-
tent trophoblastic disease. Patients should be advised to practice
contraception for at least 6 months.
C The diagnosis of GTN is made when the hCG level is stationary or
rising after a molar pregnancy or when choriocarcinoma is found.
PSTT are ETT are separate disease entities as their cell origin and
clinical behaviours are different.
C The FIGO committee have recommended a clinical anatomical
staging system together with the modified WHO risk scoring sys-
tem. Global standardisation of the staging systems and treatment
criteria is important for comparison of treatment results.
C Low-risk disease is treated by single-agent chemotherapy and
high-risk disease is treated by multi-agent chemotherapy. The
overall response rate is more than 90%. However, systematic
reviews have failed to identify the best regimen.
C The relapse rate is about 3% in low-risk GTN and 7e20% in high-
risk GTN. More than 80% of patients are salvaged by further
chemotherapy. The overall 5-year survival rate is more than 90%.
C Patients should be advised to refrain from pregnancy for at least
12 months. They can be reassured that their fertility potential is
not jeopardised and that the risks of disease recurrence and
foetal abnormality are small.
C The psychosocial aspects of these patients are often overlooked.
Detailed explanation about the disease should be given and a
multidisciplinary approach should be adopted.
C PSTT and ETT are rare intermediate trophoblast tumours. They are
not very chemo-sensitive and hence hysterectomy is the mainstay
treatment.
21 2014 Elsevier Ltd. All rights reserved.
 REVIEW
Complications in early
pregnancy
Anna Graham
Sangeetha Devarajan
Shreelata Datta
Abstract
The pregnant woman presents a diagnostic challenge as physiological,
anatomical and biochemical changes of pregnancy may mask symptoms
and signs, as well as the pregnancy itself being the source of the problem.
The pathologies occurring in early pregnancy are common but some may
be life threatening and it is therefore essential to promptly diagnose and
treat complications to achieve the best fetal and maternal outcomes. This
review considers the common clinical problems that occur in early preg-
nancy, including the common clinical and diagnostic features of obstetric
and non-obstetric related causes, treatment methodologies and
implications.
Keywords early pregnancy; ectopic pregnancy; first trimester; hyper-
emesis gravidarum; miscarriage; molar pregnancy; ovarian cyst rupture
Introduction
The symptoms and signs that women present with in early
pregnancy (i.e. in the first trimester) are often non-specific,
commonly including tiredness, headache, abdominal pain, uri-
nary symptoms and nausea and vomiting. A systematic approach
should be employed, similar to that of the non-pregnant patient,
with history, examination, and appropriate investigations.
Abdominal pain in early pregnancy is a common symptom, with
both obstetric and non-obstetric causes, and whilst the vast
majority of women do not have any significant intra-abdominal
pathology (40e50% have no identifiable cause), a number of
life threatening complications can occur. These may present with
an acute abdomen, a rapid onset of severe symptoms including
abdominal pain and muscle rigidity for which consideration of
emergency surgery is vital. Timely diagnosis and appropriate
treatment is therefore essential for improving maternal and
perinatal outcomes.
Physiological, anatomical and biochemical alterations occur
through each trimester of pregnancy. Approximately 80% of
women will experience nausea and vomiting during normal early
pregnancy, therefore confusing clinical presentation.
Anna Graham MBBS is a Specialty Registrar (ST1) in Sexual and
Reproductive Health at Kings College Hospital, London, UK. Conflicts
of interest: none declared.
Sangeetha Devarajan MRCOG is a Specialty Registrar (ST7) in Obstetrics
and Gynaecology at St Heliers Hospital, London, UK. Conflicts of in-
terest: none declared.
Shreelata Datta MBBS BSc (Hons) LLM MRCOG is a Consultant Obstetrician
and Gynaecologist at St Heliers Hospital, London, UK. Conflicts of in-
terest: none declared.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
Anatomically, as the uterus enlarges, the appendix may shift
upwards and laterally which can render McBurneys point diag-
nostically futile. Peritoneal signs such as guarding may also be
absent. The stretching of ligaments and muscles supporting the
enlarging uterus may produce abdominal pain. A physiological
leucocytosis and raised amylase and alkaline phosphatase may
also occur, as well as a reduced haemocrit due to the dilutional
effect of plasma expansion. Imaging options in pregnancy remain
limited due to the risk of teratogenicity from ionising radiation,
although exposures of less than 0.05 Gy have not been associated
with pregnancy loss or fetal malformations. Ultrasound remains
the primary imaging modality of choice, followed by MRI and CT
to avoid exposing the fetus to irradiation.
Table 1 outlines the common conditions in early pregnancy
and the key areas covered in this article. Rarer causes include
intestinal obstruction, aortic dissection or rupture, and sickle cell
crisis in patients with active sickle cell disease.
Pregnancy-related complications
Ectopic pregnancy
Ectopic pregnancy is derived from the Greek work ektopos
meaning out of place and is defined as the implantation of a
fertilised egg anywhere outside the uterine cavity, most
commonly in the fallopian tubes (95%); however, rarer non-
tubal ectopics can also implant cervically, in Caesarean section
scars, in ovaries, and abdominally. Ectopic pregnancy remains
the leading cause of early pregnancy maternal mortality in the
UK, with two thirds of these deaths attributed to atypical pre-
sentation and delayed diagnosis. Risk factors for ectopic preg-
nancies include increased maternal age, previous pelvic infection
or surgery, infertility, assisted conception and smoking.
Typically, patients present between 5 and 9 weeks gestation
with a positive pregnancy test, vaginal bleeding (usually spot-
ting) and pelvic pain (usually unilateral). They may however be
asymptomatic, present with shoulder tip pain secondary to dia-
phragm irritation, in haemodynamic shock, or with gastrointes-
tinal (particularly diarrhoea) or urinary symptoms. Particularly
highlighted in the most recent triennial report into maternal
deaths were patients presenting with atypical symptoms
including diarrhoea, dizziness and vomiting and problems with
diagnosis in women whose first language was not English. It is
therefore essential to have a high degree of suspicion while
reviewing patients to obtain an early diagnosis.
Common problems in early pregnancy
Pregnancy-related Gynaecological causes Other causes
causes
Ectopic pregnancy Adnexal masses ovarian Appendicitis
cyst rupture and torsion
Miscarriage Urinary tract infections Gastroenteritis
Molar pregnancy Acute pancreatitis
Hyperemesis Peptic ulcer disease
gravidarum Cholecystitis
Table 1
1 2014 Published by Elsevier Ltd.
 REVIEW
Examination may reveal pelvic, abdominal or cervical motion
tenderness. Key first line investigations include transvaginal ul-
trasound (TVUSS) scanning and serum concentrations of human
chorionic gonadotrophin (hCG). Serial serum hCG levels denote
the degree of trophoblastic proliferation and in a normal preg-
nancy, double every 48e72 hours, whereas ectopic pregnancies
produce lower concentrations of hCG. Over 90% of ectopic
pregnancies should be visualised on TVUSS beyond a gestational
age of 6 weeks and 6 days.
Treatment options for an ectopic pregnancy are expectant,
medical and surgical management and will depend on the clinical
status of the patient as well as her informed choice. Expectant
management involves no intervention and allows the pregnancy
to resolve spontaneously while medical management involves
administration of intramuscular methotrexate. Both may be
considered in stable women but patients require regular follow
up to ensure that serum hCG levels are reducing, and the ectopic
remains at risk of rupture until it resolves completely. If the
woman is haemodynamically unstable, in severe pain or a live
fetal pole and fetal heartbeat is seen within the ectopic preg-
nancy, surgical intervention is indicated. This most commonly
involves laparoscopic removal of the affected fallopian tube,
where there is no contralateral tubal disease.
The most common concern from patients is of future fertility
and studies suggest spontaneous conception rates following an
ectopic pregnancy is between 38 and 89%. Reported recurrent
rates of ectopic pregnancies are between 6 and 18% independent
of the treatment type.
Miscarriage (Table 2)
Miscarriage is defined as the loss of a pregnancy at any time up to
the 24th week and occurs in 20% of all women with a positive
pregnancy test. The majority occur in the first trimester and
whilst little is known about the aetiology, chromosomal abnor-
malities are thought to play a key role. Maternal age is the single
biggest predictor of miscarriage (11% at 21e25 years, 60% 41
e45 years).
Common presentations include lower abdominal pain and
vaginal bleeding. Miscarriage is diagnosed by a combination of
the patients history, examination findings, TVUSS and serum
hCG and progesterone. Patients may require more than one scan
if no intrauterine or extra uterine pregnancy is initially identified.
Once miscarriage is confirmed patients can be managed expec-
tantly, medically or surgically. Conservative management may
be considered in all cases for 7e14 days as the first line strategy
unless the patient is haemodynamically unstable or the method is
unacceptable to the patient. This involves no intervention and
the patient does not need routine follow up. Medical manage-
ment using oral misoprostol (a prostaglandin) can be offered if
expectant or surgical management is not acceptable to the pa-
tient. For both expectant and medical management, women
should be counselled regarding what to expect (pain and
bleeding or resolution of symptoms) and told to return if their
bleeding does not settle in 2 weeks or if they have not bled in this
period of time. Women should take a pregnancy test 3 weeks
post treatment and return for assessment if positive.
Surgical management involves passing a suction cannula
into the uterus and removing the products of conception. This
can be performed in theatre under general anaesthetic;
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
WHO classification of the stages of spontaneous
miscarriage
Threatened A threat of miscarriage that exists when unprovoked
miscarriage vaginal bleeding, with or without lower abdominal
pain, occurs in a pregnancy of <22 weeks gestation
(pregnancy may continue).
Inevitable A miscarriage deemed inevitable when specific
miscarriage clinical features indicate that a pregnancy is in the
process of physiological expulsion from within the
uterine cavity (pregnancy will not continue and will
proceed to incomplete or complete miscarriage).
Incomplete A miscarriage in which early pregnancy tissue is
miscarriage partially expelled. It is possible that many incomplete
miscarriages are unrecognised missed miscarriages.
Complete A miscarriage in which early pregnancy tissue is
miscarriage completely expelled.
Missed A miscarriage with ultrasound features consistent
miscarriage with a non-viable or non-continuing pregnancy, even
in the absence of clinical features. Early pregnancy
tissue may be partially expelled. Missed miscarriage
is usually an incidental finding because there is rarely
any indication that anything was wrong with the
pregnancy. Some women do recall a transient and/or
brownish vaginal discharge, or a vague reduction in
symptoms of early pregnancy.
Table 2
alternatively, for a select group of patients, manual vacuum
aspiration under local anaesthetic can be performed in an
outpatient setting.
Women should be reassured that they have not done anything
to cause the miscarriage and that future pregnancies will not be
affected. Maternal investigations are not advised until three
consecutive miscarriages have occurred and a diagnosis of
recurrent miscarriage has been made.
Gestational trophoblastic disease GTD (molar pregnancy)
Although rare (0.57e1.1 per 1000 pregnancies), gestational
trophoblastic disease (GTD) is an important diagnosis to
consider. GTD includes a spectrum of interrelated tumours
including complete and partial hydatidiform mole, invasive
mole, choriocarcinoma, and placental site trophoblastic tumour,
which are diagnosed definitively using histology. All forms
originate from the placental trophoblast with different pro-
pensities for local invasion and spread.
The most common form of GTD is the hydatidiform mole or
molar pregnancy of which there are two types: complete and
partial. A complete molar pregnancy is diploid, and contain only
paternally derived genes. There is no embryo and an abnormal
placenta. Partial moles are usually triploid in origin, with an
extra set of paternally derived chromosomes. In a partial molar
pregnancy there is an abnormally large placenta and some fetal
development may occur.
The main risk factors for molar pregnancy include advanced
or very young maternal age and a history of previous molar
pregnancy. The majority of molar pregnancies present as first
2 2014 Published by Elsevier Ltd.
 REVIEW
trimester miscarriage with a uterus palpating large for dates
(25%) and the vaginal passage of grape-like vesicles (10%).
Exaggerated pregnancy symptoms including hyperemesis (10%),
hyperthyroidism (5%) or early pre-eclampsia (5%) may also be
seen, although these are less common in partial molar preg-
nancies. Serum HCG levels will be greatly raised (greater than
two multiples of the median). TVUSS of complete moles may
initially show a fine vascular or honeycomb picture and later
may have the classical snowstorm appearance. Partial moles
are less easily diagnosed however developmental abnormalities
may raise suspicion. A definitive diagnosis can only be made by
histological examination. Once the diagnosis of a molar preg-
nancy is suspected, hypertension, hyperthyroidism, and pre-
eclampsia, as well as metastases must be investigated.
The treatment of molar pregnancy is surgical suction evac-
uation and curettage by a senior surgeon. Women are followed
up for a minimum of six months after treatment to ensure that
hCG levels return to normal. In the rare case that a viable
pregnancy co-exists with a partial or complete mole, the patient
should be counselled on the complications of persistent GTD,
increased risk of bleeding and a termination of pregnancy may
be considered. In pregnancies which continue, up to 40% will
result in normal viable pregnancies. The outcome of partial
hydatidiform mole after uterine evacuation is almost always
benign, but persistent disease occurs in 1.2e4% of cases, and
metastases in 0.1%; these risks are five times greater in com-
plete moles.
Hyperemesis gravidarum
Nausea and vomiting is common in early pregnancy, affecting
about 80% of pregnancies; however in 0.3e1% of women this
progresses to hyperemesis gravidarum. Hyperemesis gravidarum
is poorly defined but is generally diagnosed when severe nausea
and vomiting lead to dehydration, electrolyte imbalance, keto-
nuria and weight loss. It is a diagnosis of exclusion and other
causes should be first considered.
Risk factors include younger age, non-smokers, non-Cauca-
sian, multiple gestation, previous hyperemesis, molar pregnancy,
diabetes, depression or psychiatric illness, asthma and gastroin-
testinal disorders. The aetiology is poorly understood but it is
thought to be due to combination of hormonal changes in preg-
nancy. Recently H. pylori infection has been implicated but
further research is needed to confirm this.
Patients typically report symptoms in the first trimester,
usually commencing by week 8, peaking around week 12 and
then resolve by week 20. All patients presenting with nausea and
vomiting should have a clinical assessment to exclude other di-
agnoses including ectopic or molar pregnancies, urinary tract
infections and gastroenteritis. Investigations should include
bloods to check renal, liver and thyroid function as well as full
blood count, c-reactive protein, phosphate, magnesium, calcium
and glucose levels. A urine dip should be performed to measure
ketones and to exclude infection; where a UTI is suspected, a
mid-stream urine should be sent. An USS should be performed to
exclude molar or multiple pregnancies.
Fetal and maternal complications associated with untreated
hyperemesis gravidarum include anaemia and electrolyte dis-
turbances, peripheral neuropathies and rarely Wernickes
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
encephalopathy, Mallory-Weiss tears secondary to persistent
vomiting, as well as associated psycho-social problems. In
addition there is significant morbidity associated with time off
work, and significant healthcare cost through hospital admission.
Fetal complications include pre-term labour and low birth weight
babies.
Treatment involves dietary and lifestyle modifications,
avoiding food that stimulates nausea, eating and drinking small
amounts more frequently and eating at times when nausea is less
severe. Additionally oral ginger has been shown to be effective in
a number of trials. Many women can be managed as outpatients
with oral or intravenous fluids alone, possibly because dehy-
dration contributes to nausea. Care should be taken to avoid
dextrose due to the risk of Wernickes encephalopathy. Patients
can be managed with antiemetics, including anticholinergics,
antihistamines, dopamine agonists and 5-HT antagonists. Po-
tassium supplementation should be considered if hypokalaemic.
In resistant cases, senior review and medical input may be
indicated, together with thiamine hydrochloride or Pabrinex,
with consideration of steroids on an individual basis.
Non-obstetric complications in early pregnancy
Adnexal masses
The adnexal areas sit adjacent to the uterus and contain the
fallopian tubes, ovaries, vessels and ligaments. Table 3 summa-
rises the main types of adnexal masses.
The incidence of adnexal masses in pregnancy has been re-
ported to vary widely, between 1/81 to 1/8000. This figure has
greatly increased with the routine use of USS in the first trimester
incidentally identifying masses, and varies significantly depend-
ing on the definition criterion employed. The majority of adnexal
masses are physiological ovarian cysts and resolve spontane-
ously; however others lead to torsion (up to 7%), rupture, hae-
morrhage and later labour obstruction, additionally there is an
overall incidence of malignancy of 1e8%.
Masses identified on USS should be followed up as necessary
depending on their characteristics. Ultrasound has been found to
be accurate in determining the malignant potential of adnexal
Differential diagnosis of an adnexal mass in pregnancy
Benign Malignant
C Corpus luteum C Germ cell tumour
C Simple cyst C Epithelial tumour
 Low malignant potential
 Invasive
C Haemorrhagic cyst C Sex cord stromal tumours
C Dermoid
C Cystadenoma
C Endometrioma
C Pedunculated fibroid
C Ovarian hyperstimulation
C Hydrosalpinx
C Paraovarian/tubal cyst
C Theca lutein cyst
Table 3
3 2014 Published by Elsevier Ltd.
 REVIEW
masses. Tumour markers such as Ca125 are of limited use as
they can be raised during normal pregnancy, particularly in the
first trimester. Investigations aim to identify which masses can be
managed expectantly and which require surgery, balancing the
risks involved in unnecessary intervention versus the risk of
torsion or potential missed malignancy.
Ovarian cyst torsion
It has been reported that up to 7% of ovarian cysts will undergo
torsion during pregnancy, and 20% of all ovarian cyst torsions
occur during pregnancy, suggesting that pregnancy may predis-
pose to torsion. The most likely ovarian mass to undergo torsion
is the dermoid cyst, due to the weight of the cyst itself.
The vast majority of adnexal masses are ovarian cysts and the
incidence of these found in pregnancy is outlined in Table 4.
Risk factors for torsion include pregnancies of assisted
conception, and ovarian cyst(s) over 6 cm in size. Ovarian tor-
sion most commonly presents in late first trimester, early second
trimester and during the immediate post-partum period. Patients
typically present with sudden onset, severe, unilateral (right side
to left ratio 3:2) lower abdominal pain that may be constant or
intermittent. Many have associated nausea and vomiting and an
adnexal mass can be felt in over 90% of cases. They can also
present with an acute abdomen.
Prompt diagnosis is essential using ultrasound with Doppler
studies. If the patient has an acute abdomen or is haemody-
namically unstable, an exploratory laparoscopy or laparotomy is
the first line management. Current research suggests that a
laparoscopic approach has a similar success rate to an open
approach with significant cost savings.
Ovarian cyst rupture and haemorrhage into cysts
Ovarian cyst rupture and haemorrhage into cysts present in a
similar way to torsion. Both usually occur with functional and
corpus luteal cysts and are generally uncomplicated. Non-
haemorrhagic cyst fluid is reabsorbed within 24 hours and
symptoms resolve within a few days. Whilst outpatient man-
agement is possible with simple analgesia, women with hae-
morrhagic cysts may be admitted for observation and analgesia.
If the case is complicated by haemodynamic shock, sepsis, acute
abdomen, enlarging haemoperitoneum or persists for over 48
hours surgical management must be considered. Surgical
Incidence (%) of most common ovarian masses in
pregnancy
Type of mass %
Dermoid (cystic teratoma) 25
Corpus luteul cyst, functional cyst, paraovarian 17
Serous cystadenoma 14
Mucinous cystadenoma 11
Endometrioma 8 presentation is suspicious of appendicitis. An abdominal X-ray
Carcinoma 2.8
Low malignant potential tumour 3 should be considered where there is any doubt.
Leiyomyoma 2 Persistence or worsening of symptoms is highly suggestive of
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
intervention in the first trimester of pregnancy is associated with
a 1% risk of miscarriage.
Urinary tract infections
Urinary tract infections (UTIs), including asymptomatic bacteri-
uria, cystitis, and pyelonephritis are more common in pregnancy
(up to 20% of all pregnancies). The prevalence is increased due
to higher levels of progesterone leading to relaxation of the pel-
vicalyceal system and compression of the ureters by the
expanding uterus, these in turn lead to a reduced rate of urinary
flow and urinary stasis predisposing to infection. UTIs are asso-
ciated with pre-term rupture of membrane, pre-term labour,
chorioamnionitis, post-partum fever in the mother and neonatal
infection. If untreated, complications such as acute pyelone-
phritis, septic shock, kidney injury and even death.
Patients are routinely screened for asymptomatic bacteriuria
and should be treated to prevent the infection progressing to
cystitis and pyelonephritis. Patients with cystitis classically pre-
sent with dysuria, increased urinary frequency, suprapubic pain,
nausea, and vomiting. Pyelonephritis occurs in 2e4% of preg-
nancies and has additional symptoms of pyrexia, renal angle
tenderness and rigors.
A diagnosis should be made on the history, clinical symp-
toms, and presence of leukocytes and nitrites in the urine. The
patient will require a mid-stream urine culture and blood culture
as well as bloods to check renal function, CRP, liver function
tests and amylase to exclude pancreatitis or cholecystitis. Renal
calculi should be considered as a differential diagnosis as this can
present in a similar manner to pyelonephritis. If suspected an
USS should be performed. Patients should be treated with anti-
biotics according to local protocols, be rehydrated and have their
electrolytes rebalanced.
Appendicitis in pregnancy
Acute appendicitis is the most common non-obstetric surgical
emergency during pregnancy. The incidence is estimated to be
between 1/500 to 1/2000 pregnancies, which is similar to the age
equivalent non-pregnant population. The morbidity and mortal-
ity is increased during pregnancy partly due to a delay in the
diagnosis secondary to blunting of signs and symptoms and
changes in the location of the appendix. Signs and symptoms
such as nausea, vomiting and anorexia are non-specific. The risk
of perforation is 25%, so early diagnosis is paramount.
In the first trimester patients may present with umbilical pain
localizing to McBurneys point, however at later gestations as the
appendix is displaced upward and laterally, pain may be felt in
the umbilical or right hypochondrial areas. On examination
Rovsings sign may be present together with rebound tenderness
and guarding. Mild pyrexia is sometimes present. The patient
should have a septic screen, remembering that a physiological
leucocytosis may be present; CRP and neutrophilia are likely to
be more helpful. An USS may aid the diagnosis if an experienced
operator is available, however this should not delay surgery if
can also be performed to exclude other pathology and an MRI
appendicitis and should be an indication for surgery. A delay in
4 2014 Published by Elsevier Ltd.
 REVIEW
diagnosis can lead to perforation and peritonitis or appendicular
abscess which significantly increases fetal mortality to upto 35%,
from 1.5% in uncomplicated cases. The low threshold for lapa-
roscopy and appendicectomy is justified even with the possibility
of negative findings due to the increased maternal and perinatal
mortality if the diagnosis is delayed or missed.
Acute cholecystitis
Gallstones are more common in pregnancy as increased levels of
progesterone cause smooth muscle relaxation leading to biliary
stasis and delayed gall bladder emptying. This coupled with
higher levels of oestrogen and increased synthesis of cholesterol
make pregnancy a significant risk factor for gallstones. The
prevalence of gallstones is estimated to be approximately 3% and
biliary sludge approximately 30% during pregnancy although
acute cholecystitis is not more common in the pregnant state.
The presentation of cholecystitis is the same as in the non-
pregnant state with colicky right upper quadrant pain which
may radiate to the back, nausea and vomiting, intolerance of
fatty food, jaundice and fever. Murphys sign is less often present
in pregnancy due to the enlarging uterus.
Investigations may reveal raised bilirubin, leucocytosis and
transaminases. Leucocytosis and raised alkaline phosphatase
occur in normal pregnancy and therefore may complicate the
picture. Ultrasound scan is the diagnostic modality of choice for
gallstones and will detect 95e98%.
First line management has traditionally been conservative
with iv fluids, analgesia, iv antibiotics and naso-gastric suction,
however recent studies have advocated the first line use of
cholecystectomy due to the overall safety of laparoscopic pro-
cedures during pregnancy and the high recurrent rate of chole-
cystitis and the complications associated with this.
Other non-obstetric related causes
Acute pancreatitis is a rare condition seen in 1 in 1000 to 1 in
10000 pregnancies. Presentation includes sudden onset acute
abdominal pain together with nausea, fever and jaundice.
Treatment is supportive, with intravenous fluids and correction
of electrolyte imbalance, glucose and calcium levels. In severe
cases, naso-gastric suction may need to be considered.
Peptic ulcer disease is rare in pregnancy, although heartburn
is common. This is due to increased intra-abdominal pressure,
the displacement of the gastro-oesophageal junction and the
relaxation of the lower oesophageal sphincter. Heartburn is
treated by avoiding foods that trigger reflux together with H2
receptor antagonists.
Conclusion
The most common symptoms seen in early pregnancy are
abdominal pain, vaginal bleeding and nausea and vomiting.
These may be caused by conditions that are directly related to
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
pregnancy, gynaecology pathology or those that are unrelated to
pregnancy. Pregnancy may alter the symptoms and signs seen
and their timing. As such, it is useful to have a low threshold of
suspicion for serious problems in order to manage them accu-
rately and quickly. Whilst ultrasound scanning has a key role in
obtaining early diagnoses it should not delay management in the
clinically unstable patient to optimise maternal and fetal
outcomes. A
FURTHER READING
Boelig RC, Berghella V, Kelly AJ, Barton SJ, Edwards SJ. Interventions for
treating hyperemesis gravidarum. Cochrane Database Syst Rev
2013; 6.
Centre for Maternal and Child Enquiries (CMACE). Saving mothers lives:
reviewing maternal deaths to make motherhood safer: 2006-08. The
eigth report on confidential enquiries into maternal deaths in the
United Kingdom. BJOG 2011; 118(suppl 1). 1-203.
Chandraharan E, Arulkumaran S. Acute abdomen and abdominal pain in
pregnancy. Obstetrics, Gynaecol Reproductive Med 2008; 18: 205e12.
Jarvis S, Nelson-Piercy C. Management of nausea and vomiting in preg-
nancy. BMJ 2011; 342. d3606.
Jurkovic D, Wilkinson H. Diagnosis and management of ectopic pregnancy.
BMJ 2011; 342. d3397.
NICE Clinical Guideline 154. Ectopic pregnancy and miscarriage, diagnosis
and initial management in early pregnancy of ectopic pregnancy and
miscarriage. 2012. London: NICE, http://www.nice.org.uk/nicemedia/
live/14000/61854/61854.pdf.
Royal College of Obstetricians and Gynaecologists. The management of
gestational trophoblastic disease. Green-top Guideline No. 38.
February 2010. London: RCOG, http://www.rcog.org.uk/files/rcog-corp/
GT38ManagementGestational0210.pdf.
Vazquez JC, Abalos E. Treatments for symptomatic urinary tract infections
during pregnancy (Review). Cochrane Database Syst Rev 2011; 1.
Practice points
C It is important to consider the anatomical, biochemical and
physiological changes that occur in pregnancy in order to
distinguish between the normal physiological and pathological
changes seen.
C Clinicians should have a low threshold of suspicion for serious
pathology in pregnancy as delayed diagnoses leads to increased
morbidity and mortality for both mother and fetus.
C Ectopic pregnancies may present atypically with dizziness and
gastrointestinal symptoms.
C Appendicitis is the most common non-obstetric surgical emer-
gency to occur in pregnancy and can be difficult to diagnose due
to the anatomical displacement of the appendix as pregnancy
progresses.
C Ovarian cyst torsion is more common in pregnancy and presents
in a similar way in both the pregnant and non-pregnant state.
5 2014 Published by Elsevier Ltd.
 CASE-BASED LEARNING
Fetal anaemia
Alec McEwan
Abstract
Fetal anaemia is a rare condition which can result from a failure of produc-
tion of fetal red blood cells, accelerated haemolysis, or fetal bleeding. The
three most common causes are parvovirus B19 infection, red cell isoim-
munisation and fetomaternal haemorrhage. All obstetricians are likely
to encounter these clinical scenarios at some point, even if management
is predominantly by fetal medicine specialists. All three topics have been
covered in previous articles of this journal, but here are presented three
real cases illustrating these causes of fetal anaemia, and emphasising
again the key points.
Keywords anti-D antibodies; fetal anaemia; fetomaternal haemorrhage;
hydrops; Kleihauer; middle cerebral artery peak systolic velocity; parvo-
virus B19; red cell isoimmunisation
Introduction
Fetal anaemia is a relatively rare recurrence, usually managed by
fetal medicine specialists and neonatologists. Red cell alloim-
munisation is one of the most common causes, and this topic was
covered in detail in Volume 20 of this journal (issue 2). This
article describes three case histories which illustrate the causes
and presentations of fetal anaemia and emphasises the need for
all obstetricians to have knowledge of this uncommon condition.
Anaemia develops when red cell production is inadequate, or
when breakdown of erythrocytes is accelerated, or when red cells
are lost through bleeding. All three mechanisms can also be seen
to cause anaemia in the fetus (Table 1).
Diagnosing anaemia in a child or adult is simple to do by
measuring haemoglobin values on venous blood. Red cell size
and haemoglobin concentration, and a blood film, go a long way
towards isolating a cause when combined with the full clinical
picture. Fetal blood sampling is possible, but very much more
technically challenging and hazardous, requiring specialist skills
only found in a few tertiary fetal medicine centres. Under ultra-
sound guidance, a 20 gauge needle is inserted into the umbilical
vein either at the placental cord insertion, or as it passes through
the fetal liver, and 1 ml of blood aspirated for testing. The risks of
fetal bradycardia and bleeding, and membrane rupture or cho-
rioamnionitis are quoted at approximately 1e2% per sampling,
not to mention the possibility of failure. For many years,
amniocentesis and spectrophotometric measurement of liquor
bilirubin was used as a surrogate for fetal anaemia in haemolytic
conditions (mostly Rhesus D isoimmunisation). Although easier
to perform than fetal blood sampling, it still carried risk, and also
was known to have a significant false positive and negative rate.
Non-invasive methods of testing for fetal anaemia using the CTG
(see cases 1 and 2) and ultrasound scanning for fetal hydrops
Alec McEwan MRCOG is a Consultant Obstetrician and Subspecialist in
Fetal and Maternal Medicine at Nottingham University Hospitals NHS
Trust, Nottingham, UK. Conflicts of interest: none declared.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
Causes of fetal anaemia
Mechanism of anaemia Fetal examples
Failure of red cell Parvovirus B19 infection
production Alpha Thalassaemia major
Fetal erythroleukaemia (eg trisomy 21)
Congenital erythropoietic porphyria
Accelerated red cell Alloimmunisation (fetal haemolytic
destruction disease)
Fetal G6PD deficiency
Loss of red blood cells Fetomaternal haemorrhage
(bleeding) TTTS and its variants
Vasa praevia
Table 1
(see case 2 and 3) are also highly insensitive, with hydrops only
occurring when the fetal haemoglobin is life threateningly low,
and usually only when the development of the fetal anaemia has
occurred over a prolonged time frame i.e. not with acute fetal
bleeding.
The breakthrough with screening for fetal anaemia came with
the development of Doppler sonography. Blood in an anaemic
fetus is less viscous and the velocity of blood flow in certain fetal
vessels can be measured and be seen to be elevated above the
normal range. Cardiac output may also be elevated somewhat in
these fetuses, further contributing (although to a much lesser
extent) to the increase in peak systolic blood flow velocities. A
group led by Mari are usually credited for bringing the use the
use of middle cerebral artery peak systolic velocity (MCA PSV)
measurements into widespread mainstream practice for the non-
invasive assessment of fetal anaemia. The middle cerebral artery
is usually readily accessible for Doppler measurements, and the
use of angle correction means that absolute velocities can be
recorded (unlike when assessing a growth restricted fetus when
pulsatility index i.e. a ratio, is used). The fetus must be quies-
cent, and a few measurements are usually taken. The Doppler
gate should be placed at the proximal part of the near field MCA,
just as it emerges from the Circle of Willis. The value is plotted
on a chart, and significant anaemia is highly unlikely with values
which lie below 1.5 multiples of the median for the gestation in
question. As values exceed this threshold, the likelihood of sig-
nificant fetal anaemia increases.
It must be recognised that the use of MCA PSVs is only a
screening test for fetal anaemia, and there is a risk of both false
positive and negative results. The overall accuracy of this test for
predicting moderate and severe fetal anaemia has been quoted as
85%, which is 9% better than the use of serial amniocentesis and
DOD450 estimations and also clearly avoids the risk and un-
pleasantness of multiple needle insertions. Furthermore, it is
useful for detecting fetal anaemia from any cause, not just those
causing haemolysis. However, the false positive rate is 12% and,
although less common, false negatives do also occur. Neverthe-
less, it is now considered the gold standard for screening for fetal
anaemia. Fetal blood sampling remains the diagnostic test.
In some circumstances, the fetal anaemia may only be rec-
ognised after birth. However, there is treatment available for
prenatally diagnosed fetal anaemia distant from term. The first
ever fetal intrauterine transfusions (IUTs) were performed into
22 2014 Elsevier Ltd. All rights reserved.
 CASE-BASED LEARNING
the fetal peritoneal cavity, from where, incredibly, the red cells
were absorbed across the bowel wall to reach the fetal circula-
tion. Alternatively, intracardiac transfusions were performed.
With very significant improvements in real time ultrasound
scanning, these routes are only utilised now in severe cases at
extremely preterm gestations. More usually, at the time of fetal
blood sampling from the umbilical vein, blood is transfused
directly into the intravascular space, the volume determined by
fetal size and haemoglobin. The quoted risk of complications
(2%) increases to 5e20% in an hydropic fetus.
Case 1
A woman in her first pregnancy, with a previously straightfor-
ward antenatal course, presented at 38 weeks gestation with a
three day history of reduced fetal movements. She had experi-
enced no pain or vaginal bleeding, and her BP was normal and
urine clear. Her uterus was soft and non tender on examination.
A CTG was performed (Figure 1) and the registrar raised the
possibility that the trace was sinusoidal and performed a vaginal
examination with ARM. The patient was 3 cm dilated and the
liquor was clear. Fifteen minutes later the decision was made to
perform an emergency caesarean section. The baby was born 35
min later and was noted to be pale and floppy at delivery but
required minimal resuscitation and was given Apgar scores of 8
at 1 min, 8 at 5 min and 9 at 10 min. The venous cord pH was
7.27 (BE -6.4) and the arterial pH 7.19 (BE -8.0). A review of the
baby at 1 h of life was reassuring. However, 30 min later the baby
was admitted to the neonatal unit pale and floppy and went onto
develop seizures and required ventilation for 5 days. The hae-
moglobin on admission to the NNU was found to be 4.9 g/dl and
a blood transfusion was given. A direct Coombs test was nega-
tive, however a maternal Kleihauer test was found to be strongly
positive. A subsequent newborn MRI showed widespread
ischaemic changes in the cortical deep and periventricular white
Sinusoidal CTG
Figure 1
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
matter, and the thalamocapsular region. These changes were
indicative of an injury occurring a few days before birth. Limb
stiffness was detectable by discharge and the parents were
warned of a high chance of their child developing cerebral palsy.
The obstetric and neonatal team concluded that the fetus had
suffered a massive fetomaternal haemorrhage (FMH) at some
point at least three days prior to delivery and that this probably
occurred over a relatively short duration.
Fetomaternal haemorrhage (FMH)
FMH can be defined as the passage of fetal red blood cells across
the trophoblast layer and into the maternal circulation, but also
includes the movement of maternal erythrocytes in the opposite
direction. Loss of fetal red cells into the maternal circulation
occurs in most pregnancies but the volume of blood in the ma-
jority of cases is less than 0.025 ml. In less than 1% of preg-
nancies is the volume 15 ml or more. Massive FMH has been
variably defined as a loss of >80 ml or >150 ml, and this occurs
in approximately 1 in 1000 and 1 in 5000 births respectively.
There are two well established methods of measuring the size
of a fetomaternal bleed. The KleihauereBetke screen relies on
the fact that adult haemoglobin can be eluted from erythrocytes
by acid, whereas fetal Hb is resistant to this. A maternal blood
smear can be treated with acid and then stained with erythrosine
B. Maternal erythrocytes appear as ghosts on microscopy,
whereas the fetal red blood cells are stained cherry red. The fetal
Hb containing cells can be counted manually, and a volume
calculated using a simple formula. This test is labour intensive
and very imprecise, but nevertheless widely available. Flow
cytometry is the second method. Fluorescently labelled mono-
clonal antibodies against HbF are mixed with the maternal blood
sample and fluorescent cells (those containing HbF) are sorted
and counted separately. This test is fast, and more accurate, but
is not available universally, and often not out-of hours.
23 2014 Elsevier Ltd. All rights reserved.
 CASE-BASED LEARNING
Both tests can overestimate the size of an FMH if the mother
has high levels of persistent HbF herself, and can underestimate
if ABO incompatibility or isoimmunisation against other red cell
antigens means that fetal red blood cells are cleared very quickly
from the circulation. Some fetal red blood cells may survive for a
number of weeks in the maternal blood, so these tests do not
allow estimates of the timing or duration of the FMH.
Even if the quantity of blood could be very accurately
measured, the impact on the fetus would depend on the gestation
and the time frame over which the bleeding occurred. The feto-
placental blood volume expands from approximately 30 ml at 20
weeks gestation to 80e90 ml/kg by term. Larger bleeds will be
less well tolerated at earlier gestations. Slow haemorrhage over a
number of weeks will be tolerated better than the same total
volume of blood loss occurring over a few minutes, which is
likely to be associated with fetal hypotension and acute acidosis.
It is not uncommon for a fetus to drop its haemoglobin below 50
g/l in the setting of fetal haemolytic disease or parvovirus
infection. However, these babies usually do very well in the long
run, following transfusions. They develop their anaemia gradu-
ally, and there is no haemodynamic compromise associated with
it, as opposed to the hypotension occurring with a sudden
massive FMH.
The exact pathophysiology of FMH is not well understood,
although there are a number of situations associated with it (see
Table 2). The most common time for FMH is at delivery, but if
the bleed occurs after the cord is clamped then there will be no
consequence for the fetus/newborn. The estimates of the inci-
dence of FMH judged by positive Kleihauer tests taken following
birth therefore grossly overestimate the incidence of fetomaternal
bleeds which occur antenatally. Furthermore, it is not known if
breaches in the trophoblast layer can heal themselves or what
might make a small defect suddenly increase in size.
Table 2 also lists the most common causes of FMH, and the
most common presentations. In the majority of cases the cause is
not clear and it may only present itself with neonatal anaemia.
Fetomaternal Haemorrhage (FMH) and its associations
Causes of FMH Delivery
Manual removal of placenta
Caesarean section
Abruption
Trauma
Pre-eclampsia
ECV
Invasive testing (amniocentesis and CVS)
Placental tumours
Consequences of FMH Neonatal anaemia
Decreased or absent fetal movements
Stillbirth
Hydrops fetalis
Caesarean section
Non reassuring CTG
Sinusoidal CTG
Fetal growth restriction
Neurological injury eg cerebral palsy
Table 2
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
However, a sudden cessation or slowing of fetal movements is a
relatively common warning sign and performing a Kleihauer test
or an MCA PSV routinely in this situation would occasionally
lead to the diagnosis. If an FMH is proven prior to delivery, the
options are to observe, perform a cordocentesis/fetal blood
transfusion, or deliver (after steroids if necessary). Bleeds
occurring at significantly preterm gestations will encourage fetal
blood sampling and intrauterine transfusion, but even after a
fetus is topped-up with blood, there can be no reassurance that
another sudden and possibly heavier bleed wont occur. A
number of small case series attest to the relative safety of
transfusing the fetus in this situation, but an occasional stillbirth
is to be expected because of the unpredictability of the bleeding.
Women who are Rhesus D negative will of course need sufficient
exogenous anti-D to protect themselves against isoimmunisation.
Unfortunately, if the bleed has been occurring, or has occurred, a
few days prior to presentation then the administration of the anti-
D may be too late to prevent this happening. If an FMH has been
treated then it would seem appropriate to deliver the baby after
34 weeks gestation has been reached.
Managing subsequent pregnancies is no less daunting.
Although the recurrence risk might be expected to be low (and
probably is) there are cases on record of repeated FMH causing
problems in subsequent pregnancies. It is tempting to offer serial
Kleihauer tests and MCA Dopplers to women who have experi-
enced FMH in previous gestations, but there is no good evidence
to support this, and the risk of false positive MCA peak systolic
velocities is a real one. Despite this, most women will feel the
need for some form of surveillance and indeed we have seen in
our department a woman who had a stillbirth with her first
pregnancy, presumed secondary to a large FMH, who went on to
have repeated silent bleeds in her subsequent pregnancy,
detected by serial Kleihauers, requiring two intrauterine trans-
fusions followed by elective preterm delivery.
Case 2
A 39 year old RhD negative woman presented at 37 weeks in her
first pregnancy with a three day history of reduced fetal move-
ments. Ultrasound scanning confirmed intrauterine fetal death. A
Kleihauer was performed, along with many other investigations,
and this showed a massive fetal maternal haemorrhage of 105
ml. A similar volume was estimated using flow cytometry. A
silent FMH was felt to be the cause of the fetal death and her
husband was found to be homozygous RhD positive. 7500 IU of
Anti-D were given by slow intravenous injection, in an attempt to
prevent isoimmunisation, however tests at 4 and 6 months
postpartum showed maternal Anti-D levels of 22 and 9 IU/ml,
confirming isoimmunisation against RhD. She was counselled
that any future pregnancies with her husband would be
complicated by haemolytic disease of the fetus and newborn, but
reassured that first affected pregnancies were usually only mildly
affected, and that treatments were available.
A year later, she conceived again. Figure 2a shows the anti-D
levels over the course of the earlier part of the pregnancy. Reg-
ular MCA PSV Dopplers were performed and these remained
reassuring until 28 weeks gestation at which point they became
severely abnormal (Figure 2b). This was associated with a
marked increase in the level of Anti-D antibodies. These changes
24 2014 Elsevier Ltd. All rights reserved.
 CASE-BASED LEARNING

b
MCA PSV values (Case 2) during the second pregnancy,
a
showing marked elevation at 28 weeks gestation,
Anti-D levels (Case 2) during the second pregnancy just prior to the first IUT when the fetal Hb was 3 g/dl
60 120

110
50 100
1.5 MoM
90
40
Anti-D levels, IU/ml

80

70

cm/s
30 Median
60

50
20
40

10 30

20

0 10
7 11 16 20 23 25 27 15 17 19 21 23 25 27 29 31 33 35 37 39
Gestational age, weeks Gestational age, weeks

c
CTG (case 2) at 28 weeks gestation, associated with reduced fetal
movements, just prior to the first IUT when the fetal Hb was 3 g/dl
180 180 180 180

160 160 160 160

140 140 140 140

120 120 120 120

100 100 100 100

80 80 80 80

60 60 60 60

40 40 40 40

100 100

80 80

60 60

40 40

20 20

0 0

Figure 2

were detected on a Friday, and the plan made for fetal blood
sampling and intrauterine transfusion on the following Monday.
However, over the weekend she complained of reduced fetal
movements and the CTG became abnormal (Figure 2c). An
emergency IUT was performed on the Sunday, which brought the
fetal Hb from 3.0 to 11.2 g/dl. Of note, there were no hydropic
changes on ultrasound scanning. Ten days later, the second IUT
was performed. The fetal Hb had slipped back down to 6.9 g/dl
and was elevated to 14.8 g/dl by this second transfusion. A third
transfusion was performed three weeks later, when the Hb rose
from 13.2 to 17.0 g/dl. The Anti-D levels continued to rise
throughout the pregnancy, reaching 1000 Iu/ml by the end.
Steroids were administered and the baby was delivered at 35
weeks gestation in good condition, with a normal cord Hb.
Phototherapy was given, and immunoglobulin, to the neonate,
however exchange transfusion was not required. Following
discharge, the baby became very anaemic again (due to persis-
tent haemolysing maternal red cell antibodies and suppressed

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1 25 2014 Elsevier Ltd. All rights reserved.
 CASE-BASED LEARNING
neonatal bone marrow) and three top up blood transfusions were
needed at 5, 10 and 15 weeks of age, along with erythropoietin
injections.
Two years later, she presented with her third pregnancy. She
had been counselled that any future pregnancies would be
complicated by earlier and more severe fetal haemolytic disease,
and that intrauterine transfusions at less than 24 weeks gestation
were very likely, but also more hazardous. Free fetal DNA
studies were performed to confirm that the fetus was in fact RhD
positive (as would be expected from the paternal blood group).
Thereafter, she received weekly injections of intravenous
immunoglobulin (IVIG) from 14 weeks in an effort to ameliorate
the haemolytic process in the fetus. Maternal Anti-D levels were
relatively slow to rise, and the MCA PSV remained normal until
28 weeks, at which time successful IUTs began, resulting in the
birth of a healthy baby at 36 weeks gestation. There was general
agreement that the maternal IVIG therapy had reduced the
severity of the disease process from what would have been
expected.
Rhesus D isoimmunisation
Red cell alloimmunisation has been covered fully in this journal
previously, and the intention of this article is only to illustrate
key points with real cases. Although Rhesus D isoimmunisation
is the focus in this case, fetal anaemia can also be caused by
maternal antibodies generated against the c, E, Kell and Duffy
antigens.
The woman in case 2 isoimmunised following a large silent
fetomaternal haemorrhage, despite the use of large doses of IV
Anti-D. She then developed a very aggressive immune response,
generating large amounts of intensely haemolytic endogenous
Anti-D. Her second pregnancy shows how a fetus can appear
normal on scan (i.e. no hydrops) even when the fetal Hb is very
low, and also that CTG abnormalities associated with severe fetal
anaemia may not be the classic sinusoidal pattern. Further-
more, this case emphasises the need for very close surveillance
because changes to the MCA Doppler PSV may only occur sud-
denly and only with severe anaemia.
In Rhesus D haemolytic disease, haemoglobin values decline
between transfusions, on average, by 0.4 g/dl per day, but this is
quite variable. Subsequent IUTs are normally scheduled for
approximately two week intervals, but this will depend on the Hb
level following the previous transfusion and the rate of Hb
decline does seem to slow down somewhat after the second IUT,
probably because the transfused red cells are RhD negative and
not at risk from the Anti-D antibodies. Although MCA Dopplers
can be used to guide subsequent transfusions, they are said to
become less reliable after the second IUT, and also after 35 weeks
gestation. Somewhat paradoxically, babies born from severely
isoimmunised pregnancies, where 3 or more IUTs have been
performed, are less likely to become seriously jaundiced and
require exchange transfusion. This is because their blood is
almost exclusively RhD negative transfused blood by the time of
delivery, and these cells are not at risk of rapid haemolysis from
the maternal Anti-D which is only slowly cleared from the
newborn circulation over the first three months post delivery.
However, their own bone marrow erythropoiesis may have been
suppressed and emerging RhD positive red cells are still at risk of
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
chronic haemolysis whilst the maternal antibodies clear. Top up
blood transfusions are often required a few weeks after birth.
It is usually the case that subsequent pregnancies with a RhD
positive fetus will be affected from an earlier gestation, and to a
greater degree. The immune response becomes more aggressive
with subsequent exposures to the RhD antigen. Intrauterine
transfusions are technically more challenging at earlier gesta-
tions. For some time, it has been known that administration of
IVIG to newborn infants with ongoing haemolysis from maternal
red cell antibodies become less jaundiced and are less likely to
need exchange transfusion. The exact mechanism is unclear, but
non-specific binding of the IVIG may ameliorate the process of
immune haemolysis. There is no high quality evidence sup-
porting the use of IVIG during pregnancy, but case reports and
small case series of severely isoimmunised women suggest that
it is a beneficial thing to do. In the case presented here, it is
reasonable to expect that the first IUT would have been needed
significantly earlier than 28 weeks gestation had the IVIG not
been given. However, it is an expensive product, and not without
risk, and it should only be considered in women with a severe
history who have been fully counselled by a haematologist.
Case 3
A 33 year old woman with a significantly raised BMI presented in
her first pregnancy at 18 weeks saying that she had had multiple
exposures to parvovirus infection. She worked with children, and
there had been a recent outbreak of slapped cheek at the
nursery where she worked. Serological testing showed IgM an-
tibodies to parvovirus B19 and she was subsequently referred to
a fetal medicine centre when the middle cerebral artery peak
systolic velocities reached 1.5 multiples of the median.
Ultrasound scanning showed a lateral placenta with a more
posterior cord insertion. Repeat MCA Dopplers confirmed values
just above the threshold for intervention with fetal blood sam-
pling. However, the fetus was active and there were no signs of
hydrops. A fetal blood sampling was thought to be technically
very difficult due to the relatively early gestation and maternal
body habitus. The MCA Doppler was repeated four days later and
was stable. It was unclear if fetal anaemia was resolving or
developing, and a further scan was planned five days later (23
weeks gestation). At this point the MCA Doppler values fell
mostly below 1.5 MoM and another scan was planned one week
later. However, at this point, ultrasound scanning showed skin
oedema, ascites (Figure 3a), a pericardial effusion and car-
diomegaly (Figure 3b) and a very raised peak systolic velocity in
the MCA (Figure 3c). The following day, a partial intrauterine
transfusion was performed, elevating the fetal Hb from 1.8 to 9.8
g/dl. A further week later, the hydrops was still present, but the
MCA PSV was normal. However, a second intrauterine trans-
fusion was given at 25 weeks gestation, taking the fetal Hb from
7.7 to 13.6 g/dl. Thereafter, the MCA Dopplers remained normal
and the hydrops resolved. Her care was returned to the referring
unit, and she went on to have a term normal delivery of healthy
baby boy, with a normal cord Hb value.
Parvovirus B19 infection
Parvovirus B19 is a DNA virus which most commonly causes a
childhood coryzal illness known as erythema infectiosum, or
26 2014 Elsevier Ltd. All rights reserved.
 CASE-BASED LEARNING
Figure 3 (a) Fetal ascites associated with parvovirus infection. (b) Fetal pericardial effusion and cardiomegaly associated with parvovirus infection. (c)
Elevated MCA PSV.
slapped cheek syndrome because of the characteristic facial
rash it may cause. Infected adults are often asymptomatic,
although an arthropathy has been reported. Serious illness is
only found in immunocompromised patients, or those with rapid
red cell turnover. The virus has a propensity to infect red cell
precursors in the bone marrow, temporarily shutting down
erythropoiesis. Individuals with haemolytic anaemia may suffer
an aplastic crisis during this time, and become much more
anaemic than normal. Fetal red blood cells also have a shorter
life span, and an infected fetus may develop severe anaemia.
This may either resolve spontaneously, or lead to fetal hydrops
and death. Direct cardiac and hepatic infection may also
contribute, by causing cardiac failure secondary to myocarditis
and hypoproteinaemia secondary to hepatitis.
50e60% of pregnant women are non-susceptible to infection,
having been infected at some point in their life beforehand. They
will show IgG antibodies against parvovirus on serological
testing of a booking sample. Susceptible women (IgM and IgG
negative) show a seroconversion rate of approximately 1%
during their pregnancies, but this may be three fold higher during
a parvovirus epidemic. There is a 50e90% risk of maternal
infection if there is a household contact, and susceptible women
who work with children have a 1 in 3 risk of infection if there is
an outbreak.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
The incubation period is 5e10 days, and the rash normally
develops 16 days after exposure. The infected individual is most
infectious in the 10 days prior to the rash appearing, and much
less so thereafter. In a susceptible individual, serum IgM anti-
bodies will be detectable within 10 days, and IgG antibodies
shortly thereafter. If an exposed individual is found to be sus-
ceptible on serological testing they should have a blood sample
repeated two weeks later to see if infection has actually occurred.
IgM antibodies are usually a reliable sign of a recent infection,
but can occasionally persist for many years. Testing the booking
sample can be very helpful in determining if the IgM antibodies
have arisen during the pregnancy, indicating a definite recent
infection.
The risk of vertical transmission to the fetus is 15% at 5e16
weeks and 20e75% after that. The closer to term the pregnancy
is the greater the risk of vertical transmission.
Parvovirus does not seem to have any obvious teratogenic
effects but is said to cause spontaneous fetal loss in approxi-
mately 15% of cases before 20 weeks gestation and 1e2% after
that. Hydrops and fetal anaemia is only evident in a small pro-
portion of these fetal losses and it has been suggested that
parvovirus is more often the cause of spontaneous abortion than
is actually recognised. Following maternal seroconversion, most
fetal medicine units recommend fetal surveillance for 10e12
27 2014 Elsevier Ltd. All rights reserved.
 CASE-BASED LEARNING
weeks with weekly to fortnightly MCA peak systolic velocities. If
fetal anaemia does not develop during this time, the woman can
be reassured and returned to normal care. The decision for
intervention with fetal blood sampling is usually made on the
MCA Dopplers exceeding the 1.5 MoM threshold. However, un-
like fetal haemolytic disease caused by red cell alloimmunisation,
the natural history of the anaemia in parvovirus infections is not
necessarily progressive. Case 3 however illustrates well the po-
tential hazards of a more conservative approach. The risk of
complications with fetal blood sampling and intrauterine trans-
fusion is variably quoted at approximately 2%. However, the
risks are significantly higher if the fetus is already hydropic and it
is common practice to give a partial transfusion first, followed by
a second one a week later if this is the case. The hydropic fetus is
far less well equipped to cope with the volume load of a full
transfusion. It is the case though that one or two transfusions will
normally suffice. The bone marrow will recover spontaneously,
and fetal red cell production does resume. The long term
outcome for these children is extremely good, even those with
severe fetal anaemia and hydrops, provided they survive the
critical time in utero. A specialist capable of IUTs.
FURTHER READING
Giorgio E, De Oronzo M, Iozza I, et al. Parvovirus B19 during pregnancy: a
review. J Prenat Med 2010; 4: 63e6.
Ismail K, Kilby M. Human parvovirus B19 infection and pregnancy. TOG
2003; 5: 4e9.
Kumar B, Ravimohan V, Alfirevic Z. Red-cell alloimmunisation. Obs Gynae
Repro Med 2010; 20: 47e55.
Wylie B, DAlton M. Fetomaternal hemorrhage. Obs Gynecol 2010; 115:
1039e51.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
Practice points
C Fetal anaemia is rare but can be caused by failure of red cell
production (e.g. parvovirus), accelerated red cell haemolysis (e.g.
red cell isoimmunisation), or fetal bleeding (e.g. fetomaternal
haemorrhage).
C Measuring the peak systolic velocity in the middle cerebral artery
is a safe and sensitive way of detecting fetal anaemia, but there is
a risk of false positive and negative results.
C Be aware that CTG changes and fetal hydrops only occur with
severe fetal anaemia.
C The diagnosis can only be made with certainty by fetal blood
sampling, which carries a 1e2% risk of complications.
C Consider FMH as a cause of sudden slowing or cessation of fetal
movements, and investigate this possibility with a Kleihauer test,
or MCA PSV.
C Once the maternal red cell antibody thresholds recommended by
blood transfusion service have been reached, the care of an
isoimmunised woman should be transferred to a fetal medicine
C Immunoglobulin therapy is not strongly evidence based for use in
ameliorating fetal haemolysis, but small case studies do lend
support.
C Women exposed to parvovirus during pregnancy should have
blood taken to see if they have pre-existing immunity. If they are
non-immune, then they should avoid working with children if
there is a parvovirus outbreak, and they should have repeated
serological tests to detect if they have become infected.
28 2014 Elsevier Ltd. All rights reserved.
 REVIEW
Surgical management of
tubal disease and infertility
Grace WS Kong
TC Li
Abstract
With the advance in assisted reproductive technology (ART), the role of
reproductive surgery as the primary treatment of infertility has been ques-
tioned. Tubo-peritoneal factor is common, and accounts for 30e40% of
female infertility. The pathology of tubal disease ranges from peritubal
adhesion, proximal and/or distal tubal blockage, hydrosalpinx to previous
sterilization. In tubo-peritoneal infertility, reproductive surgery remains an
important option and is complementary to ART. It should be considered
as the first-line treatment if a good result is expected when the pathology
is amendable or if untreated will adversely affect the results or increase
the risks of ART. The success of reproductive surgery depends on careful
patient selection using proper investigative tools, performed in units with
expertise following microsurgical principles.
Keywords peritubal adhesion; reproductive surgery; sterilization; tubal
disease
Introduction
Tubal and peritoneal factors accounts for 30e40% of female
infertility. Some tubo-peritoneal pathologies are amendable to
surgery. Nevertheless, with recent advances in assisted repro-
ductive technology (ART) producing pregnancy rate as high as
50%, the role of reproductive surgery as the primary treatment
for infertility has been questioned. On the other hand, with
careful patient selection using proper investigative tools, per-
formed in units with expertise following the microsurgical prin-
ciples, the result of therapeutic surgery can be superior to, or at
least as good as that of In-vitro fertilization (IVF). More impor-
tantly, surgery offers a permanent cure to the underlying pa-
thology. Patients may have repeated attempts to conceive
naturally without being subjected to the complications of ovarian
hyper-stimulation syndrome and multiple pregnancies from ART.
Therefore, reproductive surgery may still be considered a pri-
mary treatment on its own or complementary to IVF in the
management of female infertility.
The development of operative endoscopy evokes a revolu-
tionary change in reproductive surgery. Laparoscopic surgery are
minimally invasive with significantly less post-operative pain,
hastened recovery and fewer cardiopulmonary complications
compared with traditional laparotomy. The quality of the
Grace W S Kong MRCOG is Assistant Professor at the Department of
Obstetrics and Gynaecology, The Chinese University of Hong Kong,
Hong Kong. Conflicts of interest: none declared.
T C Li MRCP FRCOG MD PhD is a Professor at the Department of Obstetrics
and Gynaecology, The Chinese University of Hong Kong, Hong Kong.
Conflicts of interest: none declared.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
laparoscopic image has improved tremendously with fibreoptic
technology, improved camera and light system, which together
allow better visualization. In addition, the availability of more
versatile instruments allows better exposure, easier identification
of pelvic anatomy and more precise surgery. The feasibility of
laparoscopic suturing also allows more and more cases of
reproductive reconstructive surgery to be carried out lapa-
roscopically. Besides, laparoscopic surgery can be done on a day
case basis with lower cost and shorter hospitalization.
Apart from being an alternative choice for women with tubo-
peritoneal infertility, reproductive surgery may also be a com-
plementary treatment option to ART in case of hydrosalpinges,
submucosal fibroids and endometrial polyps. Women should be
well informed about the option of therapeutic surgery in case of
tubo-peritoneal infertility before formulating the management
plan.
Causes of tubal disease
The fallopian tubes are essential for natural fertility. They have
an important role in picking up ova and transporting ova,
sperms, and the embryos. They are also essential for sperm
capacitation and ovum fertilization. However, the fallopian tubes
are vulnerable to infection, endometriosis and surgical damage.
Tubal blockage can occur at the proximal, middle or distal por-
tions of the tube, or involving both the proximal and distal
portions of the tube (bipolar tubal disease). Pelvic inflammatory
disease is a major cause of tubal subfertility. When salpingitis
involves the luminal endothelium, ciliated cells lining the
ampullary and infundibular portions of the lumen of the fallopian
tube are destroyed. These ciliated cells, responsible for the
transport of the gametes and embryo to their proper location,
often do not recover after resolution of the infection. Loss of
ciliated cells, post inflammatory fibrosis and pelvic adhesion
impair normal function of the fallopian tubes and can cause oc-
clusion of the tubes in more severe cases. Chlamydial tracho-
matis accounts for around 50% of acute pelvic inflammatory
disease in developed countries. Chlamydial salpingitis is usually
asymptomatic and has a long incubation period. A prolonged,
untreated infection is more likely to cause permanent endothelial
damage. Gonorrhoea is another common infection, especially in
young women of low socioeconomic groups. It may presents as
pelvic inflammatory disease, disseminated disease with systemic
manifestations, or it may be totally asymptomatic. Besides, co-
infection with chlamydia may occur up to 30e50% of cases.
Despite successful antibiotic treatment, the risk of persistent
tubal damage leading to infertility in laparoscopically confirmed
PID is approximately 8e12%. This risk doubles with each sub-
sequent episode of PID so that infertility affects approximately
24% of patients following two documented episodes of PID, and
approximately 54% of patients after three episodes.
Prior abdomino-pelvic surgery, endometriosis, post-
pregnancy sepsis, previous sterilization and pelvic inflamma-
tory disease have all been implicated in causing tubal blockage.
The causes of tubal infertility are listed in Table 1.
Assessment of the fallopian tubes
There are various methods for assessing the tubal patency.
Traditionally, hysterosalpingogram (HSG) and laparoscopy with
6 2014 Elsevier Ltd. All rights reserved.
 REVIEW
dye are the two widely used methods for assessing the patency of
the tubes. The National Institute for Clinical Excellence (NICE)
recommends that women who are not known to have co-
morbidities (such as pelvic inflammatory disease, previous
ectopic pregnancy or endometriosis) should be offered HSG
because this is a reliable test for ruling out tubal occlusion, and it
is less invasive and makes more efficient use of resources.
Although HSG is regarded as safe, the procedure exposes women
to ionizing radiation and potentially allergic reaction to contrast
media. Where appropriate expertise is available, screening for
tubal disease using hysterosalpingo-contrast-ultrasound
(HyCoSy) may also be considered as an alternative because it
has comparable accuracy to that of HSG, but avoids radiation and
allows simultaneous assessment of the uterus and ovaries. Lap-
aroscopy with dye is recommended in women who have
increased likelihood of pelvic pathology on account of a history
of pelvic inflammatory disease, pelvic surgery and significant
pelvic symptoms such as severe dysmenorrhoea and
dyspareunia.
Fertiloscopy, also known as transvaginal hydrolaparoscopy
(THL) is a relatively new approach, which permits direct visu-
alization of the pelvic organs and confirm tubal patency under
local anaesthesia or sedation. However, the procedure is not
without risk, bowel and rectal injuries following fertiloscopy
have been reported.
However, tubal patency does not necessarily equate to normal
tubal function. We currently judge the severity of tubal damage
mainly by tubal patency and the extent of peritubal adhesion, as
determined by the American Fertility Scoring System, rather than
by the functional status of the tubal mucosa. Salpingoscopy or
falloscopy permits examination of the tubal mucosa, which
provides important information on the function of tubes. Fallo-
poscopy is a microendoscopy of the fallopian tube from the
uterotubal ostium to the fimbriae by a transcervical approach. It
allows direct visualisation of the entire fallopian tube lumen.
However, it has limited clinical application partly because the
procedure is expensive and partly because the quality of image
obtained is at best mediocre.
Cause of tubal blockage related to the site of obstruction
Site of obstruction Causes
Proximal tubal blockage C Mucus, polyps and intramural debris
C Pelvic inflammatory disease
C Salpingitis isthmica nodosa
C Endometriosis
C Obliterative fibrosis
C Intrauterine adhesion
Midsegment tubal C Post-surgery
blockage
Previous sterilization

Segmental salpingectomy for
ectopic pregnancy
C Congenital segmental absence
Distal tubal blockage C Pelvic inflammatory disease
C Post-surgical adhesion
C Endometriosis
Table 1
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
The measurement of chlamydial antibodies in serum has been
used in the screening of infertile women for tubal disease. High
serum titres of chlamydial antibodies are associated with tubal
damage resulting from previous pelvic inflammatory disease.
However, it cannot locate the site of damage nor assess the
extent of tubal disease, so it cannot completely replace laparos-
copy in the diagnosis of tubal disease.
The various tests available to assess the tubal patency and
function are summarized in Table 2.
Tubal disease and surgery
Peritubal adhesiolysis
Pelvic adhesions are often associated with tubal disease. Peri-
tubal adhesion limits tubal mobility, create a physical barrier for
ovum pick-up and gametes transport within the fallopian tube.
Periovarian adhesion may inhibit ovulation. The effect of tubal
and ovarian adhesions on fertility was investigated by Tulandi
et al. (1990), in an early controlled study which evaluated the
effect of salpingo-ovariolysis on subsequent fertility. The cumu-
lative pregnancy rate in the group that underwent salpingo-
ovariolysis was three times higher than in the non-treated
group (32% vs 11% at 12 months and 45% vs 16% at 24
months). This study confirmed that pregnancies can occur
spontaneously in women with periadnexal adhesions and patent
tubes, but also established the significant therapeutic value of
salpingo-ovariolysis in such cases.
The overall intrauterine pregnancy rates following adhesiol-
ysis vary from 21 to 62%. The therapeutic outcome of adhe-
siolysis will be affected by the extent of adhesion and the type of
adhesion (filmy or dense), the presence of inflammation and the
degree of tubal disease. In patient with filmy adhesion, the cu-
mulative pregnancy rate after adhesiolysis was 68% at 24
months (Oelsner et al., 1994). It is obviously better than the
cumulative pregnancy rate after five IVF cycles reported by Tan
et al. (1992, 51%) and by Guzick et al. (1986, 49%). Therefore, it
is no doubt that adhesiolysis is of benefit to women with filmy
adhesions. However, the pregnancy rate fell sharply to 19% in
women who underwent adhesiolysis for dense adhesion (Oelsner
et al., 1994). Thus, women with dense pelvic adhesion may be
more suited to have IVF treatment.
Studies have shown a reduced amount of de novo adhesion
formation following laparoscopy when compared with laparot-
omy. There are two possible explanations. Firstly, laparoscopy
avoids tissue desiccation which predisposes to inflammation and
subsequent adhesion formation. Secondly, laparoscopy elimi-
nates manual tissue handling leading to inadvertent serosal
damage which is a pre-requisite for adhesion formation. Lapa-
roscopic lysis of dense adhesions can be occasionally difficult,
especially for thicker, vascular, dense adhesions involving the
bowel. In such cases, it may be necessary to convert laparoscopy
to laparotomy and lysis of adhesion with the use of microsurgical
techniques including gentle tissue handling and frequent irriga-
tion to avoid desiccation.
Proximal tubal disease
Proximal tubal blockage occurs in 10%e25% of women with
tubal disease. The narrow lumen, its thick muscular wall, along
with the physiological constrictor mechanism in the proximal
tube makes it prone to blockage. The blockage may be
7 2014 Elsevier Ltd. All rights reserved.
 REVIEW

A summary of the tests available to assess tubal patency and function

Diagnostic test Description Advantages Disadvantages

Hysterosalpingram (HSG) Injection of contrast media into the
uterine cavity and X-ray taken to
visualize the contour of the uterus
and patency of the tubes
Laparoscopy with dye Gold standard for tubal
evaluation. Involves laparoscopy
and injection of methylene blue
into the uterine cavity to test for
tubal patency
Hystero-contrastsonography Ultrasound guided procedure
(HyCoSy) whereby galatose microparticles
are injected into uterine cavity, air
bubbles are followed into the
uterine cavity and used to assess
tubal patency
Fertiloscopy Combination of transvaginal
hydrolaparoscopy (THL), dye test,
fimbrioscopy or salpingoscopy and
hysteroscopy
Falloposcopy Transvaginal microendoscopy is
used to visualized the entire
fallopian tube
Chlamydia testing Blood test for chlamydia antibodies
C Outpatient procedure
C No need for general anaesthesia
C Provides information on uterine
cavity and ampullary folds
C Offers the opportunity for tubal
canulation if proximal tubal
blockage is encountered
C Relatively low cost
C Able to directly visualize pelvic
cavity (assess uterus, tubes and
ovaries)
C Able to treat pelvic pathology if
present
C Outpatient procedure
C Provides information about
uterine cavity and ovaries
C No risk of radiation
C May be performed under local
anaesthesia
C Able to combine detail in-
vestigations of pelvic, tubes
and uterine cavity
C Permits visualization of tubal
mucosa
C Titres related to severity of
tubal disease
C Easy to perform and non-
invasive
C Patient discomfort on injection
of contrast media, may resulted
in abandoning the procedure
C No information on ovaries, per-
itubal adhesion and pelvic pa-
thology such as endometriosis
C Overdiagnosis of tubal occlu-
sion possibly due to tubal
spasms
C Risk of radiation
C Risk of allergy
C Invasive procedure
C In-patient or day-surgery
C General anaesthesia required
C Complications of laparoscopy
C Relatively expensive
C Skills not widely available
C Operator dependent
C Cannot assess the ampullary
folds
C Skills not widely available;
special training required
C Absence of a panoramic view
C A small risk of bowel perfora-
tion during insertion of fertilo-
scopy needle into pouch of
Douglas
C Rarely perform nowadays partly
because of cost
C Risk of tubal perforation
C Does not establish the site or
extend of tubal disease

Table 2

functional, due to spasm of uterotubal ostium or organic, due to a
mucus plug or uterine debris, or fibrosis associated with salpin-
gitis isthmica nodosa (SIN) resulting from endometriosis or
infection.
The findings of cornual or proximal tubal blockage on HSG
should be interpreted with caution. False positive result may
arise from tubal spasm, especially in case of bilateral proximal
blockage. Spasm can result simply from the increased intrauter-
ine pressure in response to the transcervical injection of contrast
medium. This phenomenon may be avoided by introducing the
contrast medium slowly into the uterine cavity, thereby avoiding
abrupt increase in intrauterine pressure which predisposes to
tubal spasm. Alternatively, the administration of a smooth
muscle relaxant such as buscopan before the procedure may also
reduce the incidence of spasm. The sensitivity and specificity of
HSG are only 65% and 83% respectively. In one study of resected
tubes thought to be proximally occluded by HSG, 40% of tubes
were found to be occluded by amorphous material. In fact, such
non-structural occlusion can often be dislodged by application of
hydraulic pressure. A systematic review of eight RCTs showed a
significant increase in pregnancy rates with tubal flushing using
oil-soluble contrast media when compared with no treatment

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1 8 2014 Elsevier Ltd. All rights reserved.
 REVIEW
(OR 3.57, 95% CI 1.76e7.23). Tubal flushing with oil-soluble
contrast media was associated with an increase in the odds of
live birth (OR 1.49, 95% CI 42 1.05e2.11) when compared with
tubal flushing with water-soluble media. There were no signifi-
cant differences in miscarriage, ectopic pregnancy and infection
rates between tubal flushing with oil or water.
Surgical options of proximal tubal blockage include tubal
cannulation or, failing which, microsurgical tubal anastomosis.
Tubal catheterization or cannulation can be performed by either
a radiographic approach (selective salpingography with tubal
cannulation) or a hysteroscopic approach (hysteroscopic tubal
cannulation). Selective salpingography consists of passing a
catheter through the cervix into the proximal tubal ostium under
fluoroscopic guidance, followed by injection of contrast medium.
If tubal blockage cannot be overcome by the flushing action of
the contrast medium, a small inner catheter with a flexible guide
wire is advanced through the proximal tube. In hysteroscopic
proximal tubal cannulation, the catheter system included an
outer sheath, inner catheter and a guide wire. With the use of
operative hysteroscopy, the ostium can be identified, though
which the catheter set is introduced. Once the cornual segment is
cannulated with the inner catheter and guide wire, diluted
methylene blue dye is injected into the catheter to assess if
recanalization has been achieved. Usually, hysteroscopic tubal
cannulation is performed under laparoscopic guidance which
minimizes the risk of tubal perforation, confirms the restoration
of tubal patency and permits simultaneous inspection of pelvic
organs to detect any unsuspected pelvic pathology. A systemic
review of 10 cohort and 11 other observational studies of selec-
tive salpingography and tubal cannulation (n 482 women),
and four observational studies of hysteroscopic tubal cannulation
(n 133 women) in the treatment of women with bilateral
proximal tubal blockage showed that the cannulation rate was
w85% and about half of the patients conceived. The incidence of
tubal perforation has been reported to range from 3% to 11%,
almost always without any clinical consequence. The ectopic
pregnancy rate in a subsequent pregnancy ranged from 0 to 6%,
which was acceptable. In our unit, the cannulation rate was
w72% and the intrauterine pregnancy rate was 55%. Our study
confirmed the reported benefit of hysteroscopic proximal can-
nulation. Although tubal patency rates are similar with both
radiographic or hysteroscopic approach, a meta-analysis found
that on-going pregnancy rates are higher with hysteroscopic
cannulation. This may due to the fact that cannulation may be
less traumatic under hysteroscopic guidance or the opportunity
to diagnose and treat co-existing pelvic pathology.
If tubal cannulation cannot overcome the proximal tubal
blockage, it would be necessary to resort to microsurgical tubo-
cornual anastomosis, whereby the blocked cornual segment of
the tube is resected followed by anastomosis. A case series re-
ported that the live birth rate of women who underwent micro-
surgical tubocornual anastomosis was 27%, 47% and 53% at
one, two and 3.5 years of surgery respectively. Adverse prog-
nostic factors for future fertility include a significant reduction of
the residual length of tube, evidence of pelvic inflammatory
changes involving the other segment of the tube and the presence
of other infertility factors. Specialized training, experience and
availability of equipment all have a major effect on the outcome
of tubal surgery.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
Distal tubal disease
Distal tubal disease may range from thin, filmy adhesions to
complete occlusion resulting in hydrosalpinx. The inflammatory
response may be limited to the serosal surface of the fallopian
tube or may cause extensive destruction of mucosal folds and the
tubal lumen. There are two types of cells lining the tubal lumen,
the secretory cells and the ciliated cells. The former cells produce
secretion which provide the a unique nurturing environment that
enhances oocyte maturation and sperm function leading to
improved fertilization, and is essential for early embryo devel-
opment during the first 3e4 days mainly in the ampulla. The
ciliated cells, on the other hand, are involved in transport of the
gametes and embryos. It was observed in both animal and
human studies that the reduction of fertility is proportional to the
degree of mucosal damage.
Incomplete distal tubal blockage is referred to phimosis or
fimbrial agglutination, while complete distal tubal blockage is
called hydrosalpinx. Fimbrioplasty is the lysis of fimbrial adhe-
sions or dilatation of fimbrial strictures while neosalpingostomy
is the creation of a new tubal opening in a fallopian tube with a
distal occlusion. The prognosis of therapeutic surgery for distal
tubal blockage depends very much on the severity of tubal
damage. The tubal wall thickness, diameter of hydrosalpinx and
the extent of peritubal adhesion are other factors affecting the
prognosis. In women who have mild distal tubal disease, 80%
achieved intrauterine pregnancy after therapeutic surgery. In
women who have moderate distal tubal disease, the conception
rate was 17%. On the other hand, the pregnancy rate dropped to
5% in women with severe distal tubal disease, which is also
associated with and increased the ectopic pregnancy rate of up to
20%.
Careful preoperative and intraoperative assessments are
important to identify those patients who are most likely to be
benefit from distal tubal surgery. If HSG films are available,
evidence of concurrent proximal disease including constriction
of and leakage of dye into muscular layer of the isthmic portion
(which is indicative of salpingitis isthmica nodosa) should be
carefully examined, as bipolar tubal disease is associated with
a poor prognosis and is often considered as a contra-indication
for reconstructive surgery. During the operation, the luminal
surface of the distal part of fallopian tube should be examined
by salpingoscopy to rule out any intra-luminal adhesion and
fibrosis, the presence of which should prompt a decision to
proceed to salpingectomy in favour of salpingostomy.
Hydrosalpinx
Hydrosalpinx is the dilation of fallopian tube in the presence of
distal tubal obstruction. It is well known that women with
hydrosalpinx have a worse prognosis than those with other
types of tubal infertility undergoing IVF. In women undergoing
IVF, the presence of hydrosalpinx is associated with early
pregnancy loss, poor implantation and pregnancy rates. It is
probably due to the leakage of embryotoxic hydrosalpingeal
fluid into the uterine cavity causing hostile endometrial envi-
ronment for embryo implantation and development, or simply
mechanical washout of embryos. A meta-analysis demonstrated
that women with hydrosalpinx had a 50% reduction in clinical
pregnancy rates and two-fold increase in spontaneous miscar-
riage rate.
9 2014 Elsevier Ltd. All rights reserved.
 REVIEW
Hydrosalpinx should be diagnosed and treated because it may
impair the result of IVF. The impact of salpingectomy prior to IVF
treatment had been examined in a multicenter randomized
control trial in Scandinavia. A Cochrane analysis concluded that
laparoscopic salpingectomy significantly increased live birth rate
(OR 2.13; 95% CI 1.24e3.65) and pregnancy rate (OR 1.75; 21
95% CI 1.07e2.86) in women with hydrosalpinx before IVF
when compared with no treatment. The findings suggested that
prophylactic salpingectomy and IVF are complementary to each
other in the treatment of hydrosalpinx-related infertility. How-
ever, there are concerns about the potentially negative impact of
salpingectomy on ovarian function and the response to ovarian
stimulation during IVF treatment. During laparoscopic sal-
pingectomy, special care should be exercised to avoid compro-
mising the ovarian blood supply by staying close to the fallopian
tube.
Treatment options other than salpingectomy may also be
considered. Laparoscopic proximal tubal ligation is an alternative
if salpingectomy is not technically possible due to the presence of
pelvic adhesions. Occlusion of the tube serves the purpose of
interrupting the passage of embryotoxic hydrosalpingeal fluid to
the endometrial cavity. Data from recent Cochrane review sug-
gested that laparoscopic proximal tubal ligation is as effective as
laparoscopic salpingectomy in the increase of IVF success rate by
approximate 2-fold. However, leaving the hydrosalpinx behind
may interfere with the aspiration of oocytes. In addition, women
may experience exacerbation of pain after proximal tubal ligation
because of on-going inflammation and distension of the fallopian
tube resulting from occlusion at both distal and proximal ends.
Consequently, it is advisable to perform salpingectomy whenever
feasible, but to reserve proximal tubal occlusion to cases
complicated by severe, dense adhesions involving the distal part
of the tube or when the risk of damaging the vascular supply to
ovary is high.
It is also possible to achieve proximal tubal occlusion with
hysteroscopic placement of a micro-insert such as Essure. The
Essure micro-insert is 4 cm in length and 2 mm in diameter in
its expanded form. Polyethylene terephthalate fibres run along
through the inner coil and these fibres induce a tissue reaction
resulting in tubal occlusion, thereby preventing hydrosalpingeal
fluid from entering the endometrial cavity. The nickel titanium
outer coil serves as an anchor within the uterotubal junction. A
recent systemic review of 11 observational studies (115 women)
demonstrated that women who had hysteroscopic proximal end
occlusion with Essure and who underwent further IVF cycle had
a pregnancy rate of 38.6% and a live birth rate of 27.9% per
embryo transfer, which is similar to results following laparo-
scopic salpingectomy, although direct comparative data is not
available. Hysteroscopic proximal end occlusion by micro-insert
Essure may be carried out as an office procedure without the
use of anaesthesia, which is an advantage. However, perforation
of fallopian tube and flare up of infection because of the presence
of foreign body in an inflamed environment are recognized
complications.
Ultrasound guided aspiration of hydrosalpingeal fluid is not
usually recommened because the underlying pathology is not
altered and the fluid often rapidly re-accumulate. The procedure
is associated with a risk of infection and the efficacy has not been
demonstrated.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
Sterilization reversal
Between 0.2% and 3% of women who have had surgical tubal
sterilization will request a reversal procedure. The younger is the
patient at the time of a tubal sterilization procedure, the more likely
that she will regret her decision. The most frequently cited reason for
requesting a reversal procedure is the desire for children with a new
partner.
In general, sterilization reversal is associated with a high preg-
nancy rate of up to 80%. Several factors may affect the outcome.
Firstly, age of the women is important. In one large series, the
pregnancy rate after sterilization reversal among women aged 15
e30 years, 30e33 years, and 34e49 years were 73%, 64% and 46%,
respectively. Secondly, procedures that destroy the least amount of
the tube have the highest success rates after reversal. The use of
Filshie clips or Falope rings for sterilization is associated with a
higher chance of success following the reversal procedure. Tubal
cautery usually destroys a longer segment of the tube and is asso-
ciated with a reduced chance of success. Higher pregnancy rates and
a lower median interval between surgery and pregnancy are ex-
pected when the length of the tube after re-anastomosis is more than
4 cm. The prognosis is better when there is no significant discrep-
ancy in diameters of the two ends of the tube at the site of anasto-
mosis, e.g. isthmic to isthmic, or cornual to isthmic anastomosis.
The length of time between sterilization and reversal is not generally
regarded as important, but one study noted an increased risk of
damaged mucosa with flattening of epithelium and polyp formation
in the proximal portion of the tube after 5 years of sterilization.
Tubal anastomosis may be carried out via laparoscopy or
laparotomy. Despite the advantages of laparoscopic surgery,
many reproductive surgeons continue to perform tubal re-
anastomosis via laparotomy because laparoscopic approach re-
quires superb suturing skill and special laparoscopic microsur-
gical instruments. Nevertheless, in experienced hands, the result
of laparoscopic sterilization reversal has produced result com-
parable to that of microsurgery performed via laparotomy,
around 80% conception rate at 12 months. On the other hand,
robot-assisted suturing is particular suited for tubal anastomosis.
General consideration and patient selection
The management of tubo-peritoneal infertility is highly individ-
ualized. The age of the patient, ovarian reserve, prior fertility,
number of children desired, site and extend of the tubal disease,
presence of other infertility factors, experience of the surgeon,
success rates of the IVF program, patient preference, religious
beliefs and the cost are all important factors to be considered.
Prior to making a decision on how the best to manage tubal
disease, proper work-up to rule out any co-existing infertility
factor is essential. Semen analysis must be performed as a grossly
abnormal result may be a contra-indication to surgery.
The rationale, potential benefits and complications of the
proposed treatment should be clearly discussed before formu-
lating the management plan. Tubal therapeutic surgery can offer
a permanent cure in some women so that they can have repeated
attempts to conceive naturally and avoid the risks associated
with IVF. However, women with tubal therapeutic surgery will
have a higher risk of ectopic pregnancy in general. They should
be informed about other possible surgical risks like bleeding,
infection, iatrogenic injuries and anaesthetic risks. On the other
10 2014 Elsevier Ltd. All rights reserved.
 REVIEW
hand, IVF treatment is associated with ovarian hyper-stimulation
syndrome.
Laparoscopy remains the gold standard to diagnose the tubal
disease and assess the severity of tubal damage. Therapeutic
surgery remains a viable option in the management of tubo-
peritoneal infertility. The success of therapeutic surgery de-
pends on prudent selection of cases. Ideal candidates for thera-
peutic surgery are those who are young, with minimal degree of
tubal damage, and no concomitant infertility factor.
Microsurgical principles
Microsurgery is a concept as well as the utilization of a set of
microsurgical principles and specially designed micro-instrument
to minimize tissue injury and to achieve optimal anatomical
reconstruction. The relevant techniques include: appropriate
magnification, good lighting, complete removal of diseased tis-
sue, meticulous haemostasis, avoidance of peritoneal desiccation
with continuous irrigation of exposed peritoneal surface and the
use of micro-suture. The use of microsurgical technique should
lead to a reduced risk of iatrogenic adhesion formation. Micro-
surgical principles should be followed not only in reconstructive
surgery of the fallopian tube, but whenever gynaecological sur-
gery is performed in women of the reproductive age group.
Conclusion
Reconstructive surgery remains a viable option in women with
tubal infertility. In selected cases, it produces the result compa-
rable to IVF treatment. It may also complement IVF treatment by
improving the success rate in women with hydrosalpinges.
Women with infertility resulting from tubal disease should have
ready access to experienced reproductive surgeons to contribute
to the formulation of optimal treatment plan. A Obstet Gynecol 2000; 43: 641e9.
FURTHER READING
Arora P, Arora R, Cahill D. Essure for management of hydrosalpinx prior
to in vitro fertilisation-a systematic review and pooled analysis. Br J
Obstet Gynaecol 2014; 121: 527e36.
Camus E, Poncelet C, Goffinet F, et al. Pregnancy rates after in-vitro fertilization
in cases of tubal infertility with and without hydrosalpinx: a meta-analysis
of published comparative studies. Hum Reprod 1999; 14: 1243e9.
Forsey JP, Caul EO, Paul ID, Hull MG. Chlamydia trachomatis, tubal disease
and the incidence of symptomatic and asymptomatic infection
following hysterosalpingography. Hum Reprod 1990; 5: 444e7.
Honore GM, Holden AE, Schenken RS. Pathophysiology and management
of proximal tubal blockage. Fertil Steril 1999; 71: 785e95.
Johnson N, van Voorst S, Sowter MC, Strandell A, Mol BW. Surgical treatment
for tubal disease in women due to undergo in vitro fertilisation.
Cochrane Database Syst Rev 2010. Issue 1. Art. No.:CD002125.
Johnson N, Vandekerckhove P, Watson A, Lilford R, Harada T, Hughes E.
Tubal flushing for subfertility. Cochrane Database Syst Rev 2002. Issue
3. Art. No.:CD003718.
Johnson NP, Mak W, Sowter MC. Laparoscopic salpingectomy for women
with hydrosalpinges enhances the success of IVF: a Cochrane Review.
Hum Reprod 2002; 17: 543e8.
Lan JA. Tubal microsurgery. I. The principles. Gynecol Obstet Invest 1987;
23: 73e8.
Mol BW, Swart P, Bossuyt PM, van der Veen F. Is hysterosalpingography an
important tool in predicting fertility outcome? Fertil Steril 1997; 67: 663e9.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:1
National Institute for Clinical Excellence. Fertility: assessment and treat-
ment for people with fertility problems (update). Clinical Guideline.
London: NICE, May 2012.
Oelsner G, Sivan E, Goldenberg M, Carp H, Admon D, Mashiach S. Should
lysis of adhesions be performed when in-vitro fertilization and embryo
transfer are available? Hum Reprod 1994; 9: 2339e41.
Z1 Pandian, Akande VA, Harrild K, Bhattacharya S. Surgery for tubal
infertility. Cochrane Database Syst Rev 2008 Jul 16. Issue 3. Art. No.:
CD006415.
Posaci C, Camus M, Osmanagaoglu K, Devroey P. Tubal surgery in the era
of assisted reproductive technology: clinical options. Hum Reprod
1999; 14: 120e36.
Practice Committee of the American Society for Reproductive Medicine.
Committee opinion: role of tubal surgery in the era of assisted
reproductive technology. Fertil Steril 2012; 97: 539e45.
RD1 Saunders, Shwayder JM, Nakajima ST. Current methods of tubal
patency assessment. Fertil Steril 2011; 95: 2171e9.
Singhal V, Li TC, Cooke ID. An analysis of factors influencing the outcome
of 232 consecutive tubal microsurgery cases. Br J Obstet Gynaecol
1991; 98: 628e36.
Spielvogel K, Shwayder J, Coddington CC. Surgical management of ad-
hesions, endometriosis, and tubal pathology in the woman with
infertility. Clin Obstet Gynecol 2000; 43: 916e28.
Sulak PJ, Letterie GS, Coddington CC, Hayslip CC, Woodward JE, Klein TA.
Histology of proximal tubal occlusion. Fertil Steril 1987; 48: 437e40.
Trussell J, Guilbert E, Hedley A. Sterilization failure, sterilization reversal,
and pregnancy after sterilization reversal in Quebec. Obstet Gynecol
2003; 101: 677e84.
Tulandi T, Collins JA, Burrows E, et al. Treatment-dependent and
treatment-independent pregnancy among women with periadnexal
adhesions. Am J Obstet Gynecol 1990; 162: 354e7.
Van Voorhis BJ. Comparison of tubal ligation reversal procedures. Clin
Practice points
C Tubo-peritoneal infertility is common, and accounts for 30e40%.
C The common causes of tubal disease are infection, endometriosis,
previous surgery, and inflammatory disease.
C Hysterosalpingram should be routinely offered to women with a
low risk of tubal disease. In women with a high risk of tubal
disease, or if HSG suggests tubal blockage, a laparoscopy and
dye test should be offered.
C Tubal patency does not equate with normal tubal function; direct
inspection of the mucosa (salpingoscopy) provides important
additional information about the function of tube.
C Reversal of sterilization is associated with a conception rate of
w80%, higher than that achieved with one cycle of IVF treatment.
C Hysteroscopic proximal tubal cannulation is a recognized effective
treatment for proximal tubal blockage.
C In women with hydrosalpinges, salpingoscopy should be per-
formed to assess the degree of tubal damage. In the absence of any
evidence of mucosa damage, salpingostomy should be considered.
On the other hand, if the mucosa has been significantly damaged or
destroyed, salpingectomy is a better surgical option.
C Microsurgical principles should be followed not only in reconstruc-
tive surgery of the fallopian tube, but whenever gynaecological
surgery is performed in women of the reproductive age group.
11 2014 Elsevier Ltd. All rights reserved.