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Obstetrics,

Gynaecology
and Reproductive
Medicine
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Editor-in-Chief
Philip N Baker FRCOG, FMedSci
Pro-Vice-Chancellor and Head of the College of Medicine, Biological Sciences and Psychology,
Dean of the School of Medicine, University of Leicester, UK

Deputy Editor-in-Chief
Alec McEwan BA BM BCh MD MRCOG
Consultant in Fetal and Maternal Medicine, Department of Obstetrics and Gynaecology,
Queens Medical Centre, Nottingham, UK

Associate Editors
Sabaratnam Arulkumaran MBBS MD PhD FRCS (Ed) FRCOG
Professor of Obstetrics and Gynaecology,
Department of Obstetrics and Gynaecology,
St. Georges Hospital Medical School, London, UK

Fiona Reid MD MRCOG


Consultant Urogynaecologist,
St Marys Hospital, Manchester, UK

Shreelata Datta BSc(Hons) MBBS MRCOG LLM


Consultant Obstetrician and Gynaecologist,
Kings College Hospital, London, UK

Mahmood I Shafi MB BCh MD DA FRCOG


Consultant Gynaecological Surgeon and Oncologist,
Addenbrookes Hospital, Cambridge, UK

Tahir A Mahmood MD FRCOG FRCPI MBA FACOG(Hon)


Consultant Obstetrician and Gynaecologist,
Victoria Hospital, Kirkcaldy, Fife, UK

Trainee Editor
Catherine Aiken MB/BChir MA PhD MRCP MRCOG
Specialist Registrar (ST5) and Academic Clinical Lecturer in Obstetrics and Gynaecology,
Addenbrookes Hospital, Cambridge, UK
Obstetrics, Gynaecology and Reproductive Medicine has an eminent editorial board, all of whom are recognized experts in their field.
Visit our website at: www.obstetrics-gynaecology-journal.com for previous issues, subscription information and further details.

REVIEW

Antepartum haemorrhage

haemorrhage. The report does not distinguish the women who


presented with APH, but three women were diagnosed with
placental abruption and placenta praevia.
The aim of this review is to define causes of APH and discuss
management in accordance with recent guidelines and published
evidence. The MBRRACE-UK report reminds us that APH and
PPH are not only important causes of maternal mortality but also
of maternal and perinatal morbidity. Therefore the early recognition and management of women presenting with genital tract
blood loss is an important aspect of antenatal assessment. It is
essential that the obstetrician be prepared for potential sequelae,
and thorough antenatal, intrapartum, and postpartum planning
is required.

Nadia Amokrane
E R F Allen
Anna Watereld
Shreelata Datta

Abstract
Antepartum haemorrhage (APH) is bleeding from or into the genital
tract occurring between 24 0 weeks gestation until birth. It complicates 3e5% of pregnancies. The 2006e2008 report of the Condential
Enquiries into Maternal Deaths in the UK (CMACE) reported APH as
the cause of death in four women. The high prevalence of APH, and
its associated perinatal mortality and morbidity makes a thorough understanding of APH is essential for the practising obstetrician. The
objective of this review is to consider the most common causes of
APH (placenta praevia, placental abruption and local causes), together
with their management.

Causes of APH
Cervical and vaginal causes
A common cause of APH is bleeding from the cervix. A cervical
ectropion or erosion is where the columnar epithelium that
lines the cervical canal protrudes further onto vaginal surface of
the cervix. This is more common in pregnancy, and is thought to
be related to high oestrogen levels. The tissue of the ectropion is
very friable and contact bleeding can occur, usually at sexual
intercourse or even on passing hard stools. Ectropion can be
easily diagnosed on speculum examination of the cervix.
Cervicitis (inflammation or infection of the cervix) may be an
under-diagnosed cause of bleeding in pregnancy and may be
caused by sexually transmitted infections (STIs) such as chlamydia and gonorrhoea, which can present with abnormal vaginal
bleeding. A high vaginal swab and screening for STIs should be
undertaken. Treatment of STIs presenting in pregnancy is
important, as they can be associated with preterm labour and
neonatal morbidity. Bleeding or spotting can also occur from the
vagina and vulva secondary to non-sexually transmitted infections such as thrush, folliculitis, and from trauma.
Benign cervical polyps are a further cause of APH. If the
bleeding does not clinically compromise the mother or fetus, and
the polyp appears non-suspicious then these should not usually
be removed in pregnancy.
Cervical carcinoma presenting in pregnancy is uncommon
and a detailed history at booking appointment should assess a
womans smear history and history of previous cervical treatments. If a cervical carcinoma is suspected on assessment of the
cervix then urgent referral to colposcopy is indicated.

Keywords antepartum haemorrhage; obstetric haemorrhage;


placenta accreta; placenta praevia; placental abruption

Introduction
Bleeding in pregnancy is a common reason for presentation to
labour wards, maternity triage units, GP surgeries and early
pregnancy centres in the UK.
The management of bleeding in pregnancy varies according to
gestation. In this review we specifically address antepartum
haemorrhage (APH) which is defined as bleeding from the genital
tract that occurs from viability onwards, defined here as greater
than 24 weeks gestation. Obstetricians may see women with
genital tract bleeding from 16 to 23 weeks gestation however
management of this group of women may differ.
APH and post-partum haemorrhage (PPH) are the leading
causes of maternal death worldwide. In the UK, maternal deaths
have continued to decrease. The recent MBRRACE-UK report
published in December 2014 showed that maternal mortality in
the UK had decreased from 11:100, 000 women between 2006
and 2008 to 10:10,000 between 2009 and 2012. Between 2009
and 2012, 17 mothers in the UK and Ireland died due to

Placental causes
Placental abruption: abruptio placenta is the premature separation of a normally sited placenta from the uterus. Placental
abruption can lead to maternal and fetal complications, and ultimately mortality. Bleeding occurs when the placenta starts to
separate from the decidua basalis. The presentation of placental
abruption usually includes pain (50%) and bleeding (70e80%)
however, a concealed abruption (20% of cases) can present with
no pain or bleeding. Premature labour is seen in nearly a third of
cases of abruption, however, the contraction pains may be
atypical in nature, with the patient describing severe unremitting
pain.
The incidence of placental abruption is reported between
0.26% and 0.80% in literature depending on the type of study

Nadia Amokrane MBChB is a Specialist Registrar in Obstetrics and


Gynaecology at Kings College Hospital, London, UK. Conicts of
interest: none declared.
E R F Allen MBBS BSc MRCOG is a Locum Consultant Obstetrician and
Gynaecologist at Kings College London (PRUH), London, UK.
Conicts of interest: none declared.
Anna Watereld MRCOG is a Senior House Ofcer in Obstetrics and
Gynaecology at Kings College Hospital, UK. Conicts of interest:
none declared.
Shreelata Datta MBBS LLM BSc (Hons) MRCOG is a Consultant
Obstetrician and Gynaecologist at Kings College Hospital, London,
UK. Conicts of interest: none declared.

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REVIEW

and population. The biggest risk factor for abruption is a previous abruption with a 10-fold increased risk of abruption if there
has been an abruption in the previous pregnancy. The risk increases to nearly 25% if a woman has had two previous
abruptions.
Although there is no single aetiology for placental abruption, a
number of risk factors have been identified. These include hypertension and pre-eclampsia. Notably, when examining risk
factors in a control population, chronic hypertension has a
stronger association with abruption (OR 3.13) than preeclampsia (OR 1.73). Smoking is associated with a 90% increase in the risk of abruption. There is a three-fold increased
risk in pregnancies complicated by prolonged rupture of membranes (PROM). Cocaine use has also been linked to a higher rate
of placental abruption. However, despite numerous risk factors
and associations, abruption is usually an unexpected event and
the vast majority will occur in low risk pregnancies.

suggest that transvaginal scanning in suspected placenta praevia


cases is unsafe.
Women with a low-lying placenta at 20 weeks should be
followed up in the third trimester, usually at 32e36 weeks.
However, if women have had a previous Caesarean section and
have a low-lying placenta, then a placenta accreta should be
suspected. If major placenta praevia is suspected in the third
trimester, then this significantly raises the risk of morbidity and
preterm delivery. However the diagnosis of placenta praevia
should be considered in any patient who presents with painless,
fresh vaginal bleeding or bleeding after intercourse.
The most likely symptom from a placenta praevia is painless
bleeding in contrast to abruption where pain is likely to copresent. The bleeding is usually fresh, red and the amount of
APH can vary. The patient may also present with fresh bleeding
in early labour, with the onset of labour and cervical dilatation
triggering the bleed or vice versa.

Placenta praevia, placenta accreta, increta and placenta percreta: placenta praevia is the insertion of the placenta partially or
entirely within the lower segment of the uterus after 32 weeks. If
the placenta does not cover the internal os then it is described as
a minor praevia and if it partially or fully covers the os then it is
classified as a major praevia. A morbidly adherent placenta such
as a placenta accreta, increta or percreta invades through the
decidua basalis. In placenta accreta the chorionic villi attach to
the myometrium. In placenta increta the placenta has invaded
into the myometrium; in placenta percreta the placenta invades
through the myometrium and breaches the uterine serosa.
Placenta percreta may then invade other organs such as the
bladder.
The incidence of low-lying placenta can be up to 28% at the
routine 20 week anomaly ultrasound scan, but the majority of
these will have migrated higher by the following scan, usually at
32 weeks or later. The incidence of true placenta praevia at term
is approximately 3%.
There are several hypotheses about the aetiology of placenta
praevia. One theory is that the position of the placenta depends
on the site of implantation of the discoid trophoblast when the
pregnancy is developing and from where the placenta will arise.
A further theory postulates that areas of deficient endometrium
from procedures such as caesarean sections, surgical management of miscarriage and myomectomies may affect how the
placenta attaches in these cases.
The risk factors for placenta praevia include multiparity,
increasing maternal age, smoking, previous praevia and surgical
procedures that may result in deficient endometrium (Table 1).
The number of previous Caesarean sections also increases the
risk of placenta praevia.
In well-resourced settings such as in the UK, the majority of
placenta praevia cases may be picked up on ultrasound scan at
20 weeks. Currently the UK National Screening Committee does
not recommend screening for placenta praevia however, alongside the RCOG, they support most local practice of identifying
women by ultrasound whose placenta lies near the internal os at
the routine 20 week scan. Evidence shows that at the second
trimester scan about 26e60% of women with a low lying
placenta on abdominal ultrasound would be reclassified with a
more accurate transvaginal scan. There have been no reports to

Other causes
Uterine rupture: uterine rupture is a rare event that is defined as
loss of the full thickness of the uterine wall integrity. It usually
occurs during labour in a woman with a previous Caesarean
section or myomectomy. Within this group the risk is still small;
the incidence of uterine rupture has been estimated at 7 per
10,000 planned vaginal births after Caesarean section. Uterine
rupture may present with CTG abnormalities, pain or APH. Early
recognition and quick stabilisation of the mother and baby is
required as mortality and morbidity is high.

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:2

Vasa praevia: vasa praevia is a rare obstetric complication where


fetal blood vessels cross the internal cervical os. As the incidence
is rare (between 1 in 2000 and 1 in 6000 pregnancies) it is not
currently screened for during routine ultrasound. The risk of APH
mainly comes with rupture of the membranes or labour, as a
direct consequence of tearing of the blood vessels. The fetus can
be comprised quickly and management if diagnosed or suspected
is usually by immediate category 1 Caesarean section.

Unexplained APH
Some women will present with bleeding that cannot be attributed
to any of the above causes. The RCOG Greentop Guideline references a number of studies over the last four decades that
demonstrate that pregnancies with unexplained APH are at
higher risk of preterm birth and stillbirth. A recent retrospective,
observational study noted that pregnancies complicated by APH
of unknown aetiology are at a higher risk of preterm birth, lower
birthweight, induction of labour, and neonatal unit admissions.
Repeated presentations with unexplained APH in pregnancy
should raise suspicion and the pregnancy should be monitored as
high risk, with the need for additional ultrasound scans for fetal
growth.
Healthcare providers should be aware that maternal trauma,
including domestic violence, can result in APH, possibly from
placental abruption. A third of domestic violence is known to
start or escalate in pregnancy. A retrospective study of 2070
women subjected to physical violence in pregnancy found an
increased odds ratio of APH in this cohort, compared with controls, of 3.79 (95% CI 1.38e10.40). Women who present with

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multidisciplinary team including a senior obstetrician, anaesthetist, and senior midwife. Input is also frequently required
from blood transfusion technicians, haematologists, neonatologists, and porters. Obstetric units will usually have fixed
protocols for the management of massive obstetric haemorrhage
that should be activated if a woman presents with or develops
massive haemorrhage. These protocols should be actively
rehearsed in annual skills training in order to prepare for such
cases.
The RCOG Greentop Guideline defines the severity of APH, as
outlined in Table 2. However, it should be remembered that the
amount of blood lost can be underestimated, particularly as the
amount of blood seen on vaginal examination may not be an
accurate representation of the total blood lost.
The initial assessment of a woman with APH should include
the ABC approach to stabilise the patient (Table 3) and assess the
total estimated blood loss. However, it is important to remember
that not all blood loss is revealed, so the clinical features of blood
loss are extremely important (e.g. grade of shock) to formulating
appropriate management plans.
Patients with major or massive obstetric haemorrhage should
be managed in left lateral tilt to reduce hypotension secondary to
uterine compression of the inferior vena cava. Resuscitation and
stabilization of the mother is the key priority. Following the
initial survey and after commencing resuscitation, the cause and
extent of the APH should be assessed by history taking and
carrying out a full examination.
Abdominal examination may illicit a woody or tense uterus,
which is characteristically seen in placental abruption or it may
show the patient is contracting and could be in labour. If a patient with known placenta praevia presents with bleeding, then a
digital examination or speculum examination is not necessary. A
digital examination or speculum may be indicated where
placenta praevia has been excluded to check for a cause for the
APH and to assess cervical dilatation. The diagnosis of vasa
praevia should be considered when the APH has been associated
with rupture of membranes.

Risk factors for placenta praevia


Risk factors
Placenta praevia

Placental abruption

Vasa praevia

Uterine rupture

Uterine rupture

Large placental area


(multiple pregnancy)
Advanced maternal age
High parity
Uterine scar (caesarean section,
myomectomy)
Previous placenta praevia
Smoking, cocaine use
Placental pathology
Previous placental abruption
Hypertension
Pre-eclampsia
Smoking, cocaine use
Premature rupture of membranes
Coagulopathies
Multiple gestation
Advanced maternal age
Abdominal trauma
Velamentous insertion of umbilical cord
Succenturiate, bilobe placenta
Multiple gestation
IVF pregnancy
Multiparity
Congenital uterine anomalies
Uterine scar (secondary to caesarean
section, myomectomy etc)
Maternal age
Abnormal placentation
Uterine distension (multiple gestation,
polyhydramnious, macrosomia)
Gestation >40 weeks
Obstructed labour

Table 1

Investigations
The RCOG guideline recommends that all patients with APH
should have a full blood count (FBC) and a group and save. A
Kleihauer test is also necessary for all Rhesus negative women.
Women who present with major or massive haemorrhage should
also have liver and renal function blood tests and a coagulation
screen including fibrinogen. They also may benefit from a
bedside blood check such as a Hemacue since the FBC may not
give an accurate immediate estimate of blood loss.

APH and other signs suggestive of domestic violence or, who


disclose violence, should be identified and managed appropriately by a multidisciplinary team who have been specially
trained in domestic violence to safeguard pregnant women.

Diagnosis and management of APH


Women who present with major haemorrhage and signs of
shock should be seen in a maternity unit with involvement of a

RCOG definition of APH severity


Description

Blood volume

Spotting
Minor haemorrhage
Major haemorrhage
Massive haemorrhage

Staining, streaking or blood spotting noted on underwear or sanitary protection


Blood loss less than 50 ml that has settled
Blood loss of 50e1000 ml, with no signs of clinical shock
Blood loss greater than 1000 ml and/or signs of clinical shock

Table 2

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Resuscitation pathway for major APH


Assessment
A(irway)
B(reathing)

C(irculation)

D(isabilty)
E(xposure)

F(etus)

Management
Check patency
Respiratory rate
Oxygen saturations
10e15L via non rebreathing mask
Heart rate
Capillary refill time
Blood pressure
IV access (consider x 2 16 gauge cannulas)
IV fluid resuscitation crystalloid/colloid/blood
Assess blood loss
Consider catheterisation (input/output monitoring)
Glasgow coma score
Abdominal examination
Speculum
Vaginal examination
CTG
Auscultation FHR
Ultrasound

Method used gestation dependent

Table 3

Even with bedside haemoglobin checks and laboratory FBC, it


should be noted that after acute major blood loss these tests can
be misleading during or soon after the initial haemorrhage.
Therefore, initial diagnosis and management of APH should be
based on clinical criteria and observations.
After stabilizing the mother, the fetal heart rate should be
checked. There is no clear guidance or evidence to support
monitoring fetuses during APH as there may be transient abnormalities with the CTG. Clinical judgement is essential to make
a decision regarding mode and timing of delivery based on likely
diagnosis and the maternal and fetal status. For example, if an
abruption is suspected and there is an abnormal CTG then the
CTG findings are likely to be associated with fetal hypoxia and so
delivery would be indicated for fetal benefit.
Ultrasound can be used to determine placental site, or to
check fetal growth, liquor and Doppler studies once the bleeding
has settled. It is not recommended as a diagnostic tool to diagnose abruption as the reported sensitivity is only between 25
and 50%.
Generally most clinicians currently do not recommend tocolysis if a patient is actively bleeding. The RCOG recommends a
single course of steroids between 24 and 34 weeks if delivery is
likely to be preterm.

be hospitalised until elective delivery although there is no evidence to support this. In accordance with the RCOG Green-top
guideline, women with placenta praevia in the third trimester
should be counselled about the risks of preterm delivery and
obstetric haemorrhage. The place and package of care should be
individualised to meet the needs of each patient. If care is at
home, the woman should be within close proximity to the hospital, have a constant companion at home, and be aware of when
she should attend hospital immediately.
Blood products
Managing severe antepartum haemorrhage frequently requires
blood transfusion and considering delivery with surgical interventions to arrest the bleeding. If women require blood
transfusion then individually cross-matched blood is ideal.
Rarely, if blood loss is so excessive that the processing time for
this would be clinically unacceptable then Group O Rhesus
negative red cells should be utilised. Commencing red cell
transfusion is based on clinical evaluation and haematological
investigations, if available. If a coagulopathy develops then fresh
frozen plasma (FFP) should be administered before one blood
volume is lost. Haematological investigation and specialist
advice should guide the further use of FFP, cryoprecipitate, and
platelets in massive obstetric haemorrhage. The RCOG Green-top
guideline on blood transfusion in obstetrics advises that cryoprecipitate may be indicated when there is bleeding with
fibrinogen concentration below 1 g/L. The platelet count should
be maintained at above 75  109/L.
It is important that women who will refuse blood products in
an emergency, including Jehovahs witnesses, are identified in
the antenatal period and referred to consultant-led care. These
women are at higher risk of morbidity and mortality in the case
of APH. The healthcare provider and patient should discuss what

Conservative management of placenta praevia


Women with placenta praevia were previously advised to remain
as inpatients from 34 weeks until elective delivery. Currently
there is limited evidence to support either hospital-based or
home-based care in the third trimester. Women with placenta
praevia who have APH that resolves spontaneously without
requiring immediate delivery are likely to remain in hospital until
bleeding has completely ceased. With recurrent APH in the third
trimester for any pathology, it is common practice for patients to

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blood components and blood derivatives (for example clotting


factor concentrates) would be acceptable to the woman in the
event of serious blood loss, and also if autologous transfusion in
the form of cell salvage can be used. There should be a signed
advanced directive and all discussions clearly documented.
Antenatally, any woman who would refuse blood transfusion or
blood products should have their haemoglobin levels optimised.
In the event of major APH or indeed PPH, a consultant obstetrician, anaesthetist and haematologist should be informed. If a
woman who would refuse donor blood is diagnosed antenatally
with placenta accreta or this is suspected, it is recommended that
delivery is planned in a facility with access to interventional
radiology. There is insufficient evidence on whether prophylactic
catheter placement for balloon occlusion or embolisation is
advantageous.

audits and reviews are imperative for individual units to learn


through previous experiences and near-misses. All maternity
multidisciplinary team must be regularly updated in their obstetric haemorrhage protocols e both antenatal and postpartum.
A
FURTHER READING
Antepartum haemorrhage RCOG Green top guideline 63. 2011,
https://www.rcog.org.uk/globalassets/documents/guidelines/gtg_
63.pdf.
Anath CV, Savitz DA, Williams MA. Pracental abruption and its association with hypertension and prolonged rupture of membranes: a
methodologic review and meta-analysis. Obstetrics Gynecol 1996
Aug; 88: 309e18.
Blood transfusions in Obstetrics RCOG Green top guideline 47.
https://www.rcog.org.uk/globalassets/documents/guidelines/
gt47bloodtransfusions1207amended.pdf.
Knight M, Kenyon S, Brocklehurst P, et al., eds. on behalf of
MBRRACEUK. Saving lives, improving mothers care e lessons
learned to inform future maternity care from the UK and Ireland
condential enquiries into maternal deaths and morbidity 2009e12.
Oxford: National Perinatal Epidemiology Unit, University of Oxford,
2014.
Neilson JP. Interventions for suspected placenta praevia. Cochrane
Database Syst Rev 2003 (2):CD001988.
Neilson JP. Interventions for treating placental abruption. Cochrane
Database Syst Rev 2003 (1):CD003247; reviewed 2009.
Royal College of Obstetricians and Gynaecologists. Placenta praevia,
placenta praevia accreta and vasa praevia: diagnosis and management. Green-top Guideline No. 27. London: RCOG, 2011.
Royal College of Surgeons. Code of practice for management of Jehovah witnesses. London: IBSA Press, 2002.
Tikkanen M, Nuutila M, Hiilesmaa V, et al. Clinical presentation and risk
factors of placental abruption. Acta Obstetricia Gynecol Scand
2006; 85: 700e5. http://dx.doi.org/10.1080/00016340500449915.
Toivonen S, Heinonen S, Anttila M, et al. Reproductive risk factors,
Doppler ndings, and outcome of affected births in placental
abruption: a population-based analysis. Am J Perinatol 2002; 19:
451e60.

Delivery techniques and post-partum care


Placental abruption and placenta praevia can lead to ongoing
bleeding after delivery. Bleeding should be managed according to
normal post-partum haemorrhage protocols, with uterotonic
agents and surgical interventions such as intrauterine balloons,
B-Lynch suture, uterine artery embolization and hysterectomy as
required. In cases of placenta accreta managed by Caesarean
section, where the placenta fails to separate, managament options include leaving it in situ and proceeding to either elective
hysterectomy or conservative management. There are no randomised control trials to compare approaches directly but case
series show successful outcomes with both approaches. If the
placenta is left in situ and the uterus is spared, conservative
management involves prophylactic antibiotics and lengthy
follow-up with beta-HCG measurement and imaging to ensure
resolution. Women should be warned of the risk of persisting
bleeding and infection.

Conclusion
APH can be a traumatic and concerning event for women in
pregnancy. Early recognition and management is therefore vital,
together with a relevant postnatal debrief. The MBRRACE-UK
report highlights that haemorrhage is still a significant contributor to UK maternal morbidity and mortality. Therefore, local

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Twin pregnancy

The relationship between the different types of twin


gestation with regard to the timing of embryo cleavage
following fertilisation

Emma Long
Emma Ferriman

Time of cleavage
after fertilization

Nature of membranes

Abstract

0e3 days
4e8 days
9e12 days
13 days or more

Dichorionic Diamniotic (DCDA)


Monochorionic Diamniotic (MCDA)
Monochorionic Monoamniotic (MCMA)
Conjoined twins

Twins account for 2e3% of all births. They carry signicant risks to
both mothers and babies. These risks include preterm delivery, intrauterine growth restriction, and pre-eclampsia. In addition, monochorionic gestations confer an even higher rate of perinatal morbidity
and mortality arising from a shared placenta due to placental anastamoses, which may lead to twin-to-twin transfusion syndrome (TTTS). It
is essential that chorionicity is established in the rst trimester in order
to initiate the appropriate antenatal management and surveillance. In
view of the high risk of both maternal and fetal complications, twin
pregnancies are ideally managed in a dedicated clinic according to
agreed protocols with both obstetric, midwifery and neonatal input.

Table 1a

Monochorionicity confers major increases in perinatal


morbidity and mortality when compared to dichorionic gestations. Chorionicity may be accurately determined by ultrasound
between 11 and 14 weeks gestation. A number of methods are
widely used, including the presence of the lambda or twin peak
sign for dichorionicity and the T sign for monochorionicity. In
addition, the thickness of the intertwin membrane may be
determined e a membrane thickness of less than 2 mm is suggestive of monochorionicity. Other indicators in the second
trimester may be the presence of two separate placental masses
or discordant fetal sex. All twin pregnancies should be offered an
ultrasound scan between 11 and 13 6 weeks to assess viability,
determine chorionicity and to screen for Downs syndrome.
If a woman with a twin pregnancy presents after 14 weeks, it
is important to determine chorionicity at the earliest opportunity
by ultrasound using the number of placental masses, the lambda
or T sign, the membrane thickness and discordant fetal sex. If
chorionicity remains uncertain, even after senior review, the
pregnancy should be managed as monochorionic.

Keywords chorionicity; dichorionic; monochorionic; twins

Introduction
Twin pregnancies account for approximately 3% of all live
births, but account for 6.3% of stillbirths and 12.7% of neonatal
deaths. Twins are more at risk of pregnancy complications
(Table 1). Monozygotic twin frequency rates remain relatively
stable worldwide at 3e5/1000 maternities, but dizygotic twins
have a variable rate depending on a number of factors including
geographical location, assisted reproductive techniques and
increasing maternal age. Rates vary from 1.3 to 49/1000 maternities. Monochorionic twin gestations are associated with even
higher perinatal risk. Multiple pregnancies have been described
as a modern epidemic and carry considerable resource implications for health providers. In order to reduce the numbers of twin
pregnancies conceived as a result of assisted conception techniques, a number of strategies have been proposed such as
elective single embryo transfer, selective fetal reduction and
single blastocyst transfer.

First trimester screening


The risk of Downs syndrome (Trisomy 21) is 1 in 700 pregnancies. The risk for monozygotic twins is the same as for singletons, but for dizygotic twins this risk is doubled as each twin
has its own individual risk. The screening test of choice for twins
is combined first trimester screening at between 11 and 13 6
weeks gestation with a combined risk for the pregnancy in
monochorionic twins and an individual risk per baby in
dichorionic twins. Combined screening uses the measurement of

Zygosity and chorionicity


Twin pregnancy usually results from the fertilization of more
than one oocyte, producing dizygotic or non-identical fetuses.
Splitting of a single fertilized oocyte produces a monozygotic
twin pregnancy with two genetically-identical co-twins. Nonidentical twins develop their own placentae: monozygous twins
may share a placenta according to the time of separation
(Figure 1). Dichorionicity occurs in 80% of twins, and genotyping is required to confirm zygosity in these cases.

Frequency of fetal complications in twins

Miscarriage
11e23 weeks
Perinatal death
IUGR
Preterm delivery
<32 weeks
Major defects

Emma Long MRCOG is a Specialist Registrar at The Jessop Wing,


The Royal Hallamshire Hospital, Shefeld, UK. Conicts of interest:
none declared.
Emma Ferriman MBChB FRCOG is a Consultant in Feto-Maternal
Medicine at The Royal Hallamshire Hospital, Shefeld, UK. Conicts
of interest: none declared.

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:2

Singleton

Dichorionic

Monochorionic

1%

2%

10%

0.5%
5%
1%

1.5%
20%
5%

3%
30%
10%

1%

1%

4%

Table 1b

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REVIEW

The relationship between zygosity and chorionicity


MONOZYGOTIC
(identical)

DIZYGOTIC
(non-identical)

MONOCHORIONIC

DICHORIONIC
Figure 1

different types of anomaly are thought to be more commonly


seen in twin pregnancies, including neural tube defects and
congenital heart disease. In monozygotic twinning, abnormal
vascular connections predispose to limb reduction defects and
bowel atresias.
Disorders of laterality occur when embryonic migration has
begun prior to zygotic splitting and may explain the increased
incidence of cardiac anomalies in monozygotic twin pregnancies,
where a fetal echocardiogram is ideally offered at 22e24 weeks.
While the majority of monozygotic twins appear to be almost
identical, there are monozygotic offspring who are genetically
and phenotypically dissimilar. Mechanisms may include unequal
allocation of blastomeres between the two embryos, disrupted
embryonic migration, somatic mosaicism or chimerism, and
variations in penetrance producing phenotypic discrepancy.
Twins may be discordant for chromosomal, genetic and
structural anomalies. Discordant single gene disorders,
imprinting defects and aneuploidy have all been reported in
monozygotic twins. Case reports detail a range of discordant
structural anomalies found in monozygotic twin pairs, from
neural tube defects and holoprosencephaly to lateral and ventral
body wall defects, and anomalies related to the VATER
association.

the nuchal translucency combined with first trimester measurements of (pregnancy associated plasma protein A (PAPP-A)
and human chorionic gonadotrophin (HCG). The detection rate
variesdepending on the chorionicity of the pregnancy: in monochorionic twins the detection rate should be the same as for
singletons (75e80% with a 3% false positive rate), however, in
dichorionic twins where one baby is affected with aneuploidy,
the detection rate may fall between 40 and 50% with a 3% false
positive rate. Detection rates can be improved further using
additional ultrasound markers such as the presence of the nasal
bone and ductus venosus and tricuspid Doppler waveform analyses. Additional biochemical markers, alpha-fetoprotein (AFP)
and oestriol (uE3), can increase the detection rate further (up to
87%). For women who present beyond 14 weeks the quadruple
test may be offered up to 20 weeks gestation.
Finally the advent of non invasive prenatal testing (NIPT)
offers a further choice in screening with detection rates between
98 and 99% and false positive rates of <0.4%.
Following detection of an increased nuchal translucency, the
option of invasive testing should be discussed. Both amniocentesis
and CVS are possible in twin pregnancy, but these procedures
should be performed in a specialist fetal medicine unit, ideally by
the same specialist, to ensure that the pregnancy is mapped
correctly. The risks of miscarriage and other procedure-related
complications are quoted as around 1 in 50 in twin pregnancies.
Both amniocentesis and chorionic villus sampling are valid options, but there is some evidence to suggest that a double amniocentesis has a lower risk of sampling the same fetus.

Management of twins discordant for fetal anomaly


The diagnosis of discordant anomaly in twins creates significant
dilemmas for parents, and careful counselling is required in
centres with expertise in this area. Accurate diagnosis and
determination of chorionicity is critical for subsequent management. Depending on the anomaly detected, parents may be faced
with a choice of continuing the pregnancy and delivering both a
normal and an affected baby, or of terminating the affected fetus
and risking the viability of the healthy co-twin. Invasive testing
for chromosomal abnormality in dichorionic twins requires dual
puncture in most cases. In general, monochorionic twins require

Anomaly screening
The frequency of fetal abnormality in dizygotic twins is comparable to that of singleton pregnancies (2e3%). This contrasts
with the increased frequency of anomalies seen in monozygotic
pregnancies where rates of up to 10% have been reported, or 2
e3 times those which occur in dizygotic twinning. Several

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a single puncture but in cases of discordant anomaly, both fetuses should be sampled.
Selective feticide of the affected fetus is only possible in
dichorionic twin pairs due to their separate inter-twin circulations. It is associated with an increased risk of pregnancy loss,
and if not performed in the first trimester, is usually delayed until
the third trimester when viability of the normal twin is more
certain. This must be balanced against the risk of spontaneous
premature labour, especially in cases complicated by polyhydramnios such as anencephaly.

Abnormalities specic to twins


Complications specific to both mono- and dichorionic twin
pregnancies include vanishing twin and fetus papyraceous. Abnormalities unique to monochorionic pregnancies only are the
twin-to-twin transfusion syndrome (TTTS) and the twin reversed
arterial perfusion syndrome (TRAP). Monoamniotic pregnancies
will also be discussed.

Figure 2 Shows the enlarged bladder of the recipient twin with polyhydramnios in twin to twin transfusion syndrome.

connections are unidirectional, and require the presence of


balancing superficial anastomoses to prevent TTTS. Superficial
anastomoses are bi-directional and are commonly found between
arteries (arterio-arterial anastomoses) and veins (veno-venous
anastomoses). Bidirectional flow allows compensatory activity in
the event of pressure differences within the placenta, and if
reduced or absent this predisposes to TTTS.

Vanishing twin and fetus papyraceous


Up to 21% of twin pregnancies are complicated by either
miscarriage or loss of one twin in the early stages. This vanishing twin phenomenon is increasingly detected by highresolution ultrasound, and it is suggested that the miscarriage
rate in these pregnancies is about five times higher than that of
normal twins. No increased monitoring should be necessary if
the baby appears structurally normal, as the pregnancy is most
likely to progress as expected for a singleton.
Loss of a co-twin in the second or third trimester carries a risk
of preterm delivery, neurological sequelae or death to the
remaining fetus. It may result in the phenomenon known as fetus
papyraceous, where the anatomically-preserved demised fetus
can be identified at the later delivery of the surviving twin.

Diagnosis of TTTS
Most commonly, the diagnosis of TTTS is made in the second
trimester following the detection of discordant growth or
discrepant liquor volumes. A stuck twin may be visible, compressed against the uterine wall, where the donor is constricted
by anhydramnios and the tense sac of the polyhydramniotic cotwin. A discrepancy in nuchal translucency measurement in the
first trimester is also said to be an early marker for TTTS. Acute
TTTS may present as sudden onset of maternal discomfort and
increasing girth, following rapid development of polyhydramnios. Mortality is extremely high usually as a consequence of premature delivery, either spontaneous or iatrogenic.
A diagnostic staging system proposed by Quintero describes a
progression from early (stage I) to late (stage V) disease
(Table 2). High stage at diagnosis is associated with increased
neurological morbidity and mortality, but progression of disease
from early to more advanced stage is also important for prognosis. Uncertainty exists regarding the optimum management of
early (stage I) disease, where there is some evidence that
aggressive treatment may confer little benefit.

Anomalies conned to monochorionic gestations


Twin to twin transfusion syndrome (TTTS)
Twin-to-twin transfusion syndrome (TTTS) complicates 10e20%
of monochorionic twin pregnancies. Feto-fetal transfusion occurs
via multiple vascular anastomoses between the circulations of
each co-twin, such that there is a net flow of blood from one twin
(the donor) to the other (the recipient). This results in hypovolaemia and oligohydramnios in the donor twin and hypervolaemia and polyhydramnios in the recipient.
Progression of the syndrome in the donor leads to growth
restriction and in severe cases, absent or reversed end-diastolic
frequencies in the umbilical artery. The recipient may develop
organomegaly, with abnormal ductus venosus Doppler frequencies related to polycythaemia and hydrops. Tricuspid
regurgitation is an ominous sign of cardiac dysfunction in the
recipient and is associated with significant postnatal cardiac
dysfunction (Figure 2). Twin-to-twin transfusion syndrome accounts for about 20% of stillbirths in multiple pregnancies.

Management options
Several management options exist for the treatment of TTTS,
including laser ablation of the communicating placental vessels,
serial amnioreduction with or without septostomy, and occlusive
feticide. It may be appropriate to consider conservative or
expectant management, or to offer a termination of pregnancy if
the fetuses are extremely premature or severely compromised.

Pathophysiology
Both superficial and deep placental vascular connections are
present in the monochorionic placenta. Deep anastomoses occur
between arteries and veins. These arteriovenous (AV)

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:2

Laser ablation: endoscopic placental laser ablation aims to


coagulate the vascular anastomoses contributing to TTTS, and
may be selective or non-selective. Non-selective coagulation

40

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REVIEW

destroys all vessels crossing the intertwin membrane, including


the healthy circulation, and may increase mortality in the donor
twin. This method has been largely superseded by selective
ablation, which ablates only specific connections. Amnioreduction is performed following laser ablation in most cases.
The Eurofetus randomised trial demonstrated increased survival of one or both twins following laser (76%) compared with
serial amnioreduction (56%). Median gestational age at delivery
was increased in the laser group (33 weeks vs 29 weeks) and
laser was associated with a reduced incidence of periventricular
leukomalacia. As live birth rates were similar in both groups, this
survival advantage may reflect the differences in gestation rather
than a consequence of the therapy. In addition, early stage disease was not well-represented in this study, leaving persistent
doubt about the benefit of laser in early disease.
A systematic Cochrane review in 2008 included only two
randomised controlled trials (including Eurofetus) with similar
results. Long term, neurological sequelae have a reported incidence of 13e17% and do not appear to be reduced following
laser compared with amniodrainage. In addition, in a randomised controlled trial comparing laser ablation to serial
amnioreduction in survivors of TTTS aged six months, the incidence of neurological sequelae was 48% in the laser group
compared to 69% in the amnioreduction group.
Following successful laser ablation, the incidence of intrauterine death is reported to be 13e33%, and that of ruptured
membranes approaches 10%. High stage disease is more likely to
result in mortality. Late complications of laser are increasingly
reported, and mainly related to the presence of persistent
communicating vessels causing recurrent TTTS or reversal of
flow (reverse TTTS). Despite this, since the Eurofetus study, laser
has been considered the first-line treatment for TTTS.

available evidence, singleton survival rates would appear to be


similar to survival rates achievable by laser ablation.
Twin reversed arterial perfusion sequence (TRAP)
Acardiac anomaly is a rare complication of monochorionic twin
pregnancies, occurring in approximately 1 in 35,000 cases. In this
condition, arterial blood flows in a retrograde fashion from the
pump twin towards the affected twin via a single arterio-arterial
anastomosis, hence the synonym twin reversed arterial perfusion
syndrome (TRAP). The poorly oxygenated blood entering the
circulation of the affected twin preferentially perfuses the caudal
structures rather than the cephalad, resulting in abnormal
development of all organ systems. The head and the heart are
commonly absent, with a preserved central trunk and rudimentary spine. Lower limbs may be more preserved due to the
improved blood supply. Acardiac twins are frequently hydropic
due to their abnormal lymphatic and vascular drainage.
The diagnosis of TRAP usually follows the detection of a
grossly abnormal co-twin within a monochorionic pair. The
absence of cardiac pulsation in the acardiac twin is usually
evident, although rudimentary cardiac tissue or transmitted
pulsations may produce appearances of normal cardiac function.
Paradoxical blood flow may be visualised by colour Doppler ultrasound to confirm the diagnosis.
Once diagnosed, the primary aim of management is to
improve survival chances for the structurally normal pump twin.
Poor prognostic features include increasing size of the acardiac
twin, with signs of cardiac insufficiency in the donor secondary
to increased demand. Management options for intervention
include cord occlusion techniques, or an intrafetal approach to
ablate the vasculature in the acardiac twin.
Monochorionic, monoamniotic twins
Monoamniotic twinning occurs in 1e2% of monochorionic
gestations (1 in 3000e6000 pregnancies) and occurs as a result
of zygotic separation beyond eight days of conception. The
diagnosis is usually made following first trimester ultrasound,
showing a single placenta and two freely moving fetuses with no
inter-twin membrane evident.
These pregnancies are associated with the highest perinatal
loss rate of all twin forms, at around 30e60% in most series.
Umbilical cord accidents and prematurity account for much of
this loss rate, along with higher rates of congenital anomaly (20
e25%) and growth restriction. More recent series suggest a fall
in perinatal mortality, possibly associated with earlier diagnosis
and intensive surveillance in these cases. Despite the shared
placenta, chronic TTTS appears to be less common in these
gestations (5%).
Up to 60% of the antenatal fetal deaths occur prior to 32
weeks gestation. This is thought to be related to cord entanglement and occlusion, although cord entanglement will be present
in almost all gestations. Consequently this complication is not
preventable and cannot be predicted by cardiotocographic
monitoring. Strategies have been reported to reduce amniotic
fluid levels, limiting fetal movement to prevent tightening of the
tangled cords. Medical amnioreduction with oral prostaglandin
synthase inhibitors has been described with 100% survival of
forty fetuses (twenty pairs) in one study. However, the majority
of monoamniotic pregnancies undergo intensive surveillance

Serial amnioreduction and septostomy: amnioreduction aims


to reduce liquor volume in the recipient twin and to prevent
premature delivery. It is likely to require repeated procedures
and does not treat the underlying cause of feto-fetal transfusion.
Associated risks include premature labour, ruptured membranes,
chorioamnionitis and placental abruption. Septostomy aims to
disrupt the inter-twin membrane allowing normalisation of liquor volume between the two sacs, and may be followed by
amniodrainage as an adjunctive treatment.
A randomised controlled trial comparing amnioreduction with
septostomy in TTTS before 24 weeks of gestation found that the
rate of survival of at least one twin was similar in both groups
(78% vs 80%), with no significant advantage of septostomy with
amnioreduction over amnioreduction alone.
Possible disadvantages of septostomy include the fact that the
resulting chorioamniotic separation may hinder subsequent laser
ablation. Amnioreduction is now most commonly utilised at later
gestations or where laser ablation is not feasible, and is useful in
stage I disease where the evidence for laser ablation is less
robust.
Selective occlusion: the termination of one fetus by cord occlusion is an option, particularly in the presence of discordant
anomaly. Parents may choose to terminate a severely affected
twin to increase survival chances in the other, less affected twin
and reduce the risk of losing both babies. From the limited

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with CTG monitoring and serial ultrasound in an attempt to


detect impending cord occlusion.
Elective delivery at 32 weeks gestation following administration of steroids is usually advocated, since at this point neonatal
survival is comparable to term survival in most centres. Metaanalyses of perinatal loss report a rate of around 10% in monoamniotic pregnancies continuing beyond this point. Vaginal delivery of monoamniotic pairs has been achieved successfully, but
is associated with risks of cord prolapse and fetal impaction in
the maternal pelvis. Vaginal delivery is usually reserved for the
extremely premature or non-viable fetuses.

The Quintero classification system


Classification

There is a discrepancy in amniotic fluid volume


with oligohydramnios of a maximum vertical
pocket (MVP 2 cm) in one sac and
polyhydramnios in the other sac (MVP 8 cm).
The bladder of the donor twin is visible and
Doppler studies are normal
The bladder of the donor is not visible, but
Doppler studies are normal
Abnormal Doppler studies in either twin
characterised by reversed EDF in the umbilical
artery, reversed flow in the ductus venosus or
pulsatile umbilical venous flow
The presence of hydrops in the recipient
Death of one or both twins

II

Conjoined twins
Incomplete division of the embryo may result in conjoined twins.
Classification of this anomaly is largely descriptive and dependent on the anatomical areas joined. Conjoined thorax (thoracopagus) and conjoined thorax and abdomen (thoracoomphalopagus) are the commonest subtypes with pelvis and
head (ischiopagus and craniopagus) being less common.
With the advent of improved ultrasound techniques, most
cases are identified in the first trimester, and in view of the significant mortality and morbidity, a significant number of parents
will opt for termination. Survival depends on the organs joined.
50% are stillborn and of the survivors up to 75% may have
inoperable defects. Elective delivery is usually advocated, but
there are reports of vaginal deliveries occurring.

III

IV
V
Table 2

should take 75 mg of aspirin daily from 12 weeks until the birth


of their babies if they have one or more of the following risk
factors for hypertension:
 First pregnancy
 Age 40 years or older
 Pregnancy interval of more than 10 years
 BMI of 35 kg/m2 or more at first visit
 Family history of pre-eclampsia.

Antenatal management
Women with twin pregnancies should be given the same advice
about diet, lifestyle and nutritional supplements as in routine
standard care. There is a higher incidence of anaemia in women
with twin pregnancies therefore a full blood count should be
performed at 20e24 weeks to identify women who need supplementation of iron or folic acid. This should then be repeated at
28 weeks as in routine antenatal care.
It is vital to offer antenatal care in an appropriate setting
aiming to provide standardised care to all women with multiple
pregnancies. Clinical care for women with twin pregnancies
should be provided by a nominated multidisciplinary team consisting of named specialist obstetricians, specialist midwives and
ultrasonographers, all of whom have experience and knowledge
of managing twin pregnancies. In addition, women should have
access to a perinatal mental health specialist, womens health
physiotherapist, an infant feeding specialist and a dietician. A
dedicated clinic allows the close surveillance required by this
population along with the specialised care they may need in
terms of preparation for birth and psychological support.
Mothers with twin pregnancies are at higher risk of all obstetric
complications and should be counselled appropriately (Table 3).
In general, maternal mortality associated with multiple births is
2.5 times higher than singleton births.
NICE and the RCOG consensus document has recommended
two distinct care pathways for monochorionic and dichorionic
twins (Table 4).

Preterm birth
Twin pregnancies are at higher risk of spontaneous or iatrogenic
preterm delivery. The incidence of preterm delivery prior to 37
weeks can be up to 50%. Delivery at less than 32 weeks appears
to vary with the type of twinning, ranging from 5% for DC and
10% for MC twins compared with 1% for singleton pregnancies.
Recent evidence suggests that progesterone supplementation
does not prevent early preterm labour in twin pregnancies and
the use of untargeted single or multiple courses of corticosteroids
is not recommended.

Maternal risks associated with twins


Maternal risks associated with multiple pregnancy
Hyperemesis
Increased mechanical symptoms of pregnancy
Gastro-esophageal reflux
Hypertensive disorders
Gestational diabetes mellitus
Anaemia
Operative delivery
Post-partum haemorrhage
Perinatal mental health disorders

Hypertension
Women with twin pregnancies may be at higher risk of hypertension. NICE suggest that women with multiple pregnancies

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Stage

Table 3

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surviving twin of a monochorionic pair has a 12% risk of death,


with neurological sequelae in 18% and preterm delivery in 68%.
In dichorionic pairs, the risk of death is just 1%, with 4%
developing neurological disability and less than 50% subsequently delivering prematurely. This significant difference in risk
has been attributed to substantial haemodynamic shifts within
the shared placenta of monochorionic twins following the death
of one fetus. These patients should be carefully counselled
regarding the prognosis for the surviving twin, and an MRI of the
fetal brain is advocated.

Intrauterine growth restriction


Twin pregnancies are known to be at a significantly increased risk
of intrauterine growth restriction (IUGR), with rates varying from
20% in dichorionic twins to 30% in monochorionic pairs. Two
thirds of unexplained stillbirths in multiple pregnancies are associated with a birthweight below the tenth centile. It is important to
estimate fetal weight discordance using two or more biometric
parameters at each ultrasound scan from 20 weeks. A 25% or
greater difference in size between twins should be considered to be
a clinically important indicator of growth restriction and referral to
a tertiary level fetal medicine centre should be instigated.
Pregnancy outcome is determined by the severity of the
growth restriction and by the gestation at diagnosis. Growth in
dichorionic pregnancies reflects both genetic potential and
placental function, but monochorionic twin growth is also subject to the effects of unequal blastomere separation and placental
vascular communications. Early-onset discordant growth restriction may be detected by large inter-twin disparities between
crown-rump lengths, and should be referred to a tertiary centre
for fetal medicine opinion. In monochorionic twins where the cotwin is at risk, selective cord occlusion may be an option in
severely discrepant pairs.
The optimum surveillance for IUGR in twins less than 32
weeks with abnormal Doppler studies has not been defined. The
timing of delivery at very early gestations is a balance between
the risks of prematurity and the risk of exposing the fetus to
prolonged hypoxaemia. Surveillance of growth-restricted twins
will include monitoring of fetal Doppler waveform analyses
(umbilical artery, middle cerebral artery (MCA) and ductus
venosus (DV)), liquor volume and biophysical profile.

Delivery
NICE guidance recommends delivery from 37 0 weeks gestation for dichorionic twins and from 36 0 weeks gestations for
monochorionic diamniotic twins, but marked variability in policy
exists in practice. There is growing evidence that perinatal
mortality rates increase after 38 weeks even in uncomplicated
twin pregnancies. Additionally, intervention at 37 weeks does
not appear to be associated with a significant difference in mode
of delivery or maternal complications when compared to
expectant management. For women declining delivery, weekly
monitoring should occur.
Retrospective cohort data suggested that, when compared to
the presenting twin, the second twin is at higher risk of intrapartum mortality due to the complications of vaginal delivery.
However, the publication of the Twin Birth Study in 2013 has
refuted this. The study was a large, prospective, randomized,
controlled trial comparing planned Caesarean section to planned
vaginal birth for twins delivered between 32 and 38 weeks
gestation where the presenting twin was cephalic. It found that
planned Caesarean section did not reduce the risk of fetal or
neonatal death or serious neonatal morbidity when compared
with planned vaginal delivery. There was a higher risk of adverse
perinatal outcomes for the second twin, but this was not reduced

Single intrauterine fetal death


The death of one twin carries an increased risk to the remaining
fetus which is greater in monochorionic pregnancies. The

Schedule of antenatal scans and timing of delivery


Type of pregnancy (uncomplicated)

Scans

Delivery

Monochorionic diamniotic twins

Approximately 11 weeks 0 days to 13 weeks


6 days (viability, chorionicity, 1st trimester
screening)
and
16, 18, 20, 22, 24, 28, 32 and 34 weeks e
fetal growth and TTTS
 Fetal echo at 20 weeks
Approximately 11 weeks 0 days to 13 weeks
6 days (viability, chorionicity, 1st trimester
screening)
and
20, 24, 28, 32 and 36 weeks e fetal growth
11 weeks to 13 6 weeks (viability,
chorionicity, 1st trimester screening)
and
16, 18, 20, 22, 24, 26, 28, 30 weeks e fetal
growth, polyhydramnios, TTTS
 Fetal echo at 20 weeks

From 36 0 weeks following antenatal


steroids

Dichorionic, diamniotic twins

Monoamniotic monochorionic twins

From 37 0 weeks.
Consider steroids for elective caesarean
sections

From 32 0 weeks following antenatal


steroids.
Delivery by elective caesarean section

Table 4

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REVIEW

by a planned Caesarean section. Current practice supports the


policy of planned vaginal birth in uncomplicated pregnancies
with a cephalic first twin.
On a more practical level, delivery should be conducted in a
unit where continuous electronic fetal monitoring is available
and there is access to early recourse to Caesarean section. An
experienced operator should be present at delivery to enable
expert management of the second twin, in particular with regard
to vaginal breech delivery. Overall, there is a higher risk of a
Caesarean section for twin pregnancies (the rates in our institution are 47% overall and 3e5% for the second twin).

Nicolaides K. Multiple pregnancy. In: Nicolaides K, Sebire N,


Snijders RJM, eds. The 11-14-week scan. London: Parthenon
Publishing Group, 1999.
Pharoah POD, Adi Y. Consequences of in-utero death in a twin
pregnancy. Lancet 2000; 355: 1597e602.
Quintero RA, Morales WJ, Allen MH, Bornick PW, Kruger M. Staging of
twin-twin transfusion syndrome. Obstet Gynecol 2002; 100:
1257e65.
Senat MV, Deprest J, Boulvain M, Pauper A, Winer N, Ville Y. Endoscopic laser surgery versus serial amnioreduction for severe twinto-twin transfusion syndrome. N Engl J Med 2004; 351: 136e44.
Smith GC, Pell JP, Dobbie R. Birth order, gestational age, and risk of
delivery related perinatal death in twins: retrospective cohort study.
BMJ 2002; 325: 1004e6.

Conclusions
Multiple pregnancy is a common cause of morbidity for both
mothers and babies. Antenatal care focuses on screening for
anomalies and for early signs of complications such as growth
restriction and TTTS. Accurate diagnosis of chorionicity in the
first trimester is essential, and allows appropriate surveillance to
be planned. Following the results of the Twin birth study there is
no evidence to support a policy of elective Caesarean section for
all twins. Current practice in the UK would be to support vaginal
delivery in uncomplicated dichorionic twins in which the first
baby has a cephalic presentation. For monochorionic twins, this
practice is less clear-cut due to the incidence of acute twin-totwin transfusion occurring in labour (up to 10%).
A

Acknowledgements
Acknowledgements for Dr Kelly Cohen, Dr Medha Rathod and Dr
Elizabeth Bonney, Consultants at The Leeds Teaching Hospitals NHS
Trust.

Practice points
FURTHER READING
Bajoria R, Kingdom J. The case for routine determination of chorionicity and zygosity in multiple pregnancy. Prenat Diagn 1997 Dec;
17: 1207e25.
Barrett Jon FR, Hannah ME, Hutton EK, et al. A randomized trial of
planned Cesarean or vaginal delivery for twin pregnancy. N Engl J
Med 2013; 369: 1295e305.
Fisk NM, Duncombe GJ, Sullivan MH. The basic and clinical science of
twin-twin transfusion syndrome. Placenta 2009 May; 30: 379e90.
Management of monochorionic twin pregnancy. RCOG Green-top
Guideline No. 51 December 2008.
MBRRACE-UK: Perinatal Mortality Surveillance Report: UK Perinatal
deaths for births from January to December 2013. Published June
2015.
Multiple pregnancy: the management of twin and triplet pregnancies in
the antenatal period. National Institute for Health and Clinical
Excellence clinical guideline no 129 (Sept 2011).

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:2

44

Early assessment of chorionicity is essential for the planning of


subsequent management.
First trimester combined screening by nuchal translucency and
first trimester biochemistry should be offered between 11 weeks
and 13 weeks and 6 days.
For twins in discordant for fetal anomaly referral to a specialist
fetal medicine centre is recommended.
Clinicians should appreciate the increased risk of congenital
anomaly, in particular congenital heart defects in monochorionic
twins.
Discordant fetal growth should be referred to a specialist centre
when diagnosed.
The appropriate antenatal pathways should be followed with
increased surveillance of monochorionic twins.
In twins planning a vaginal delivery, an experienced practitioner
must be present or easily accessible during the intrapartum
period.

2016 Elsevier Ltd. All rights reserved.

REVIEW

Self-assessment
MCQs
1. With regard to twin pregnancies
a. They account for 3% of all live births

b. They account for 10% of all stillbirths

c. Rates of monozygotic twins are relatively stable

d. Rates of dizygotic twinning are affected by assisted conception techniques, geographical area and primigravid pregnancy

e. The rate of major congenital abnormality is 4 higher in dichorionic twins than in singletons

2. Screening for Downs syndrome in twins


a. Both babies will have an individual risk irrespective of chorionicity

b. Dichorionic twins have the same risk for aneuploidy as singletons

c. Combined first trimester screening is recommended

d. Second trimester biochemical screening is not an option

e. NIPT has a low detection rate and a high false positive rate in twins

3. Twin to twin transfusion syndrome (TTTS)


a. Occurs in 25% of monochorionic twin pregnancies

b. The Quintero staging system is no longer used in modern practice

c. Stage 1 TTTS should always be treated with laser ablation techniques

d. The Cochrane Collaboration found that survivors of TTTS treated with laser had long term neurological sequelae in 40% of cases F
e. Following the death of a monochorionic co-twin the risk of cerebral palsy is in the order of 15%
4. In monoamniotic twins
a. Cord entanglement is universally seen

b. Delivery by caesarean section at 35 weeks is recommended

c. The incidence of congenital anomalies approaches 50%

d. NSAIDs may be used to control polyhydramnios

e. Daily CTG monitoring beyond 26 weeks improves long-term outcome

5. When considering mode of delivery in twins


a. Caesarean section is the safest route

b. Monochorionic twins should all be delivered by elective caesarean section at 37 weeks

c. Induction should be offered in dichorionic twins at 37 weeks gestation

d. Vaginal delivery is a safe option when the first twin is a non-cephalic presentation

e. Delayed delivery beyond 38 weeks does not require additional fetal monitoring

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Renal disease in
pregnancy

Blood pressure falls in the first two trimesters and gradually


returns to baseline as the pregnancy approaches term. Increased
GFR, changes in glomerular haemodynamics and possibly alterations in renal tubular function lead to an increase in urine
protein excretion in pregnancy from an upper limit of 150 mg/
d to 260 mg/d.
Renal size increases by approximately 1 cm in bipolar length
during normal pregnancy. Smooth muscle relaxation and
compression of the ureters by the gravid uterus commonly lead
to pelvicalyceal dilatation, more prominently on the right than
the left.
The magnitude of these changes makes it unsurprising that
limitation to adaptation by CKD can lead to adverse pregnancy
outcomes.

Matt Hall
Nigel J Brunskill

Abstract
Pregnancy in women with chronic kidney disease (CKD) is associated
with risks of accelerated decline in renal function in the mother and
adverse outcomes for the infant, including prematurity and growth restriction. Managing these risks requires collaboration between patient,
nephrologist, neonatologist and obstetrician. In this review we will
discuss approaches to managing pregnancy in women with CKD.

Pregnancy in women with chronic kidney disease

Keywords chronic kidney disease; dialysis; pregnancy; transplant

Advice for women with CKD embarking upon pregnancy tends to


focus on two issues:
1. Will the kidney disease affect the pregnancy?
2. Will pregnancy affect the kidney disease?
Reports of pregnancy outcomes in women with CKD from the
1950s and 1960s painted a very bleak outlook for mothers and
infants, however, in subsequent decades many women with CKD
in pregnancy have been described who have few, if any, problems. Identification of women at higher risk can facilitate individualisation of care and optimise outcomes.

Introduction
Chronic kidney disease (CKD) is defined as abnormalities in
serum biochemistry, urinary constituents (blood and/or protein)
or renal structure that are present for 3 months or more. The
Kidney Disease Improving Global Outcomes (KDIGO) classification of CKD divides CKD into five stages dependent on the estimated glomerular filtration rate (eGFR, Table 1).
CKD whilst rare in pregnancy, affecting 0.15% of pregnancies,
is encountered with increasing frequency. However, most
affected women have early CKD, stages 1 to 3a, with eGFR >45
ml/minute. Pregnancy may be the first time that blood pressure
and urinalysis are performed for some women and hypertension,
proteinuria or haematuria detected at booking may uncover
previously undiagnosed CKD. The development of hypertension
and urinary dipstick abnormalities later in pregnancy may be a
manifestation of CKD, but more commonly represents preeclampsia. Chronic pyelonephritis is the commonest known
aetiology of CKD in pregnant women (Figure 1).

Measuring renal function in pregnancy


Glomerular filtration rate: creatinine is a metabolic by-product
of muscle metabolism that is filtered and excreted through the
renal tract, thus serum creatinine levels are inversely proportionate to GFR. Serum creatinine is also affected by age,
ethnicity, medication, diet, gender and body composition, so
absolute serum creatinine concentrations correlate poorly with
GFR between individuals.
In the general population, serum creatinine has been superseded by eGFR as a marker of renal function. eGFR is calculated
using equations, most commonly the MDRD or CKD-EPI
formulae. These are based on serum creatinine, patient age,
gender and ethnicity. Importantly, these calculations are not
validated for use during pregnancy and should not be used.
Alternatively, renal function during pregnancy can be estimated
by creatinine clearance. The utility of calculated creatinine
clearance is limited by the requirement for a 24 hour urine
collection. This is inconvenient and frequently incomplete.
Since eGFR equations are invalid during pregnancy and
creatinine clearance is inconvenient, most centres continue to
rely on changes in serum creatinine concentration to identify
potential renal dysfunction during pregnancy, mindful that
relative changes in creatinine have greater clinical utility than
absolute values. Preconception baseline values of eGFR are
useful in predicting maternal and fetal outcomes however (see
below).

Renal physiology in normal pregnancy


During normal pregnancy, the maternal cardiovascular system
undergoes important changes. Blood volume and red cell mass
increase by up to 50%, systemic vascular resistance falls and
cardiac output increases by up to 30%. These cardiovascular
adaptations have profound effects on renal function:
 renal blood flow increases by 50%
 glomerular filtration rate (GFR) increases by 30%
 serum creatinine decreases by 20%.

Matt Hall MA MB MD MRCP(UK) is a Consultant in Renal Medicine at


Nottingham Transplant and Renal Unit, Nottingham City Hospital,
Nottingham, UK. Conicts of interest: none declared.

Proteinuria: proteinuria is an independent predictor of progressive renal failure in patients with CKD and a diagnostic marker of
pre-eclampsia in pregnancy. Traditionally, protein excretion is
quantified by measurement in a 24 hour collection of urine. This

Nigel J Brunskill MB ChB PhD FRCP(UK) is Professor of Renal Medicine


at the University of Leicester, and Honorary Consultant in Renal
Medicine at the John Walls Renal Unit, Leicester General Hospital,
Leicester, UK. Conicts of interest: none declared.

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The Kidney Disease Improving Global Outcomes (KDIGO) classification of chronic kidney disease
CKD stage

Estimated GFR

Comment

G1
G2
G3

90 ml/minute
60e89 ml/minute
30e59 ml/minute

Only classified as CKD if associated with renal


structural or urinary dipstick abnormalities
May be sub-classified into:
G3a: 45e59 ml/minute
G3b: 30e44 ml/minute

G4
G5

15e29 ml/minute
<15 ml/minute or on dialysis

GFR; glomerular filtration rate.


Equation based estimated GFR calculations are not valid during pregnancy.

Table 1

occur in 18% of pregnancies in mothers with CKD compared to


9% in those without CKD. Risks can be stratified according to
baseline maternal renal function, blood pressure control, proteinuria and, to a lesser extent, aetiology of renal disease.

is inconvenient for the patient and collections are often incomplete. Nevertheless, if performed correctly, this remains the most
accurate method available.
In contemporary nephrology practice and obstetric medicine,
the urine protein:creatinine ratio (PCR) or albumin:creatinine
ratio (ACR) are accepted as surrogates for 24 hour urine collections for protein estimation. Assuming steady production and
excretion of creatinine, this method corrects for variations in
urine concentration and correlates closely with complete 24 hour
urine collection data, including in pregnant patients with CKD.
Thus PCR or ACR can be used for quantitative monitoring of
proteinuria during pregnancy.

Renal function: the risks of adverse fetal outcomes increase with


the severity of baseline renal dysfunction. Even early Stage G1
and G2 CKD, with preconception eGFR >60 ml/minute, is
associated with increased risk of prematurity and intrauterine
growth restriction as compared to the general population, predominantly, but not entirely, due to an increased risk of developing pre-eclampsia. The effect of renal function is likely to be
continuous, but mothers with more severe renal dysfunction
(baseline serum creatinine greater than 180 mmol/litre) are faced
with risks of intrauterine growth restriction 65%, preterm delivery 90% and perinatal mortality 10%.

Fetal outcomes
Adverse fetal outcomes (preterm delivery, SGA, neonatal intensive care admission, persistent congenital disability or death)

Aetiology of CKD: the aetiology of CKD has minimal impact on


fetal outcome with a few exceptions. Asymptomatic bacteriuria
and recurrent urinary tract infection, secondary to vesicoureteric
reflux or structural abnormalities, are associated with an
increased risk of preterm delivery. Diabetes mellitus and SLE
may cause CKD, but adverse fetal outcomes are also associated
with non-renal manifestations of these conditions, such as
hyperglycaemia, thrombophilia and antinuclear antibodies.

Aetiology of CKD in patients presenting to


renal-obstetric clinics in the UK
25

Percentage

20
15

Hypertension: uncontrolled hypertension in patients with CKD


prior to conception or in early pregnancy is a key independent
predictor of adverse fetal outcome. Blood pressure increases in
the second half of pregnancy may be exaggerated in women with
CKD due to limitations in vascular relaxation and increasing
circulating volume as a result of relative over-activity of the renin
eangiotensin system. Elevated blood pressure at baseline predicts the occurrence of prematurity, intrauterine growth restriction and neonatal mortality.
In optimising fetal outcomes, blood pressure treatment targets
for women with CKD are controversial. Fetal outcomes are
similar in those with mild to moderate high blood pressure
(<160/100 mmHg) and in patients treated for hypertension.
Aggressive treatment of maternal hypertension during pregnancy
(less than 120/80 mmHg) may lead to intrauterine growth

10
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restriction. In the absence of high quality evidence, the National


Institute for Health and Clinical Excellence (NICE) and the Royal
College of Obstetricians and Gynaecologists (RCOG) in
consensus guidelines, recommend that for pregnant women with
CKD a target blood pressure of <140/90 mmHg is appropriate,
predominantly to reduce maternal complications (see below).

of obstruction, pyelonephritis or pre-eclampsia. In such cases,


return to baseline renal function almost always occurs within 3
months postpartum.
In contrast, women with moderate CKD (serum creatinine
>125 mmol/litre) have a 25% risk of permanently losing 25% of
their kidney function as a result of pregnancy, increasing to a
50% risk in those with baseline creatinine >180 mmol/litre.
Furthermore, women with a preconception serum creatinine
>180 mmol/litre have a one in three chance of requiring dialysis
during pregnancy or within 6 months of delivery.

Proteinuria: elevated urine protein excretion is associated with


intrauterine growth restriction and preterm delivery. In women
without CKD this effect can be almost wholly accounted for by
concurrent comorbidity (predominantly hypertension, diabetes
mellitus or pre-eclampsia). In women with CKD, however,
increased proteinuria (greater than 1 g/d) at baseline is associated with early delivery and small infants in the absence of preeclampsia, although it remains unclear whether this reflects early
induction of labour or spontaneous premature labour.
Nephrotic syndrome (proteinuria greater than 3 g/d, serum
albumin less than 30 g/liters and oedema) occurs rarely in pregnancy and is usually a result of pre-eclampsia. Nephrotic syndrome in the first trimester generally reflects intrinsic renal disease
and previous case series reported perinatal mortality of greater
than 40%. More recent series suggest that outcomes are much
more favourable, however, with mortality less than 5% in the UK.

Aetiology of CKD: the underlying aetiology of CKD has little


impact on maternal outcome independent of renal function and
blood pressure control.
There is an increased risk of asymptomatic bacteriuria progressing to overt infection and pyelonephritis during pregnancy.
Patients with recurrent urinary tract infection or vesicoureteric
reflux are at particular risk and should be screened for bacteriuria
by dipstick analysis and urine culture. Asymptomatic bacteriuria
should be actively treated to reduce the risk of potentially serious
sepsis and reduce the incidence of preterm delivery.
Lupus nephritis often becomes quiescent during pregnancy as
a result of increased endogenous corticosteroid production.
Consequently, flares can often occur in the puerperium when
increased vigilance is recommended. If lupus flares do occur
during pregnancy they can be difficult to distinguish from preeclampsia e hypertension, proteinuria and decline in renal
function, often with thrombocytopaenia. The presence of invisible haematuria, depressed serum complement levels, a rise in
anti-double-stranded DNA titre and cutaneous manifestations of
SLE support a diagnosis of a lupus flare and should be treated
promptly. Renal biopsy may be required if renal function declines quickly, or if nephrotic syndrome develops, in order to
determine the most appropriate treatment for the renal disease.
Patients with SLE and antiphospholipid antibodies are at greatly
increased risk of thromboembolic disease and pre-eclampsia.

Maternal outcomes
Adverse maternal outcomes for women with CKD include preeclampsia, transient decline in renal function, persistent loss of
renal function, requirement for dialysis and death. As with fetal
outcomes, risks can be stratified according to baseline maternal
renal function, blood pressure control, proteinuria and aetiology
of renal disease.
Pre-eclampsia: the risk of developing pre-eclampsia for mothers
with CKD is greatly increased compared to the general population, and increases with worsening renal function; 20% for patients with mild renal dysfunction (serum creatinine <125 mmol/
litre) and 60e80% with severe impairment (serum creatinine
>180 mmol/litre), compared to approximately 5% in the general
population. These estimates vary between studies as a result of
heterogeneity in study cohorts and variations in diagnostic
criteria used. CKD is commonly associated with proteinuria and
hypertension prior to conception and the diagnosis of superimposed pre-eclampsia relies on arbitrary increases in these
parameters with or without additional clinical features of preeclampsia (Box 1).

Hypertension: chronic hypertension is common in patients with


CKD. Control may become more difficult during pregnancy due
to cardiovascular adaptations in the second and third trimesters
and the unsuitability of some anti-hypertensives during pregnancy, even in the absence of pre-eclampsia. Most notably,
angiotensin converting enzyme (ACE) inhibitors and angiotensin
receptor blockers (ARB) are commonly prescribed for patients
with proteinuric CKD due to their efficacy in blood pressure
lowering and anti-proteinuric renoprotective properties, however, they are associated with severe congenital abnormalities and
should be avoided during pregnancy (see below).
There are contradictory reports of the impact of blood pressure
during pregnancy on progression of maternal renal disease.
Contemporary prospective data suggest that baseline diastolic blood
pressure >75 mmHg or the use of antihypertensive agents is predictive of accelerated decline in renal function post-partum. Severe
hypertension (>160/100 mmHg) in the third trimester requires
treatment to reduce the risk of intracerebral haemorrhage in labour.

Renal function: decline in renal function during pregnancy occurs rarely in patients with mild renal impairment at baseline
(serum creatinine <125 mmol/litre) and often reflects an episode

Criteria for the diagnosis of superimposed pre-eclampsia


C
C
C

Blood pressure >160/110 mmHg


Blood control suddenly worsening after a period of good control
Development of proteinuria >2000 mg/d or abrupt worsening of
proteinuria
Serum creatinine increasing to >110 mmol/litre

Proteinuria: increased urine protein excretion is predictive of


progressive renal dysfunction in general nephrology where
chronic proteinuria is believed to be nephrotoxic per se. During

Box 1

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normal pregnancy, where urinary protein excretion can double,


the impact of proteinuria on kidney function is less clear,
certainly in the short to medium term.
In patients with eGFR less than 40 ml/minute before
conception, proteinuria >1 g/day is associated with an increased
rate of renal decline postpartum compared with than those with
less proteinuria. No similar effect was seen in patients with
preserved renal function.
Mothers who develop nephrotic syndrome during pregnancy
are at increased risk of venous thromboembolism. Loss of antithrombotic serum components in the urine leads to increased
thrombotic tendency and strong consideration should be given to
the use of prophylactic anticoagulation with low molecular
weight heparin (see below).
In the absence of nephrotic syndrome or renal dysfunction,
proteinuria does not appear to have a prominent independent
effect on maternal outcomes during pregnancy, however, there is
emerging evidence that baseline proteinuria may predict the risk
of loss of renal function or dialysis post-partum.

Women with a history of recurrent UTI or structural abnormalities should submit a urine sample for culture every month
irrespective of symptoms to identify asymptomatic bacteriuria.
A renal ultrasound is required during pregnancy if:
 there is a sudden decline in renal function
 there are signs or symptoms suggestive of urinary tract
obstruction or renal stone disease.
As above, mild pelvicalyceal dilatation is commonly identified
during normal pregnancy. Functional ureteric obstruction should
only be suspected if there is progressive dilatation on serial renal
ultrasound scans, suggestive signs and symptoms or obstruction,
or worsening renal function.
Investigations e suspected new diagnosis of CKD: renal disease may be discovered for the first time during pregnancy and
should be suspected in women with any, or combinations of,
hypertension, proteinuria and haematuria identified at booking
or in early pregnancy.
A renal ultrasound is helpful to characterise the aetiology and
chronicity of CKD. Large kidneys on ultrasound may reflect polycystic kidney disease, diabetic nephropathy or chronic urinary tract
obstruction. Focal scarring of kidneys may represent a congenital
abnormality of the kidney and urinary tract (CAKUT) in the mother,
most commonly vesicoureteric reflux. Small kidneys are a nonspecific finding in CKD and further diagnosis may be difficult.
Immunological investigations should be requested if there is
suspicion of intrinsic renal disease e haematuria, proteinuria,
decreased renal function and/or hypertension (Table 2). Aetiology
of intrinsic renal disease may be confirmed by renal biopsy and can
be performed during pregnancy, but should be reserved for:
 unexplained decline in kidney function in CKD or acute
kidney injury
 newly diagnosed nephrotic syndrome
 features suggestive of systemic disease or vasculitis.
A renal biopsy is not indicated to investigate stable CKD, nonnephrotic range proteinuria or pre-eclampsia, or after 32
weeks gestation when the pregnancy should be brought to an end
prior to invasive renal investigations.

Management
Preconception counselling: ideally, all patients with CKD
should be offered counselling prior to conception in order to
evaluate and discuss the risks of proceeding with pregnancy and
the likely outcomes. Medications known to be harmful to the
developing fetus can be discontinued or substituted for safer alternatives (see Tables 3 and 4 below).
Patients with active lupus nephritis or vasculitis, and those
with poorly controlled blood pressure should be advised to wait
until these are optimised before trying to conceive. Similarly,
patients with significant renal dysfunction (serum creatinine
>180 mmol/litre) may not accept the risks associated with proceeding with pregnancy and may be better advised to wait until
they have received a renal transplant (see below).
In the majority of cases, patients need not be discouraged
from trying to conceive as long as the potential risks are understood and the pregnancy is closely monitored.
Investigations e pre-existing CKD: if preconception results are
unavailable, serum creatinine, and either urine PCR/ACR or 24
hour urine collection should be performed early in pregnancy to
determine baseline renal function and urine protein excretion.
Patients should have the following recorded at every subsequent visit:
 blood pressure
 urine dipstick
 urine PCR or ACR, and/or urine culture, if dipstick
positive.
Depending on the level of renal function at baseline the
following should be measured every 6e8 weeks during
pregnancy:
 serum creatinine and urea
 haemoglobin.
More frequent measurement is required if renal function is
abnormal or deteriorating. Serum ferritin, folate and vitamin B12
should be measured if anaemia is identified; serum albumin,
calcium and vitamin D are indicated in women with heavy proteinuria (PCR >100 mg/mmol) or advanced renal dysfunction
(creatinine >180 mmol/litre).

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:2

Blood pressure control (Tables 3 and 4): methyldopa, labetalol,


nifedipine and hydralazine are the most frequently used agents to
treat hypertension in pregnancy. All appear to be relatively safe
and well-tolerated in pregnancy. Methyldopa should be avoided
in patients with depression.
ACE inhibitors and ARBs should be avoided throughout
pregnancy as they are associated with congenital malformations
and fetal urinary tract agenesis. Women for whom there is a
strong indication for these agents (heavy proteinuria, diabetic
nephropathy or heart disease) may be advised to continue therapy until conception is confirmed but a discussion regarding the
potential risks should be had as part of preconception counselling. Labetalol appears safe but other beta-blockers have been
associated with intrauterine growth restriction (IUGR). Diuretics
can exacerbate intravascular volume depletion in hypertensive
disorders of pregnancy and lead to IUGR.
For patients with CKD it is well-recognised that control of
hypertension is essential to abrogate decline in renal function.
NICE guidance and consensus guidelines produced by an RCOG
Study Group on renal disease and pregnancy recommend that a

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Immunological investigation of suspected intrinsic renal disease


Test

Comments

Antinuclear antibodies (ANA)

Associated with connective tissue diseases and SLE. Antibodies against double-stranded DNA (antidsDNA) and extractable nuclear antigens (ENA) should be performed if positive.
Associated with small vessel vasculitis (Churg Strauss disease, granulomatosis with polyangiitis and
microscopic polyangiitis).
Decreased levels are found in active SLE, post-infectious glomerulonephritis, mesangiocapillary
glomerulonephritis, subacute bacterial endocarditis, cryoglobulinaemia and heavy chain-deposition
disease.
Rheumatoid factor, cryoglobulins and C3 nephritic factor measurement may be indicated.

Anti-neutrophil cytoplasmic antibodies


(ANCA)
Complement components C3 and C4

Other tests
Table 2

throughout pregnancy for women with a PCR >100 mg/mmol,


particularly if women are obese or have other risk factors for
venous thromboembolism. Advice on thromboprophylaxis in
pregnancy is published by the RCOG. LMWH should be
continued for at least 6 weeks following delivery.

target blood pressure of 140/90 mmHg is maintained during


pregnancy. Evidence in support of blood pressure treatment
targets for patients with CKD during pregnancy is lacking,
however.
Pre-eclampsia prophylaxis: CKD is identified as a high risk
group for developing pre-eclampsia by NICE. Published data
supports the increased incidence of the condition from mild to
severe CKD. In high risk patients, aspirin (75 mg/day) reduces
the incidence of pre-eclampsia by approximately 25%. Although
not licenced for this indication, it is recommended that aspirin
prophylaxis is offered to all women with CKD during pregnancy.

Urinary tract infection prophylaxis (Tables 3 and 4): confirmed


asymptomatic bacteriuria and symptomatic UTI during pregnancy should be treated with antibiotics to reduce the risk of
ascending infection and preterm delivery. If more than one
episode of bacteriuria is confirmed during pregnancy, prophylactic antibiotics should be prescribed.
The choice of antibiotic is determined by stage of pregnancy,
sensitivities of the cultured organisms and local practice. Cephalosporins and penicillins are safe and well-tolerated throughout
pregnancy. Gentamicin may be used for severe pyelonephritis
with appropriate monitoring. Trimethoprim is a folate antagonist
and should be avoided in the first trimester. Nitrofurantoin is
associated with neonatal haemolysis if used in the third trimester
and should be avoided. Quinolones should not be used
throughout pregnancy.

Venous thromboembolism prophylaxis: pregnancy is a prothrombotic state and this is exacerbated by heavy proteinuria.
Consensus opinion recommends that patients with nephrotic
syndrome should receive prophylactic LMWH during pregnancy
and until 6 weeks post-partum. There is less evidence to support
LMWH prophylaxis for women with heavy proteinuria but
without nephrotic syndrome, or more modest proteinuria.
Nevertheless, many practitioners encourage the use of LMWH

Medication use in CKD and pregnancy


Antihypertensives
Commonly used

Rarely used

Contraindicated

Nifedipine
Labetalol
Methyldopa
Hydralazine

Beta-blockers
Alpha-blockers
Amlodipine
Verapamil

ACE inhibitors
Angiotensin receptor blockers
Aliskiren
Spironolactone
Moxonidine
Minoxidil (3rd trimester)
Thiazide diuretics
Diltiazem

Likely to be harmful
Anti-thymocyte globulin Rituximab

Contraindicated
Mycophenolate
Sirolimus
Methotrexate

Immunosuppressants
Likely to be safe
Prednisolone
Azathioprine
Ciclosporin
Tacrolimus
ACE, angiotensin converting enzyme.

Table 3

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Medications used in CKD and breastfeeding


Antihypertensives
Likely to be safe

Likely to be harmful

Contraindicated

Hydralazine
Nifedipine
Methyldopa
Most beta-blockers
Furosemide
Thiazide diuretics
Minoxidil
Immunosuppressants
Likely to be safe
Prednisolone
Azathioprine

Most dihydropyridine calcium channel


blockers
Celiprolol, nebivolol
Alpha-blockers
Moxonidine
Spironolactone

Aliskiren
Most ACE inhibitors
Angiotensin receptor blockers

Likely to be harmful
Mycophenolate
Ciclosporin
Tacrolimus
Anti-thymocyte globulin

Contraindicated
Sirolimus
Rituximab
Methotrexate

ACE, angiotensin converting enzyme.

Table 4

Other medication (Tables 3 and 4): anti-rejection medications used


in renal transplantation are discussed below. Erythropoietin,
vitamin D analogues and intravenous iron appear safe in pregnancy.

five to seven times a week. This is feasible for patients on haemodialysis at home but might not be practical for patients dialysing in units.

Dialysis and pregnancy

Peritoneal dialysis and pregnancy


Successful pregnancies can proceed in patients using peritoneal
dialysis (PD) although there is limited clinical experience
worldwide. The continuous nature of the process limits uraemia
and avoids rapid fluid shifts. As pregnancy progresses the gravid
uterus can reduce peritoneal blood flow and prevent instillation
of sufficient fluid to make PD effective. In the absence of residual
renal function, patients on PD may be unable to control fluid
status adequately during pregnancy, necessitating transfer to
haemodialysis (HD). Nevertheless, an elective change from PD to
HD is not mandatory for patients who are already established on
PD at the time of conception.

End stage renal failure reduces maternal fertility and conception


is rare in patients receiving dialysis. It is estimated that an
average sized renal unit in the United Kingdom will see one case
of dialysis and pregnancy every 4 years.
Approximately 25% of pregnancies in patients on dialysis end
with spontaneous abortion or termination in the first trimester.
Of those that progress to later pregnancy, adverse events are
common:
 intrauterine growth restriction in 90%
 preterm delivery in 90%
 pre-eclampsia in 75%
 perinatal death in 50%.

Pre-eclampsia and dialysis


Pre-eclampsia is common, can occur early and may be severe.
The diagnosis of pre-eclampsia is made in the context of worsening hypertension with additional clinical features such as
coagulopathy, liver dysfunction, intrauterine growth restriction
or neurological symptoms. Urine dipstick analysis in dialysis
patients is unhelpful because patients may always display urinary dipstick abnormalities or may be anuric, thus testing for
proteinuria is unhelpful.

Haemodialysis and pregnancy (Table 5)


The efficiency of haemodialysis (HD) in removing toxic metabolites is affected by the duration of dialysis session, the frequency
of dialysis, the surface area of semipermeable membrane and the
blood flow rate. As HD is an intermittent process, fluid and
circulating uraemic toxins accumulate between treatments.
Standard haemodialysis schedules are 4 hour sessions 3 times
per week. Observational data suggests that dialysis duration and
frequency should be increased during pregnancy to reduce the
accumulation of uraemic toxins and interdialytic fluid accumulation between sessions. Dialysis times should be increased to at
least 20 hours a week during pregnancy to achieve:

Management on dialysis
Intensive dialysis and fluid removal can accentuate the haemodynamic changes in pregnancy causing blood pressure instability
and hypotension. However, many dialysis patients have treated
chronic hypertension prior to conception, and medication may
need to be reduced to maintain a diastolic blood pressure
>80 mmHg. Lower blood pressure may contribute to IUGR. Later
in pregnancy blood pressure may rise due to pre-eclampsia

 pre-dialysis urea less than 20 mmol/litre (ideally less than


15 mmol/litre)
 intradialytic fluid loss of less than 1000 ml per session.
Much improved maternal and fetal outcomes have been
described in women undergoing nocturnal daily haemodialysis

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segment approach may be difficult due to the course of the


transplanted ureter.
In transplantation, a combination of prednisolone, azathioprine and a calcineurin inhibitor (tacrolimus or cyclosporine) can
be used during pregnancy (see Table 3). Although there is many
decades experience of use of these agents during pregnancy,
women should be informed of the recognised patterns of reported
side effects:
 At high doses (>20 mg/d) prednisolone can lead to fetal
adrenal insufficiency and risk of maternal infection.
Maintenance doses of <10 mg/d appear safe and welltolerated in pregnancy.
 Cyclosporine and tacrolimus may exacerbate hypertension
and limit renal adaptation to pregnancy. Fetal growth restriction may be associated with these agents.
 Azathioprine is teratogenic in high doses in animal studies.
In humans it has been used without obvious teratogenicity.
It may be associated with fetal growth restriction.
Trough serum levels of the calcineurin inhibitors should be
measured at every visit. Altered pharmacodynamics during
pregnancy necessitates careful titration of doses of these drugs to
maintain adequate levels whilst avoiding toxicity. A dose increase of up to 4-fold may be required and close monitoring in
the puerperium is as important as during pregnancy, if not more
so.
Mycophenolate mofetil (and mycophenolic acid) is commonly
prescribed following renal transplantation but should be avoided
during pregnancy due to a high incidence of specific congenital
abnormalities being reported. Patients should also be switched
from sirolimus prior to conception.
A

Indications for initiation of renal replacement therapy


during pregnancy
Absolute indications

Relative indications

Refractory hyperkalaemia
Refractory fluid overload
Refractory metabolic acidosis
Severe uraemia causing
encephalopathy or pericarditis

Moderate uraemia (urea >25


mmol/litre)
Resistant hypertension

Table 5

necessitating further changes in medication. Blood pressure in


patients receiving dialysis is predominantly driven by fluid status. A patients dry weight is an estimation of their weight
when euvolaemic. During pregnancy, dry weight will increase by
approximately 1.5 kg in the first trimester and then 0.5 kg per
week until delivery. These changes should be supervised by
careful clinical evaluation of the patients fluid status.
Anaemia is likely to be accentuated during pregnancy as a
result of haemodilution and increased anabolic demand. Erythropoietin replacement during pregnancy appears safe. Required
doses may increase by up to 3-fold and intravenous iron is
usually required to maintain stores. A target haemoglobin of 10
e11 g/dl has been suggested.
Kidney transplantation and pregnancy
The first successful pregnancy in a kidney transplant recipient
occurred in March 1958. Over 15000 children have been born to
mothers with renal transplants since then.
Maternal and fetal outcomes for pregnancies following renal
transplantation are far superior to those for mothers on dialysis.
The risks are predominantly related to the level of renal function
at conception and blood pressure control. Transplant rejection
and function are not affected by pregnancy assuming the
following are met:
 at least 12 months post-transplant
 stable renal function
 proteinuria <1 g/d
 minimal or well-controlled hypertension
 no recent or on-going transplant rejection
 minimal levels of appropriate immunosuppression (see
below).
For mothers with baseline creatinine <125 mmol/litre, successful pregnancy occurs in 97% of cases reaching the second
trimester. The incidence of preterm delivery, intrauterine growth
restriction and pre-eclampsia is greater than the general population and 30% of pregnancies may be affected.
With more severe baseline renal dysfunction, the incidence of
adverse fetal outcome increases. The likelihood of accelerated
maternal renal decline is also higher. In one study, all transplant
patients with creatinine >200 mmol/litre at conception progressed to dialysis within 2 years.
There is no evidence of delayed development in children born
to mothers with a renal transplant, independent of complications
associated with preterm delivery.
Normal vaginal delivery is not contraindicated following renal
transplantation. If Caesarean section is indicated then a lower

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:2

Practice points
C

Maternal and fetal risks are proportional to renal function and


blood pressure control prior to conception.
Women with CKD should be offered aspirin prophylaxis during
pregnancy to reduce the risk of pre-eclampsia.
Women with heavy proteinuria are at increased risk of thromboembolism and should be considered for prophylaxis during
pregnancy.
Asymptomatic bacteriuria and urinary tract infection should be
promptly treated during pregnancy.
Optimising timing of delivery requires multidisciplinary input from
nephrologists, neonatologists, obstetricians and patients.

FURTHER READING
Davison JM, Nelson-Piercy C, Kehoe S, Baker P, eds. Renal disease in
pregnancy. London: RCOG Press, 2008.
Gammill HS, Jeyabalan A. Acute renal failure in pregnancy. Crit Care
Med 2005; 33: S372e84.
McKay DB, Josephson MA. Pregnancy in recipients of solid organs e
effects on mother and child. N Engl J Med 2006; 354: 1281e93.
Williams D, Davison J. Chronic kidney disease in pregnancy. BMJ
2008; 336: 211e5.

52

2016 Elsevier Ltd. All rights reserved.

CASE-BASED LEARNING

Ultrasound in antenatal
diagnosis of structural
abnormalities

Committee Fetal Anomaly Screening Program (FASP) have


identified 11 structural abnormalities with anticipated detection
rates of >50%, that should be routinely screened for. These
include: anencephaly, open spina bifida, cleft lip, diaphragmatic
hernia, gastroschisis, exomphalos, serious cardiac abnormalities
and four lethal conditions including bilateral renal agenesis, trisomies 13 and 18 and lethal skeletal dysplasias. Although some
other conditions can be detected during the anomaly scan, there
is insufficient published data on detection rate to establish a
standard. If any of these or any other abnormality are suspected,
a referral to a Fetal Medicine Unit should be made to confirm
diagnosis and offer appropriate management. Identification of
any malformation at this stage allows the parents to make decisions regarding continuation of pregnancy, and if the pregnancy continues, appropriate management with intervention or
supportive care if required (antenatal or in early postnatal
period). Table 1 shows the anticipated prenatal detection rates of
these 11 structural abnormalities.
The same committee has established a series of routine views,
measurements and images that should be obtained and stored
during the anomaly scan. It is important to have a systematic
approach when examining the fetus. Before starting the fetal
biometry, it is advisable to examine the uterus and its contents,
the fetal position and orientation within the uterine cavity, confirming viability, number of fetuses and chorionicity in multiple
pregnancies. Once this has been established, the sonographer
can proceed with fetal biometry. The standard measurements
that should be obtained are: head circumference (HC), abdominal circumference (AC) and femur length (FL). These measurements need to be plotted on appropriate charts according to
gestational age. If the pregnancy has not been previously dated
(according to CRL on the first trimester), this needs to be done
according to the HC and documented in the report. A systematic
examination of fetal anatomy needs to include exam of the fetal
skull (shape, ossification), brain (views and measures of the
posterior horn of the lateral ventricles (atrium), cerebellum,
cisterna magna and nuchal fold and evidence of cavum septum
pellucidum), spine (sagittal, coronal and transverse view), face
(orbits, nose, lips, alveolar ridge and profile), thorax (lungs and
diaphragm) heart (establish situs, four-chamber view, left
outflow and three vessel view), abdomen (stomach bubble,
abdominal wall/insertion of umbilical cord), urinary tract (kidneys, renal pelvises and urinary bladder), limbs (angle of the
foot, hands/palms and feet/footprints) and genitalia. In addition,
the number of vessels in the umbilical cord needs to be reported,
assessment of amniotic fluid, placental site and fetal movements.
We have presented five cases with conditions seen commonly
in the practice of clinical fetal medicine. The discussion should
help the reader gain a better understanding of the use of ultrasound in the prenatal diagnosis of structural abnormalities.

Ana Pinas Carrillo


Amarnath Bhide

Abstract
Prenatal diagnosis commenced in the 1980s as part of routine antenatal care. Since then, the technical improvements and standardization of routine antenatal screening around the country have led to
reliable diagnosis for fetal abnormalities, allowing for appropriate management strategies to be offered in a timely fashion. The National
Screening Committee Fetal Anomaly Screening Program (FASP) recommends screening for eleven fetal conditions with a detection rate
of more than 50%. To achieve uniformity in prenatal diagnosis, this
committee has established a series of routine views, measurements
and images that should be obtained and stored during the anomaly
scan. In this article we will present some of the most common structural abnormalities through a series of case presentations.

Keywords antenatal diagnosis; cleft lip/palate; exomphalos; nuchal


translucency; talipes; ventriculomegaly

Introduction
Ultrasound was introduced in the 1980s in the UK as part of
routine antenatal care. However, uniformity on the timing and
requirements of routine ultrasound scanning has only been
standardized recently across the country. Obstetric ultrasound
has advanced rapidly since its inception, which has aided earlier
and better diagnosis of fetal abnormalities.
Currently, there are two routine ultrasound examinations
offered to all pregnant women, each with different aims. The first
trimester ultrasound is performed between 11 and 14 weeks of
gestational age; its primary objectives are to confirm viability,
date the pregnancy accurately according to the crown-rump
length (CRL) and offer screening for common chromosomal abnormalities. The technological advances of ultrasound have
improved resolution and capabilities to such an extent that has
changed our understanding and ability to visualize early fetal
anatomy. In doing so, structural abnormalities are being detected
at an earlier stage, allowing for early counselling and intervention when required. The second ultrasound scan is performed
between 18 and 21 weeks. The purpose of this scan is to identify
major fetal structural abnormalities. The National Screening

Case 1: increased nuchal translucency at the rst


trimester scan

Ana Pinas Carrillo LMS CCT Ob/Gyn (Spain) DipFM (UK) is a Consultant
Obstetrician at St. Georges University Hospitals NHS Foundation
Trust, London, UK. Conicts of interest: none declared.

A 38 year old woman in her first pregnancy attended her routine


first trimester scan. She booked at 7 weeks with unremarkable
past medical history, and normal booking bloods. The pregnancy
was dated according to the crown-rump length (CRL) as per
national guidelines, which dated her to be 12 4 weeks

Amarnath Bhide MD FRCOG is a Consultant in Obstetrics and Fetal


Medicine at St. Georges University Hospitals NHS Foundation Trust,
London, UK. Conicts of interest: none declared.

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:2

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CASE-BASED LEARNING

decided to continue the pregnancy and they had an early


anomaly and fetal cardiac scan at 16 weeks. The cardiac scan
showed a complete transposition of the great arteries (TGA) with
a ventricular septal defect (VSD). No extra-cardiac structural
abnormalities were diagnosed.
TGA represents 5e7% of all cardiac abnormalities with an
incidence of 0.3 per 1000 live births. It is more common in males.
The aorta arises from the right ventricle and the pulmonary artery arises from the left ventricle. It can be associated with
ventricular septal defects (VSD) and/or pulmonary stenosis.
Associated extra-cardiac abnormalities are rare and generally,
there is no association with chromosomal defects. TGA is well
tolerated in utero. Making the diagnosis before birth is important
as it enables delivery in a tertiary unit. At birth, a prostaglandin
infusion is required to maintain the patency of the ductus arteriosus. In some cases, an emergency balloon septostomy of the
inter-atrial septum may also be needed. Cardiac surgery is
required, involving an arterial switch of the aorta and the pulmonary artery above the valves. The prognosis is excellent provided the neonate is born at a tertiary unit and adequate
treatment is implemented immediately after birth.

Screening for fetal structural abnormalities. Detection


rates
Abnormality

Detection rate

Anencephaly
Open spina bifida
Cleft lip
Diaphragmatic hernia
Gastroschisis
Exomphalos
Major cardiac abnormalities
Bilateral renal agenesis
Lethal skeletal dysplasia
Edwards syndrome (T18)
Pataus syndrome (T13)

98%
90%
75%
60%
98%
80%
50%
84%
60%
95%
95%

Table 1

gestation. The measurement of the Nuchal Translucency (NT)


was 3.8 mm (>95th centile). No other major structural abnormalities were seen on the scan. The combined screening test
showed a high risk for chromosomal abnormalities (1 in 32). The
patient was referred to a Fetal Medicine unit for further counselling and management.
The combined screening test for chromosomal abnormalities
has been used since the 1990s. It allows detection of those
pregnancies at high risk of trisomy 21. The exponential correlation between maternal age and risk of having a fetus with Trisomy 21 (Downs syndrome) is now well established, and was
the primary driving force behind the initial screening programme
that offered amniocentesis to pregnant women above a certain
age (typically 40 years). However, maternal age alone detects
only 30% of all cases, and this approach to screening missed
women under 40, who represented the vast majority of the
pregnant population. The combination of maternal age, nuchal
translucency and serum biochemistry (b-hCG and PAPP-A) improves detection to 85e90% of fetuses with trisomy 21. Whilst
early studies used fixed cut-off values for nuchal translucency, it
is now understood that nuchal translucency is a dynamic measurement that increases as gestational age advances. The 95th
centile is therefore dependent on the gestational age (and
therefore, CRL). Nuchal translucency is increased (>95th centile)
in approximately 70% of fetuses with Trisomy 21. An increased
nuchal translucency can also be associated with other chromosomal abnormalities (Trisomy 13, 18, Turner Syndrome and
triploidy amongst others), genetic conditions and fetal structural
abnormalities (most commonly cardiac defects). In the second
and third trimesters, the presence of nuchal oedema is related to
chromosomal abnormalities in one third of the cases (75% of
them Trisomies 21 and 18). Oedema is also associated with
cardiovascular and pulmonary defects, congenital infections,
metabolic and haematological disorders and skeletal dysplasias.
After counselling regarding the possible causes of increased
nuchal translucency, our patient decided to have an invasive test.
Chorionic villus sampling was performed which showed a
normal karyotype, and array-CGH (Comparative Genomic
Hybridisation using microarrays) was also normal. The couple

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:2

Case 2: ventriculomegaly (VM)


A 33 year-old woman attended her routine anomaly scan at 21
3 days of gestational age. The patient was booked as a low risk
pregnancy at 8 3 weeks. The combined first trimester screening
test was reported as low risk (1 in 2500 risk for Trisomy 21). She
had been taking folic acid for 2 months prior to conceiving, and
had stopped after the first trimester scan.
During the scan, the posterior horn of the ventricular atrium
was measured as 12 mm on the left and 13 mm on the right side.
The posterior fossa (cerebellum and cisterna magna) appeared
normal. The cavum septum pellucidum and corpus callosum
were visualized. No other extra-cranial abnormalities were noted
on the scan and examination of the genitalia revealed a male
fetus. Fetal biometry was within the normal ranges for gestational age (Figure 1).

Figure 1 Ventriculomegaly. Transverse view of the head showing


mild ventriculomegaly of 12 mm.

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CASE-BASED LEARNING

The finding of ventriculomegaly (VM) is made when the


posterior horn of the ventricular atrium measures 10 mm or
greater at any gestational age. It can be unilateral or bilateral and
is classified as mild (10e12 mm), moderate (12e15 mm) or severe (>15 mm). The reported incidence varies between 0.5 and 3
per 1000 pregnancies. The causes of VM are diverse; it can be
secondary to an obstruction to the normal flow of the cerebrospinal fluid, brain atrophy due to fetal infections, fetal brain
haemorrhage, abnormal development of the CNS, chromosomal
defects or can be an idiopathic isolated finding.
When a diagnosis of VM is made, it is essential to exclude
other intra or extra-cranial abnormalities. It can be one of the
features present in Arnold Chiari II malformation, holoprosencephaly, agenesis of the corpus callosum, Dandy
eWalker malformation, arachnoid cyst or schizencephaly.
Although the studies investigating the additional benefit of
fetal MRI in these cases are inconclusive, an MRI should be
considered as an additional imaging modality to assess the brain
in detail, with particular interest in determining the presence of
the corpus callosum, abnormalities of the posterior fossa and the
presence of normal sulcation when performed in the third
trimester.
The presence of extra-cranial abnormalities increases the
suspicion of an underlying chromosomal defect. The most
commonly associated with VM are trisomies 13, 18 and 21 and
translocations of 7p and 9p. Invasive testing to exclude chromosomal defects should be offered when a diagnosis of VM is
made. Both PCR and culture should be performed on the sample
and, if available in the unit, array-CGH.
As previously mentioned, VM can be secondary to fetal
infection, in particular, cytomegalovirus, toxoplasmosis and
rubella. A maternal blood sample to screen for infections should
be taken as part of investigation of VM.
In the case presented, there were no other abnormalities
noted. The patient opted to have an amniocentesis. The results
showed a normal karyotype, the infection screening was negative
(CMV IgM negative, IgG positive, high avidity reflecting a past
infection, Toxo IgM and IgG negative) and the MRI confirmed the
presence of bilateral VM but normal appearances of the corpus
callosum, posterior fossa and normal sulcation of the cerebral
hemispheres. A diagnosis of isolated mild VM was made at this
point after exclusion of other causes.
The couple was counselled regarding the prognosis. It is
important to perform at least one additional scan in the third
trimester to exclude other abnormalities, which may manifest
later, and to assess progression. If the VM improves or resolves
to normal values during pregnancy, whether it was mild, moderate or severe, the prognosis is more favourable. There are a
wide variety of results reported regarding the neurodevelopmental outcome; currently, the evidence shows that
around 90% of children diagnosed with mild isolated VM have a
normal neurodevelopmental outcome at least in infancy.
Whether this percentage is different from the outcome in the
general population still needs to be established. A higher incidence of isolated mild VM has been reported in male fetuses and
there is some evidence that the prognosis is worse in female fetuses. Latest research shows however no statistically significant
difference in outcome between genders.

The parents decided to continue with the pregnancy and a


follow up scan at 32 weeks was performed. During this scan, the
ventricles measured 8 mm on the left side and 9 mm on the right
side, no other abnormalities were detected and there was normal
fetal growth and Dopplers. The patient had a spontaneous
vaginal delivery at 38 3 weeks of a male infant weighing 3250
kg. Apgar scores were 8 at 1 minute and 10 at 5 minutes. A follow
up at 6 and 12 months of life showed normal neuro-development
of the infant.

Case 3: bilateral talipes


A 25 year old woman attended her anomaly scan at 22 weeks.
This was her second pregnancy. Her first pregnancy resulted in a
miscarriage at 16 weeks. She was known to have a bicornuate
uterus, which was diagnosed during the first pregnancy. She
booked at 11 weeks and had a dating scan at 12 6 weeks; she
declined the combined screening test but the nuchal translucency
was reported as normal (1.5 mm).
During the anomaly scan, the pregnancy was reported to be in
the right horn of the bicornuate uterus. Fetal biometry was
consistent with gestational age and bilateral talipes (clubfoot)
was noted (Figure 2). No other structural abnormalities were
seen during the scan. She was referred to the Fetal Medicine Unit
and the finding was confirmed. Good fetal movements of the legs
were seen on the scan, although the talipes persisted and no
movements in the ankle joints were seen during the scan.
Bilateral talipes is the most common skeletal abnormality
identified in prenatal diagnosis. Anatomically, they can be classified as talipes equinovarus (adduction of the forefoot, inversion
of the heel and plantar flexion of the forefoot and ankle), talipes
calcaneovalgus (dorsal flexion of the forefoot with the plantar
surface facing laterally) and metatarsus varus (inversion and
adduction of the forefoot alone). The most common, talipes
equinovarus, is seen in 1:1000 pregnancies and the incidence is
higher in male fetuses. According to the ethology, they can be
classified as positional, where the foot is flexible, complex or
atypical, where the position of the foot is more difficult to

Figure 2 Talipes. Abnormal foot alignment in talipes.

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CASE-BASED LEARNING

correct, and syndromic, associated with other abnormalities.


Whether the talipes is positional/flexible or complex/fixed is
difficult to determine whilst in utero. Talipes can be unilateral or
bilateral. The prognosis is excellent when it is isolated, which
represents the majority of cases. However, this is a diagnosis of
exclusion. Bilateral talipes can be related to chromosomal defects, part of the sequence of a syndrome or a sign of neuromuscular abnormalities. Amongst the chromosomal defects,
bilateral talipes is a common feature of trisomy 18 and less
commonly in trisomies 13 and 21.
Talipes can be associated with cardiac defects, cleft lip/palate,
micrognathia, hip dislocation and inguinal hernia. The association with other structural abnormalities increases the suspicion
of a genetic syndrome or chromosomal defect. A wide range of
syndromes can be associated with talipes, such as Larsen syndrome, Gordon syndrome or Pierre-Robin syndrome. Musculoskeletal disorders associated to clubfoot include arthrogryposis,
nail-patella syndrome, congenital constrictive bands, diastrophic dysplasia and muscular dystrophies. It is also essential
to exclude neurological problems such as spina bifida. Any factor
that causes a restriction in intrauterine space can also be associated with the finding of talipes, such as oligohydramnios,
uterine malformations (bicornuate or didelphys uterus) and
amniotic bands.
Even in the absence of other structural abnormalities, the
incidence of chromosomal defects has been reported to be
elevated in some case series and karyotyping should be offered.
Our case was diagnosed with isolated bilateral talipes and the
most likely cause was deemed to be the presence of a bicornuate
uterus. Amniocentesis was offered to exclude chromosomal defects and accepted. She underwent an uncomplicated procedure
and the result was normal (PCR, culture and CGH-array). She
had a follow up scan at 28 weeks. There was normal fetal
growth, amniotic fluid and Dopplers. The finding of isolated
bilateral talipes was confirmed and good fetal movements were
seen on the scan. The patient was reassured of the good prognosis and she was comprehensively counselled about the postnatal care plan.
Postnatal management depends on the nature of the talipes.
The Ponsetti method consists of physiotherapy and the use of
casts to correct the position of the feet and frequently requires a
tenotomy to release the Achilles tendon.
The importance of prenatal diagnosis is to exclude other abnormalities including neuromuscular disorders, genetic or chromosomal defects and to manage the parents expectations in the
postnatal period.

Figure 3 Exomphalos. Transverse view of exomphalos containing


bowel and stomach.

the condition was diagnosed as exomphalos (Figures 3 and 4).


No other anomalies were noted on the scan.
The incidence of exomphalos varies between 1 in 300 and 1 in
4000 pregnancies and it increases with maternal age. The main
differential diagnosis is gastroschisis (Figure 5). Gastroschisis is a
defect of the abdominal wall, generally to the right side of a
normally inserted umbilical cord that results in a herniation of
the abdominal contents (generally bowel) not covered by membrane. The membrane that covers the bowel differentiates
exomphalos from gastroschisis.
Exomphalos most commonly contains bowel and/or the liver,
depending on the size of the defect. The insertion of the umbilical
cord is typically on the membrane covering the defect.
When seen in the first trimester, there is an association with
chromosomal defects, usually trisomy 18 and 13 in 30e40% of
the cases. This association is more prevalent when the exomphalos only contains bowel (67%) than with large defects containing bowel and liver (17%). Other structural abnormalities are
more likely with abnormal chromosomes. Equally, once aneuploidies have been excluded, other structural abnormalities can
still be frequent, most commonly, cardiac defects (30%).
Exomphalos can also be one of the features present in BeckwitheWiedemann syndrome, MeckeleGruber syndrome, pentalogy of Cantrell and cloacal exstrophy.

Case 4: exomphalos
A 30 year-old woman in her second pregnancy attended for the
routine first trimester scan. Her previous pregnancy was uneventful and she reported no pre-existing medical problems. The
pregnancy was dated at 13 3 weeks according to the CRL and
the nuchal translucency was 2.2 mm (<95th centile). During the
examination of fetal anatomy, a herniation in the abdominal wall
was noted with clear visualization of bowel being covered by a
membrane. She was referred to a Fetal Medicine unit. The finding
of bowel covered by peritoneum and amnion was confirmed and

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:2

Figure 4 Exomphalos. Longitudinal view of exomphalos containing


bowel.

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CASE-BASED LEARNING

5 weeks and the risk was low (1 in 3200). During the anomaly
scan, the fetal stomach remained small in size throughout the
examination. Amniotic fluid was normal. No other abnormalities
were detected. She was referred to the Fetal Medicine Unit to
assess the fetal stomach. The stomach was clearly visualized,
although of small size. A unilateral cleft lip was noted on the left
side. On detailed examination, a cleft palate was also noted
(Figure 6). No other structural abnormalities were diagnosed at
this point.
Cleft lip (CL) is the most common facial abnormality. It can
be isolated or associated with a cleft palate (CL/P). Detection
of a cleft of the alveolar ridge is relatively easy, but visualizing
clefts of the hard palate can be notoriously difficult. A cleft in
the alveolar ridge is most often associated with cleft of the hard
palate. The presence of a cleft palate (CP) without a cleft lip is
a separate entity with a different embryological origin. The
incidence of CL/P varies according to the ethnicity. It is higher
in Asian population, 1.5e2 per 1000, lowest in Africans, 0.5
per 1000, and around 1 per 1000 in a white population. However, the incidence of cleft palate alone is similar in all ethnicities. Approximately, 50% of the cases have a combined
cleft lip and palate, 20% isolated cleft lip and 30% isolated cleft
palate. The two first entities are more common in males
whereas the latter is more common in females. It can be unilateral or bilateral, with the unilateral left sided cleft lip the
most common finding. An isolated cleft palate is more difficult
to diagnose.
The presence of a CL/P has been related to rubella infection,
drugs such as antiepileptics, retinoic acid, thalidomide, steroids
and alcohol. A family history is not infrequent.
Prenatal diagnosis is important because of the association
with other anomalies. 18% form part of a syndrome or sequence.
It is associated with at least 100 different syndrome, including
EEC (ectrodactyly, ectodermal dysplasia, clefting syndrome),
Opitz syndrome, Meckels syndrome, Roberts syndrome, Apert
syndrome and Treacher-Collins syndrome, amongst others.
Invasive testing should be offered as up to 10% of CL/P will
have an underlying aneuploidy such as trisomy 13 or 18. This
likelihood of a chromosomal abnormality is much lower in the
absence of other structural abnormalities.
As part of the work-up, the mother was offered an amniocentesis, which showed a normal karyotype. After excluding
other structural abnormalities and chromosomal defects, the
mother was reassured and counselled about the postnatal management. Information about the surgical repair and the possible
feeding problems at birth was provided and follow up scans to
assess fetal growth and amniotic fluid were performed. In these
cases, 3D ultrasound may be useful to assess the degree of the
defect and to prepare the parents for the postnatal appearance of
the defect. They were also informed of the risk of recurrence,
which is approximately 4e7% in cases of combined cleft lip and
palate.
A

Figure 5 Gastroschisis. Note the absence of a sac covering the bowel


loops, which appear to be freely oating in the amniotic uid.

In this particular case, there were no other structural abnormalities seen, but invasive testing for karyotyping was offered
due to the strong association with trisomies (40%). The patient
opted to have a chorionic villus sampling and the results (both
karyotype and CGH-array) were normal. The couple opted to
continue the pregnancy and she had a routine anomaly scan at 21
weeks that confirmed the findings of an isolated large exomphalos containing bowel and liver. They were offered serial scans
to ensure appropriate growth and to exclude polyhydramnios
and bowel dilatation.
An appointment with the paediatric surgeons was organized
to discuss postnatal management. Serial growth scans showed
adequate growth, normal Dopplers and normal amniotic fluid
volume.

Case 5: cleft lip/palate


A 36 year-old woman in her third pregnancy attended her routine
anomaly scan. Her two previous pregnancies were uneventful
and she had two spontaneous vaginal deliveries. Of note, she had
epilepsy treated with carbamazepine and her last seizure was 2
years ago. Due to the epilepsy, she had a fetal cardiac scan which
was normal. She had her first trimester combined screening at 11

FURTHER READING
Coady AM, Bower S. Twinings textbook of fetal abnormalities. 3rd edn.
Churchill Livingstone Elsevier, 2014. ISBN: 978-0-7020-4591-2.
Nyberg D. Diagnostic imaging of fetal anomalies. 2nd edn. Lippincott
Williams and Wilkins, 2002. ISBN: 9780781732116.

Figure 6 Cleft lip. The arrow points the unilateral defect on the right
side.

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CASE-BASED LEARNING

Royal College of Obstetricians and Gynaecologists 2000. Routine


ultrasound screening in pregnancy: protocol, standards and
training. Report of the RCOG Working Party. London: RCOG,
2000.
Salomon LJ, Alrevic Z, Timor-Tritsch I, et al. ISUOG practice guidelines: performance of rst-trimester ultrasound scan. Ultrasound
Obstet Gynecol 2013; 41: 102e13.
Allan LD, Cook AC, Huggon IC. Fetal echocardiography e a practical
guide. Cambridge: Canbridge University Press, 2009.
Melchiorre K, Bhide A, Gika AD, Pilu G, Papageorghiou AT. Counseling
in isolated mild fetal ventriculomegaly. Ultrasound Obstet Gynecol
2009 Aug; 34: 212e24. http://dx.doi.org/10.1002/uog.7307.
Pagani G, Thilaganathan B, Prefumo F. Neurodevelopmental outcome
in isolated mild fetal ventriculomegaly: systematic review and
meta-analysis. Ultrasound Obstet Gynecol 2014; 44: 254e60.
http://dx.doi.org/10.1002/uog.13364.
Kilby MD, Lander A, Usher-Somers M. Exomphalos. Prenat Diagn
1998; 18: 1283e8.
Bakalis S, Sairam S, Homfray T, et al. Outcome of antenatally diagnosed talipes equinovarus in an unselected obstetric population.
Ultrasound Obstet Gynecol 2002; 20: 226e9.
Clementi M, Tenconi R, Bianchi F, Stoll C. Evaluation of prenatal
diagnosis of cleft lip with or without cleft palate and cleft palate by
ultrasound: experience from 20 European registries. EUROSCAN
study group. Prenat Diagn 2002; 20: 870e5.

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:2

Practice points
C

58

The suspicion of any fetal abnormality during routine antenatal


screening should trigger a referral to a specialized Fetal Medicine
Unit for further diagnosis and management
Increased nuchal translucency observed during the first trimester
can be associated with chromosomal defects, genetic conditions
or fetal structural abnormalities (most commonly cardiac defects)
The incidence of ventriculomegaly is 0.5e3 per 1000 pregnancies.
It can be associated with obstruction in the flow of cerebrospinal
fluid, chromosomal defects, fetal infections, fetal brain haemorrhage, abnormal development of the CNS or can be an idiopathic
isolated finding
Bilateral talipes is the most common skeletal abnormality and can
be isolated or related to chromosomal defects, part of a sequence
or a syndrome, or a sign of neuromuscular abnormalities. The
prognosis is excellent if it is isolated
Exomphalos is a herniation in the abdominal wall covered by a
membrane containing intra-abdominal viscera. It is associated
with chromosomal defects in 40% of the cases. The main differential diagnosis is gastroschisis where the herniated organs are
not covered by a membrane
Cleft lip is the most common facial abnormality. It can be isolated
or related to rubella infection, drugs and alcohol misuse. It is
associated with other anomalies in up to 50% of cases

2015 Elsevier Ltd. All rights reserved.

ETHICS/EDUCATION

Designer babies

of this form of therapy. As PGD has now become a well-accepted


method of treatment, it will not be considered in this article.

Ronald T K Pang

Tools for generating designer baby

P C Ho

A. Mitochondria DNA replacement therapy


DNA is not confined to the nucleus. Thousands of copies of
mitochondrial DNA (mtDNA), which are inherited from the
mother, are present in the cytoplasm of the cells. They are prone
to mutations. When the percentage of mtDNA with mutations
exceeds a certain threshold, it may lead to the development of
mitochondrial diseases. As there is often variation in the percentage of mtDNA mutations among cells and tissues, the clinical
manifestations and the severity of symptoms are highly variable.
Severe cases may die in the neonatal period or during infancy. It
was estimated that 1 in 5000 children are suffering from mtDNA
mutation related diseases. Up till now, there was no effective
curative treatment for mitochondrial diseases. There is also
concern about the accuracy of PGD in mitochondrial diseases
because of the variation in the percentage of mutated mtDNA
among the cells; the cell biopsied may thus not represent the
remaining cells in the embryo. Although the use of donor oocytes
can help the affected woman to have a child without the mitochondrial disease, it may not be acceptable to the woman as
there is no maternal genetic contribution to the child. In 2013,
mtDNA replacement therapy was developed and it has just been
approved in the United Kingdom to be used in the clinic as a
therapy. The therapy involves the transfer of the nuclear genome
from the pronuclear stage zygote of a mitochondria disease carrier to an enucleated healthy donor oocyte. The resulting embryo
then carries nuclear DNA from its parents and presumably
normal mtDNA of the oocyte donor. It is controversial because
the alteration is inheritable. Although pioneer experiments in
nonhuman primates are encouraging, potential problems like
nuclear-to-mtDNA incompatibility may not be identified until,
decades or even generations later. As the treatment involves
donation of oocytes or embryos from healthy oocyte/embryo
donors, the risks to these donors should also be considered.

Abstract
Designer babies are either created from an embryo selected by preimplantation genetic diagnosis (PGD) or genetically modied in order to inuence the traits of the resulting children. The primary aim of creating
designer babies is to avoid their having heritable diseases coded by mutations in DNA. With the development on mitochondria DNA transfer and
discovery of genome-editing tools, the production of precise genomeedited designer babies is no longer science ction. However, knowledge
on the risk of these editing tools is insufcient especially when modications are heritable. Furthermore, there are ethical concerns as to whether
we should apply these technologies to create designer babies. We
believe that these germline genetic editing methods should still be
considered as experimental procedures and research should continue
to improve the method and to assess its long term safety.

Keywords designer babies; embryo editing; engineering nuclease;


mitochondria

Introduction
Designer babies are babies originated from embryos created by
in-vitro fertilization (IVF) and selected because of the presence or
absence of particular genes or a baby created by genetic interventions into pre-implantation embryos in the attempt to influence the traits the resulting children will have.

Why designer babies are needed?


Today, majority of the designer babies are created with an aim to
prevent inheriting genetic defects through the selection of disease-free embryos by preimplantation genetic diagnosis (PGD).
Some diseases like cystic fibrosis and b-thalassemia, for instance,
could be prevented. However, when all embryos would carry the
disease genes from a carrier couple, genetic modification
would be necessary. Recently developed gene editing tools allow
scientists to create designer babies by active removal of disease
gene from carrier embryos. In United Kingdom (UK), the recent
approval to allow the use of mitochondria replacement therapy
has generated a heated debate. In this article, we explain the
recent developments in this area and discuss the ethical aspects

B. Genome editing tools e engineering nucleases


Recently, a novel technique had been developed by using genetic
engineering nucleases to destroy the mutated mtDNA in mice
embryos to increase the percentage of functional mitochondria
and reverse the disease status. Engineering nucleases can either
inactivate or repair a gene of interest. The major advantage is
that it does not involve the use of a third person DNA. During
application to embryo editing, the genes in the germ cells could
also be changed and they will be passed to the next generations.
However, engineering nucleases are not perfect and may cause
problems like off-target editing.

Ronald T K Pang PhD Post-doctoral Fellow and Honorary Assistant


Professor, Department of Obstetrics and Gynaecology, The University
of Hong Kong, Hong Kong Special Administrative Region; Shenzhen
Key Laboratory of Fertility Regulation. Conicts of interest: none
declared.

Safety of inheritable genomic editing


Genome editing therapy has hidden risks; off-target cleavage was
observed and serious side effects may occur when essential genes
were cleaved. Besides, unpredictable consequences may be
observed on future generations. If the efficiency of editing is too
low, the disease phenotype may remain. Genetic mosaicism has
been observed in genome-edited zygotes, and PGD screening fail
to detect successful or off-target mutations in the edited-embryo

P C Ho MD Consultant, Department of Obstetrics & Gynaecology,


The University of Hong Kong-Shenzhen Hospital, Hong Kong Special
Administrative Region; Honorary Clinical Professor, Department of
Obstetrics & Gynaecology, The University of Hong Kong; Director,
Shenzhen Key Laboratory of Fertility Regulation. Conicts of interest:
none declared.

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ETHICS/EDUCATION

while analyzing multiple blastomeres will reduce embryo quality. Thus, potential problems may not surface until after birth.

not be inheritable and also resolve the restriction of acquiring


matched donors.
Many treatment methods or drugs have the potential to be
abused but the proper response should be to regulate the use of
the method or drug to prevent abuse rather than to prohibit its
use in appropriate indications. The slippery slope argument
has been used against the development of new assisted reproductive technology such as IVF and PGD when they were being
developed but now these are all well accepted in many parts of
the world. However, the use of engineering nuclease or mtDNA
replacement therapy for enhancement of certain personal characteristics is not wise and should be prohibited. Some of the
personal characteristics like intelligence are dependent on many
genetic as well as environmental factors. The benefit to risk ratio
is too low even for experimental procedures.

Ethical considerations
Objections have been raised against mitochondrial transfer or
gene editing for several reasons. First, the safety of these procedures has not been fully established. The potential for harm
is great as the problems may be passed on to future generations. The introduction of these techniques for germline genetic
editing may lead us further down a slippery slope. These
techniques may be used for genetic enhancement and not just
for treatment of genetic diseases. In the case of treatment with
mitochondrial transfer, a healthy oocyte donor is required and
she may suffer from the complications and discomfort of the
oocyte donation procedure such as ovarian hyperstimulation
syndrome (OHSS). The use of germline genetic modifications
may also be considered to be dehumanizing and not acceptable
to some couples.

Conclusion
Many significant advances have been made in the recent few
decades in genetic editing and modifications with successful
cases reported in the literature. However, long term safety of
these procedures is still uncertain. Whether these techniques can
be used for treatment of serious genetic diseases is controversial.
We believe that while the procedures should not be considered to
be ready for clinical applications, research should continue to
improve the technology and to assess the long term safety of
these procedures.
A

Possible solutions
At this moment, the risks and complications of using engineering nuclease or mtDNA replacement therapy in creating
designer babies are still not fully known. In many countries,
these procedures are still prohibited by law. In our opinion,
these procedures should still be considered as experimental
and should not be offered as routine clinical procedures.
Nevertheless, we believe that research in this area should
continue under strict regulations and monitoring to ensure
that women who consent to undergo these procedures have
been fully informed of the procedures, the potential risks and
other alternative treatment. The use of well-established
methods like PGD or IVF, if possible, are better choices for
selecting healthy offspring and the ethical issues are often
considered minimal. Another possible option is the use of
ex vivo correction; the stem cells of the patients are isolated
for gene-editing and the corrected functional cells will then be
used for autologous transplantation. Thus, the edited gene will

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:2

FURTHER READING
Amato P, Tachibana M, Sparman M, et al. Three-parent in vitro fertilization: gene replacement for the prevention of inherited mitochondrial diseases. Fertil Steril 2014; 101: 31e5.
Kim H, Kim JS. A guide to genome engineering with programmable
nucleases. Nat Rev Genet 2014; 15: 321e34.
Reddy P, Ocampo A, Suzuki K, et al. Selective elimination of mitochondrial mutations in the germline by genome editing. Cell 2015;
161: 459e69.

60

2016 Elsevier Ltd. All rights reserved.

SELF-ASSESSMENT

Self-assessment questions
Questions

I) Perform renal biopsy

Question 1 (SBA)
A 32-year old woman in her first pregnancy attends the
antenatal clinic at 10 weeks gestation. She has a history of
chronic kidney disease secondary to reflux nephropathy. Her
eGFR measured in renal clinic 3 months ago was 40 ml/min.
She takes 10 mg amlodipine daily, which controls her blood
pressure well.
Which one of the following statements is true regarding her
management?
A) Her anti-hypertensive should be stopped and labetalol
started if her blood pressure increases during pregnancy
B) Her eGFR is irrelevant as this measure is not validated in
pregnancy
C) Her risk of developing pre-eclampsia is not elevated above
baseline as her blood pressure is well-controlled
D) She should be advised to have regular blood pressure and
eGFR checks monthly in early pregnancy and more
frequently in the third trimester
E) She is at risk of a post-partum decline in her renal function

i). A 35-year old woman, with no previous history of renal


disease, presents at 15 weeks into her second pregnancy
with oedema. Subsequent investigations reveal a creatinine of 110 mmol/L and urine PCR of 800 mg/moL. Her
serum albumin is 15 g/L. Her blood pressure is 135/85.
ii). A 38-year old woman who has had a renal transplant 4
years ago attends for pre-pregnancy counselling. Her renal
function has been stable for several years with a baseline
creatinine of 140 mmol/L. She is taking aspirin, nifedipine,
mycophenolatemofetil and Calcichew. Her blood pressure
is 130/80 and she has 2 proteinuria on dipstick.
iii). A 28-year old woman has had a right-sided renal transplant for complications of type 1 diabetes and is currently
in her first ongoing pregnancy. Her serum creatinine at
booking was 85 mmol/L. She attends clinic for her regular
check at 24 weeks, where she complains of tiredness. Her
creatinine level comes back at 230 mmol/L.
Question 4 (SBA)
A 40 year old woman in her first pregnancy, conceived
through IVF, presents in your booking clinic and wishes to
discuss prenatal screening for Down syndrome. Her scan had
suggested dichorionic twins, but the sonographer was unable
to obtain an nuchal translucency measurement for twin B.
Which of the following statements below is true in this
situation?
A) The twins must be dizygotic (non-identical)
B) The risk of both twins being affected is approximately
double her age related risk
C) The risk can be derived for both twins using the NT
measurement of twin A
D) The detection rate of the combined test is approximately
80%
E) The risk of miscarriage associated with invasive testing
would be 1 in 50

Question 2 (SBA)
A 26-year old woman attends the antenatal clinic at 16 weeks
gestation. She underwent a living-donor renal transplant 3
years ago due to IgA nephropathy. Her creatinine has been
stable at 115 mmol/L for the past 2 years. Her blood pressure is
120/70 without medication and she has proteinuria of 600 mg/
d. Which one of the following factors is NOT important in
predicting well-maintained renal function during and after
pregnancy?
A) She does not have hypertension at booking
B) Her proteinuria is <1 g/d
C) Her transplanted kidney came from a living related donor
D) Her renal function has been stable for over a year
E) Her creatinine is <125 mmol/L at booking
Question 3 (EMQ)
For each of the patients described below (ieiii), pick the single
most important first management strategy from the list below:
A) Start low molecular weight heparin
B) Start dialysis
C) Advise to avoid pregnancy
D) Stop statin treatment
E) Switch immunosuppressive regimen to azathioprine and
tacrolimus
F) Commence aspirin
G) Monitor urea, creatinine and haemoglobin every 8 weeks
H) Perform renal ultrasound scan

Question 5 (SBA)
Which of the following biological mechanisms is not an
explanation for phenotypic differences in monozygotic twins?
A) Somatic mosaicism
B) Epigenetic phenomena
C) Meiotic errors
D) Disrupted embryonic migration
E) Variable penetrance
Question 6 (SBA)
Following a routine scan at 24 weeks, one of your patients is
found to have very discordant liquor volumes between her
dichorionic twins. Which of the following is not a possible
explanation;
A) Preterm membrane rupture
B) Fetal VATER syndrome
C) Twin to twin transfusion syndrome

Alec McEwan MRCOG is a Consultant in Fetal and Maternal


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

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SELF-ASSESSMENT

D) Selective fetal growth restriction


E) Autosomal recessive polycystic kidney disease

iii). A 28-year old woman is 30 weeks into her third pregnancy.


She has had repeated episodes of small amounts of antepartum haemorrhage over the last 3 weeks. She is haemodynamically stable and her haemoglobin level is 98 g/L

Question 7 (SBA)
A 41-year old woman, who has conceived with the use of IVF,
presents initially at 28 weeks with spontaneous rupture of the
membranes. She is highly anxious because her previous baby
was stillborn following an abruption at 32 weeks. She continues
to smoke during the pregnancy despite advice from her obstetric
team. At 35 weeks, she experiences a sudden onset of severe
abdominal pain and bleeding, and an emergency Caesarean
section is performed. Her neonate requires resuscitation, but is
well enough to leave hospital after a 2-week stay in NICU.
Which of the following is the strongest risk factor for
abruption in this case?
A) Maternal age 41
B) Maternal smoking in pregnancy
C) Preterm prelabour rupture of membranes
D) Previous history of abruption
E) Conception with IVF

Answers
Answer 1
E
This patient has CKD G3b. Estimated glomerular filtration
rate is calculated using equations, most commonly the MDRD
or CKD-EPI formulae. These are based on serum creatinine,
patient age, gender and ethnicity. These calculations are not
validated for use during pregnancy, however preconception
baseline values of eGFR (this womans eGFR result is from
pre-pregnancy) are useful in predicting maternal and fetal
outcomes. Even preconception eGFR >60 ml/min is associated with increased risk of prematurity and intrauterine
growth restriction as compared to the general population,
predominantly, but not entirely, due to an increased risk of
developing pre-eclampsia. Amlodipine is rarely used during
pregnancy, but is unlikely to cause harm. It should be
switched to nifedipine or labetalol rather than stopping antihypertensives altogether, if the patient and clinician are not
happy to continue with it in the absence of good data. Women
who commence pregnancy with an eGFR 45 ml/min are at risk
of long-term decline in their renal function if they develop
significant proteinuria during the pregnancy.

Question 8 (SBA)
A 21-year old woman presents at 32 weeks into her first
ongoing pregnancy with abdominal pain and a small antepartum haemorrhage. Her pregnancy has been uncomplicated
thus far and, although she has missed several midwife appointments, she has had normal scans at 12 and 20 weeks. She
is haemodynamically stable, the CTG is normal and she is
admitted for observation. Which one of the following steps is
appropriate in her management at this point?
A) Colposcopy to examine the cervix
B) Screening for domestic violence
C) Extended clotting studies
D) US to look for vasa praevia
E) US to look for placental abruption

Answer 2
C
The origin of a transplanted kidney is not known to be a
factor predicting subsequent pregnancy outcome. Baseline
diastolic blood pressure >75 mmHg or the use of anti-hypertensive agents may be predictive of accelerated decline in
renal function post-partum. Women with serum creatinine>125 mmol/L have a 25% risk of permanently losing
25% of their kidney function as a result of pregnancy.

Question 9 (EMQ)
For each of the patients described below (ieiii), pick the single
most important first management strategy from the list below:
A) Arrange prophylactic balloon catheter placement
B) Proceed to emergency Caesarean section
C) Perform transvaginal ultrasound scan
D) Rescan at 32 weeks gestation
E) Rescan at 36 weeks gestation
F) Complete advance directive regarding blood products
G) Optimize pre-delivery haemoglobin levels
H) Transfuse packed red blood cells
I) Admit to hospital from 34 weeks

Answer 3
i). A
This patient has all the hallmarks of nephrotic syndrome
and is at high risk of venous thromboembolism. She should be
immediately started on low molecular weight heparin while
the aetiology is investigated.
ii). E
This patient is at moderate risk of a decline in her renal
function or a poor fetal outcome from pregnancy, but not to
the extent where she should be advised not to become pregnant. Her major risk factor at present is the use of mycophenolatemofetil, which is linked to a high incidence of specific
congenital anomalies. This should be changed as soon as
possible, and she should not stop her contraceptive until her
renal function is stable on the new regimen.
iii). H
A sudden jump in a previously stable creatinine mandates
urgent imaging of the transplanted kidney. Graft rejection is a
possibility in this case.

i). A 36-year old woman in her third ongoing pregnancy has


been diagnosed with a posterior low-lying placenta at a
34-week ultrasound scan. She is a Jehovahs Witness and
would refuse blood products. She has not experienced
any bleeding in the current pregnancy and her current
haemoglobin is 117 g/L.
ii). A 42-year old woman in her second pregnancy is noted to
have an anterior low-lying placenta covering the os at her
routine anomaly scan. Her haemoglobin is 108 g/L

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SELF-ASSESSMENT

Answer 4
E
The risk of miscarriage (of the entire pregnancy) when
performing double amniocentesis or double CVS should be
quoted as 1 in 50 (2%). A proportion of dichorionic twins are
monozygous, although most are dizygous. For the purposes of
prenatal screening, dichorionic twins are treated as dizygotic,
and an individual risk for Down syndrome is given to each
fetus, depending on its NT. The detection rate of the combined
test falls to 40e50% for a constant false positive rate of 3%
because the shifts in biochemical markers are diluted by the
chemical contribution made by the normal twin. Assuming
dizygosity in this pregnancy, the risk of both twins being
affected will be the age incidence multiplied by the age incidence (ie 1 in 100, multiplied by 1 in 100). The risk of at least
one of the twins being affected is double the normal age related
risk (ie 1 in 100 plus 1 in 100). For a risk to be given for each
twin in a dichorionic twin pregnancy, both NT measurements
must be made.

Answer 8
B
Clinicians should be aware that domestic violence can
result in APH, possibly from placental abruption. A third of
domestic violence is known to start or escalate in pregnancy.
Women who disclose domestic violence should be managed
appropriately by a local safeguarding team. Ultrasound is not
recommended as a diagnostic tool to diagnose abruption as
the reported sensitivity is only between 25 and 50%. While the
RCOG guideline recommends that all patients with APH
should have a full blood count (FBC), group and save and a
Kleihauer test if Rhesus D negative, there is no indication for
extended clotting studies in this case. Women who present
with major or massive haemorrhage should also have liver
and renal function blood tests and a coagulation screen
including fibrinogen.
Answer 9
i). F
This patient needs to be prepared for a large blood loss at
the time of delivery. While optimizing her haemoglobin level
will be important, this is currently within normal range. The
priority is to prepare for an emergency situation, and having a
clear record of her wish for treatment with blood products is
essential. The healthcare provider and patient should discuss
what blood components and blood derivatives (for example
clotting factor concentrates) would be acceptable to the
woman in the event of serious blood loss, and also if autologous transfusion in the form of cell salvage can be used. All
discussions must be clearly documented.
ii). D
This woman is at risk of placenta praevia due to low-lying
placenta at 20 weeks and maternal age. The placental location
should be rechecked at 32 weeks. If it is still low-lying at this
stage, then careful consideration should be given to preparing
for the possibility of major haemorrhage at delivery and to
further investigation to rule out placental invasion (accreta/
percreta).
iii). G
Whatever the aetiology of these repeated bleeds, this patient is clearly at high risk of both significantly preterm delivery and of major blood loss at the time of delivery. While a
number of careful preparations need to be made for this, the
most appropriate from the list is to optimize her haemoglobin
in case of emergency delivery.

Answer 5
C
Meiosis occurs during gametogenesis. An error at this point
will be present in the zygote, from the outset, and will be
found in both twins following division of the embryo.
Answer 6
C
Twin to twin transfusion syndrome does not occur in
dichorionic twins, whatever the zygosity. Preterm membrane
rupture of one sac, autosomal recessive (infantile) kidney
disease in one of the twin pair, and selective fetal growth restriction secondary to placental dysfunction could all cause
one of a twin pair to have markedly reduced liquor volumes.
Oesophageal atresia is a very common feature of VATER
syndrome, a mostly sporadic condition, and this will eventually cause polyhydramnios around the affected twin.
Answer 7
D
All of the above are risk factors for placental abruption with
the exception of conception by IVF. However, the strongest
risk factor for abruption is a previous abruption. There is a 10fold increased risk for mothers who have had one previous
abruption and the risk increases to nearly 25% if a woman has
had two previous abruptions.

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