Thrombocytopenia in pregnancy dx y tx

Diagnosis and management of maternal thrombocytopenia in
pregnancy
Bethan Myers1,2
1
Department of Haematology, Lincoln County Hospital, Lincoln, and 2
Obstetric Haematologist Nottingham University Hospitals,
Nottingham, UK
Summary
Thrombocytopenia is a common finding in pregnancy,
occurring in approximately 7–10% of pregnancies. It may be
a diagnostic and management problem, and has many causes,
some of which are specific to pregnancy. Although most
cases of thrombocytopenia in pregnancy are mild, and have
no adverse outcome for either mother or baby, occasionally
a low platelet count may be part of a more complex disorder
with significant morbidity and may be life-threatening. Over-
all, about 75% of cases are due to gestational thrombocyto-
penia, 15–20% secondary to hypertensive disorders; 3–4%
due to an immune process, and the remaining 1–2% made
up of rare constitutional thrombocytopenias, infections and
malignancies. In this review, a diagnostic approach to inves-
tigating thrombocytopenia in pregnancy is presented,
together with antenatal, anaesthetic and peri-natal manage-
ment issues for mother and baby, followed by a detailed dis-
cussion on the specific causes of thrombocytopenia and the
management options in each case.
Keywords: thrombocytopenia, pregnancy, immune thrombo-
cytopenia, HELLP syndrome, thrombotic thrombocytopenic
purpura.
The platelet count in pregnancy is slightly lower than in
non-pregnant women (Abbassi-Ghanavati et al, 2006). Most
studies report a reduction in platelet count during preg-
nancy, resulting in levels about 10% lower than pre-preg-
nancy level at term (Boehlen et al, 2000; Jensen et al, 2011).
The majority of women still have levels within the normal
range; however, if pre-pregnancy levels are border-line, or
there is a more severe reduction, the level may fall below the
normal range. The mechanisms for this are thought to be di-
lutional effects and accelerated destruction of platelets pass-
ing over the often scarred and damaged trophoblast surface
of the placenta (Fay et al, 1983). Platelet counts may also be
lower in women with twin compared with singleton pregnan-
cies, possibly related to greater increase of thrombin genera-
tion (Sunoda et al 2002).
Thrombocytopenia is a common finding in pregnancy,
occurring in 7–10% pregnancies (Verdy et al, 1997). It may
be a diagnostic and management problem, and has many
causes, some of which are specific to pregnancy.
Women with low platelet counts in pregnancy are gener-
ally less symptomatic due to the procoagulant state induced
by increased levels of fibrinogen, factor VIII and von Wille-
brand Factor (VWF), suppressed fibrinolysis and reduced
protein S activity (Calderwood, 2006).
Although most cases of thrombocytopenia in pregnancy are
mild, with no adverse outcome for mother or baby, occasion-
ally a low platelet count may be part of a complex disorder
with significant morbidity and may (rarely) be life-threatening.
Overall, about 75% of cases are due to gestational throm-
bocytopenia; 15–20% secondary to hypertensive disorders; 3–
4% due to an immune process, and the remaining 1–2%
made up of rare constitutional thrombocytopenias, infections
and malignancies (Burrows & Kelton, 1990). Table I summa-
rizes the causes. Non-pregnancy specific causes will only be
discussed with respect to specific pregnancy-related differ-
ences in management.
Diagnostic approach to investigating throm-
bocytopenia in pregnancy
As for the non-pregnant patient, careful history, examination
and laboratory workup is helpful. An approach to diagnostic
assessment is summarized in Table II, and a suggested
approach to management in the haematology obstetric clinic
setting is presented in Fig 1. The extent of testing for each
woman should be individualized depending on the platelet
count and clinical features.
Antenatal management – general aspects
The key initial assessment is a blood film to confirm that the
thrombocytopenia is genuine and to urgently exclude the
presence of microangiopathy. In those with no adverse
features, antenatal management depends on the extent of the
Correspondence: Dr B. Myers, Department of Haematology, Lincoln
County Hospital, Greetwell Rd, Lincoln LN2 5QY, UK.
E-mail: bethan.myers@ulh.nhs.uk
ª 2012 Blackwell Publishing Ltd First published online 3 May 2012
British Journal of Haematology, 2012, 158, 3–15 doi:10.1111/j.1365-2141.2012.09135.x
review

thrombocytopenia. In general, in women with platelet counts
above 100 9 109
/l, monthly checks by the midwife or general
practitioner are sufficient, with instructions to refer in to the
specialized Haematology Obstetric clinic if platelet counts fall
below 80–100 9 109
/l, or if there is unexplained bleeding or
extensive bruising.
In the first and second trimesters, low platelet counts are
most likely due to an immune process, or rarely, a platelet
production defect. In these cases, a multidisciplinary
approach, involving obstetricians and haematologists antena-
tally, and later anaesthetists and neonatologists, is required
for optimal care.
The aim of antenatal management in these cases is to
achieve and maintain a ‘safe’ rather than normal platelet
count. An experienced team and an individualized approach
are important. Although there are no robust trials, expert
opinion and retrospective studies advise that asymptomatic
patients with immune thrombocytopenia (ITP) and platelet
counts >20–30 9 109
/l do not need any treatment until the
third trimester (Provan et al, 2010). In the rare cases of bone
marrow production defects, such as myelodysplasia, levels
may need to be higher to avoid bleeding as platelet function
may also be impaired, and platelet transfusion may be neces-
sary (Provan et al, 2010). A conservative approach minimizes
the risks to mother and fetus from exposure to therapeutic
agents, such as prednisolone (see below).
Treatment will be necessary during the first two trimesters
if the patient is symptomatic, the platelet count falls below
Table I. Causes of maternal thrombocytopenia in pregnancy.
Pregnancy-specific conditions
Gestational thrombocytopenia ~75% cases, commonest cause of thrombocytopenia in pregnancy
(Burrows & Kelton, 1990)
Hypertensive disorders including
pre-eclampsia
HELLP syndrome
Thrombocytopenia occurs in 50% cases of pre-eclampsia (McCrae et al, 1992)
0·5–0·9% pregnancies (Kirkpatrick, 2010)
Acute fatty liver of pregnancy 1:7000–1:20 000 pregnancies (Knight et al, 2008)
Pregnancy-associated conditions: (not specific but increased association)
Thrombotic thrombocytopenic purpura One in 25 000 pregnancies (Dashe et al, 1998)
Disseminated intravascular coagulation In HELLP syndrome: 20% all cases 84% severe cases (Sibai & Ramadan,
1993; Sibai et al 1993)
In Pre-eclampsia: rarely, in severe cases
Haemolytic uraemic syndrome One in 25 000 pregnancy-associated cases (Fakhouri et al, 2010)
Non-pregnancy associated
Spurious 0·1% general population (Garcia et al, 1991)
Immune thrombocytopenia 0·1–1/1000 pregnancies (Segal & Powe, 2006)
Commonest cause thrombocytopenia in 1st and 2nd trimesters
Hereditary Rare
Marrow disease Very rare
Viral infection Common temporary cause; consider screening for CMV, EBV, hepatitis C.
HIV and hepatitis B are routinely screened in pregnancy
Folate/B12 deficiency
Drugs/hypersplenism
All rare
All rare
HELLP, Haemolysis, Elevated Liver enzymes, and Low Platelets; CMV, cytomegalovirus; EBV, Epstein–Barr virus; HIV, human immunodeficiency
virus.
Table II. Diagnostic assessment of thrombocytopenia in pregnancy.
1. History: record – any previous obstetric experience, neonatal
blood counts; past response to treatment, such as corticosteroids
for immune thrombocytopenia, family history of bleeding,
auto-immune disorders
2. Physical examination: usually normal aside from bleeding
manifestations, these are unusual unless the count is very low.
Check blood pressure (pre-eclampsia), and for abdominal
tenderness (HELLP syndrome)
3. Relevant laboratory tests depend on the stage of pregnancy and
other factors:
(a) At all stages:
Repeat blood count, blood film to confirm thrombocytopenia,
and urgently exclude presence red cell fragments (microangiopathies)
Coagulation screen – care in interpretation as APTT shortens
through pregnancy (DIC) Consider checking auto-immune
profile in selected cases
(b) 2nd trimester onwards: Liver function, haemolysis screen –
(HELLP)
(c) Post-partum: Renal function (HUS/aHUS)
(d) Family history bleeding/thrombocytopenia – von Willebrand
screen for type 2b; blood film for hereditary
macrothrombopathies
(e) Changes in white cell count +/À lymphadenopathy: consider
bone marrow N.B. left shift in white cell series is normal
in pregnancy
HELLP, Haemolysis, Elevated Liver enzymes, and Low Platelets;
APTT, activated partial thromboplastin time; DIC, disseminated
intravascular coagulation; (a)HUS, (atypical) haemolytic uraemic
syndrome.
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4 ª 2012 Blackwell Publishing Ltd
British Journal of Haematology, 2012, 158, 3–15

20–30 9 109
/l or a procedure is required. A platelet count of
50 9 109
/l is usually taken as adequate for procedures (Pro-
van et al, 2010).
The full blood count (FBC) can be checked monthly until the
3rd trimester and then 2-weekly, increasing to weekly as term
approaches (Provan et al, 2010). This pattern should be adjusted
according to the absolute platelet count and the rate of decline.
From 35 to 36 weeks, or prior to any intervention, it is
usual to give treatment to raise the platelet count to at least
50 9 109
/l, and higher levels are advised (usually
! 80 9 109
/l) to enable epidural anaesthesia or analgesia
(see below), although these levels are not evidence-based.
General measures, including avoidance of aspirin, non-ste-
roidal anti-inﬂammatory drugs, and intramuscular injections,
should also be considered depending on the platelet level and
stability. As low dose aspirin is now frequently prescribed in
pregnancy for many indications, this should not be withheld
unless risk of bleeding is considered high.
Perinatal management
Considerations for mother
The main maternal concern is haemorrhage, during delivery
or post-partum. Serious haemorrhage following vaginal deliv-
ery remains uncommon, even with severe thrombocytopenia,
in ITP (Webert et al 2003), but may be of concern post-
natally given the fall in pro-coagulant factors at this time.
Haemorrhage is unusual with platelet counts >50 9 109
/l.
The aim, usually, is to attain a platelet count of ! 80 9 109
/
l, to allow for regional anaesthesia/analgesia, as many anaes-
thetists would not consider an epidural below this level. An
anaesthetic consultation in the third trimester to discuss
options for delivery is helpful.
The mode of delivery should be based on obstetric consid-
erations given there is no evidence that Caesarean section is
safer for the fetus with thrombocytopenia than an uncompli-
↑
↑
⇒
↑
⇒
⇒
Fig 1. Suggested approach to management in the haematology obstetric clinic.
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ª 2012 Blackwell Publishing Ltd 5

cated vaginal delivery, which is usually safer than caesarean
section for the mother.
Where the maternal platelet count remains low
(<50 9 109
/l) around the time of delivery, platelets should
be available on standby, but are likely to be destroyed
quickly after transfusion if due to immune process, so
should be timed judiciously, given in well-established rather
than early labour, if there are increased bleeding complica-
tions.
Anaesthetic management
The decision regarding regional anaesthesia should ideally
made before delivery with an obstetric anaesthetist. Epidural
analgesia is of concern, as even a small increase in venous
haemorrhage has the potential for spinal cord compression.
There is little data to support a minimum ‘safe’ platelet count
and each case must be risk-assessed individually. Patients with
a platelet count >80 9 109
/l in the absence of pre-eclampsia
or additional risk factors are unlikely to have abnormal plate-
let function and most experienced anaesthetists would use
this threshold (van Veen et al, 2010). There are too few
reports of epidural haematoma following regional blockade in
obstetric patients to give an accurate incidence of this compli-
cation (Douglas, 2005). The current international guidelines
on the management of ITP recommend a threshold of
75 9 109
/l, based on expert opinion (Provan et al, 2010).
Some experienced obstetric anaesthetists consider a plate-
let count of 50 9 109
/l to be adequate (Letsky & Greaves,
1996). Spinal anaesthesia may allow a Caesarean section to
be performed without the need for a general anaesthetic, as
the risk of vascular damage is likely to decrease with needle
size.
Considerations for baby
Historically, the major concern regarding delivery in mothers
with thrombocytopenia of undetermined cause has been the
risk of neonatal thrombocytopenia and intracranial haemor-
rhage (ICH). The two main differential diagnoses that may be
difﬁcult to separate until after delivery are gestational throm-
bocytopenia and ITP, as both are diagnoses of exclusion. The
former is considered a completely benign condition for
mother and baby whereas ITP may result in the fetus having
thrombocytopenia from the passage of antibodies across the
placenta. Antibodies produced in ITP are immunoglobulin G
(IgG) in nature and are therefore able to cross the placenta,
with the potential to cause thrombocytopenia in the fetus.
There is variability in percentages reported for neonatal
thrombocytopenia, with 15–50% infants with platelet counts
<100 9 109
/l (Neylon et al, 2003; Ozkan et al, 2010; Gasim,
2011), 8–30% <50 9 109
/l, and 1–5% with severe thrombocy-
topenia (<20 9 109
/l). A recent retrospective study of 11 797
maternal-neonatal pairs found no correlation between indi-
vidual maternal and neonatal platelet counts. However, if the
lowest maternal count was <50 9 109
/l the relative risk of
thrombocytopenia in the neonate was 4·6 [95% conﬁdence
interval (CI) 1·8–33·3], and of severe neonatal thrombocyto-
penia was 7·8 (CI 1·8–33·3) (Jensen et al, 2011).
A history of splenectomy, previously thought to be an
indicator of increased risk of neonatal thrombocytopenia,
has recently been questioned (Cines & Bussel, 2005). After
splenectomy, the maternal platelet count may be normal, but
antibodies are still circulating and the infant may be affected.
Maternal ITP refractory to splenectomy correlates with a
higher risk of ICH in the fetus or neonate (Koyama et al,
2012).
Neonatal thrombocytopenia is more likely if there is a sib-
ling with thrombocytopenia (Christiaens et al, 1997). Percu-
taneous umbilical cord sampling can be performed to
measure the fetal platelet count prior to delivery, but is not
recommended, as it carries a fetal mortality risk of 1–2%, at
least as high as that from ICH (Scioscia et al, 1988).
In contrast to neonatal alloimmune thrombocytopenia, in
maternal ITP, neonatal platelet counts are rarely <10 9 109
/
l. The most feared form of severe bleeding, ICH, has a very
low risk (0–1·5%), and this risk is not increased by vaginal
delivery (Samuels et al, 1990; Payne et al, 1997). In addition,
most haemorrhagic events in neonates occur 24–48 h post-
partum at the nadir of the platelet count. Current guidelines
therefore recommend that the mode of delivery is deter-
mined by obstetric indications, with avoidance of procedures
associated with increased haemorrhagic risk to the fetus: fetal
scalp electrode/samples, ventouse and rotational forceps
(Cines & Bussel, 2005).
A cord sample should be taken to check neonatal platelet
count, and intramuscular injection of vitamin K deferred
until the platelet count is known. Consider giving orally if
the platelet count is <50 9 109
/l. Infants with subnormal
counts should be monitored, as platelet counts tend to fall
to a nadir on days 2–5 after birth (Burrows & Kelton,
1990) In those infants with a platelet count <50 9 109
/l at
delivery, transcranial ultrasonography is recommended even
if the neonate is asymptomatic. Treatment of the neonate is
rarely required, but in those with clinical haemorrhage or
platelet counts <20–30 9 109
/l, treatment with intravenous
immunoglobulin (IVIG) 1 g/kg produces a rapid response,
usually by 24 h (Ballin et al, 1988). Life-threatening haem-
orrhage is treated with platelet transfusion combined with
IVIG.
As severe thrombocytopenia in neonates due to maternal
ITP is rare, when it occurs, testing for parental platelet anti-
gen incompatibility [check parental human platelet antigen
(HPA) status] is recommended to exclude feto-neonatal allo-
immune thrombocytopenia.
Neonatal thrombocytopenia secondary to maternal ITP
may occasionally last for months and, in these cases, moni-
toring and, occasionally, further doses of IVIG are needed.
Review

Specific conditions causing thrombocytopenia
in pregnancy and their management: isolated
thrombocytopenia
Gestational thrombocytopenia
Gestational thrombocytopenia is the commonest cause of
thrombocytopenia in pregnancy (75% of cases), and is not
associated with any adverse events for either mother or baby
(McCrae et al, 1992; Verdy et al, 1997). It is a diagnosis of
exclusion, generally causes only mild thrombocytopenia, and
occurs in the latter half of pregnancy, from mid-second or
third trimester. Table III summarizes the main features of ges-
tational thrombocytopenia. Most experts consider this diagno-
sis less likely if the platelet count dips below 70 9 109
/l; the
main differential diagnosis at this level or lower is ITP. How-
ever, there are reports of more severe thrombocytopenia that
showed no response to steroids, and which resolved postna-
tally, consistent with gestational thrombocytopenia (Win et al,
2005). It is not possible to differentiate between the more
severe form of gestational thrombocytopenia, and ITP, as both
are diagnoses of exclusion. The degree of thrombocytopenia is
not generally low enough to increase risk of bleeding at deliv-
ery, but may compromise the ability to receive epidural anaes-
thesia (see below). Some suggest that a short trial of
prednisolone (generally 20 mg/d) may be helpful diagnosti-
cally and therapeutically when the platelet count is around 50–
70 9 109
/l (McCrae, 2010).
The maternal platelet count normalizes shortly after deliv-
ery, usually very quickly, but within 1–2 months in all cases.
Immune thrombocytopenia
Primary immune thrombocytopenia (ITP) occurs in 1/1000–
1/10 000 pregnancies, accounting for around 3% of women
thrombocytopenic at delivery (Gill & Kelton, 2000; Segal &
Powe, 2006). Although an uncommon cause of thrombocyto-
penia in pregnancy, it is the commonest cause of a low plate-
let count in the first and second trimesters (Gill & Kelton,
2000). A recent consensus group meeting recommended
using a platelet count of <100 9 109
/l to define ITP (Provan
et al, 2010). Most studies report two-thirds of women with
ITP have pre-existing disease, and one-third are diagnosed
for the first time in pregnancy (Webert et al 2003). Despite
improved understanding of the pathophysiology, there is no
specific diagnostic test and, like gestational thrombocytope-
nia, it remains predominantly a diagnosis of exclusion. Dif-
ferentiating ITP from alternative causes of thrombocytopenia
encountered in pregnancy can therefore sometimes present a
diagnostic challenge. The presence of other autoimmune
phenomena or a low platelet count pre-pregnancy may help
diagnostically.
Although some studies report exacerbation or relapse of
ITP during pregnancy (Fujimura et al, 2002), others found
no increase in relapse rate in those with a history of severe
ITP (Baili et al, 2009). There are also conflicting reports
from studies on maternal and perinatal outcomes. Belkin
et al (2009) reported a significant association with adverse
outcomes for mother and baby: hypertensive disorders and
diabetes mellitus, pre-term delivery (<34 weeks) and perina-
tal mortality when compared with patients without ITP.
Most other studies have reported a favourable outcome
for neonates and mothers (Ozkan et al, 2010; Gasim, 2011;
Fujita et al 2010). This may reflect differing approaches to
treatments. Current recommendations for management are
based on experience and expert-consensus (Provan et al,
2010).
Specific treatments for ITP
Primary treatment options for maternal ITP are corticoster-
oids and intravenous IVIG (Letsky & Greaves, 1996; Provan
et al, 2010). The decision regarding therapy depends on the
urgency of the platelet increment, the duration the increment
is required for and potential side effects, and should be made
on an individual patient basis.
ITP patients with moderate/severe thrombocy-
topenia (<20–30 9 109
/l)
The usual first-line treatment is prednisolone, but at much
lower doses than used out with pregnancy, 10–20 mg daily
for a week, adjusting to the minimum dose that achieves a
haemostatically effective platelet count (Provan et al, 2010).
Response time is as for non-pregnant women, 3–7 d, as is
response rate. Maternal risks include inducing or exacerbat-
ing gestational diabetes, maternal hypertension, osteoporosis,
weight gain, and psychosis. Platelet count may fall more rap-
idly near term, so defer dose adjustment until after delivery,
and then taper slowly to avoid a rapid fall in platelet count
and to ensure the mother’s psychological state is not
affected.
In the short term, low-dose steroids are considered safe and
effective for the mother. However, low dose maternal steroids
do not have any beneficial effect on the fetal platelet count
(Christiaens et al, 1990). Prednisolone is metabolized by the
placenta but high doses have the potential to cause effects on
the fetus including premature rupture of membranes, adrenal
suppression, and a small increase in cleft lip after use in the
first trimester (Ostensen et al, 2006; Gisbert, 2010).
Table III. Features of gestational thrombocytopenia.
1. No specific diagnostic test; diagnosis of exclusion
2. Causes mild thrombocytopenia, usually >70 9 109
/l
3. Not associated with maternal bleeding
4. No past history of thrombocytopenia outside pregnancy
5. Occurs in mid second/third trimester
6. No associated fetal thrombocytopenia
7. Spontaneous resolution after delivery
8. May recur in subsequent pregnancies
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ITP patients with very severe thrombocyto-
penia ( 10 9 109
/l) or significant bleeding
Intravenous immunoglobulins are used in similar dosage to
the non-pregnant population with comparable response rates
(Provan et al, 2010). Some pregnant women tolerate high
dose IVIG poorly. IVIG has the same potential side effects as
in the non-pregnant population. Duration of response is
short, usually lasting 2–3 weeks, and repeated infusions may
be needed to prevent haemorrhagic complications and attain
an adequate platelet count for delivery.
In life-threatening bleeding platelet transfusion plus com-
bination treatment with IVIG and a pulse of methyl prednis-
olone (0·5–1 g/d for 3 d) is necessary.
Intravenous anti-D at a dose of 50–75 lg/kg has been
used in non-splenectomized Rh (D)-positive patients. Experi-
ence is limited: some describe positive results with response
rates comparable to IVIG with the advantage of bolus
administration (Michel et al, 2003); however, complications,
though uncommon, may be life-threatening, and monitoring
is required for neonatal jaundice, anaemia and direct anti-
globulin test positivity after delivery. Therefore this is best
avoided until further safety data is available. This product is
currently unavailable in the UK.
Management of refractory ITP cases: - azathioprine,
ciclosporin, splenectomy, rituximab, thrombopoietin
receptor agonists
Occasionally, a patient may be refractory to standard treat-
ments. In these circumstances, a bone marrow examination
is indicated to exclude rare alternative diagnoses (see
Table I). For pregnant patients with refractory disease, the
options are limited by the toxic and teratogenic effects of
cytotoxic agents. Vinca alkaloids, cyclophosphamide and
androgen analogues should not be used. For other treat-
ments, listed below, the balance of risks of bleeding versus
potential toxic effects of more aggressive therapies needs to
be assessed on an individual basis.
Azathioprine. Older data available for pregnancy use of aza-
thioprine in systemic lupus erythematosus and renal trans-
plantation suggested that it is safe during pregnancy
(Erkman & Blythe, 1972; Price et al, 1976), and this is sup-
ported by a consensus paper (Provan et al, 2010). Recent
studies suggest a possible association between azathioprine
and intrauterine growth restriction and preterm delivery
(Cleary & Kallen, 2009; Gisbert, 2010), although it remains
unclear whether these outcomes are manifestations of the
underlying disease. The US Federal Drug Administration
(FDA) states: ‘Positive evidence of fetal risk is available, but
the benefits may outweigh the risk if life- threatening or seri-
ous disease.’ (Category D) (http://depts.washington.edu/drug-
info/Formulary/Pregnancy.pdf). Despite this, it has been used
successfully in pregnant patients for many years. The very
delayed onset of action limits its use as a steroid-sparing
agent in pregnancy.
Ciclosporin A. Ciclosporin A has not been associated with
significant toxicity to mother or fetus during pregnancy.
Data mainly comes from its use in transplant and inflam-
matory bowel disease, and show no association with con-
genital abnormalities or premature delivery (Reindl et al,
2007; Reddy et al, 2008). As hypertension is a common
side-effect, and seizures have been reported, it is not often
used, but could be considered for refractory cases (Provan
et al, 2010).
Splenectomy. This is very rarely necessary during preg-
nancy. When considered essential, the standard recommen-
dation is that it is best performed in the second trimester
(Provan et al, 2010). It may be performed laparoscopically
but the technique may be difficult beyond 20 weeks’ gesta-
tion. Pre-splenectomy immunizations can be safely given in
pregnancy, as all of the pre-splenectomy vaccines required
are inactivated. However, the British National Formulary
(BMJ Publishing Group, 2011; Joint Formulary Committee,
2011) recommendation is that inactivated vaccines should
be administered only if protection is required without
delay.
Rituximab. There is limited information regarding the anti-
CD20 monoclonal antibody, rituximab, in pregnancy. The
manufacturer recommends that women of reproductive age
avoid pregnancy during treatments and for 12 months fol-
lowing treatment. It has been assigned to pregnancy category
C by the FDA, which states: ‘animal studies have not been
conducted (or adverse results reported), and there are no
controlled data in human pregnancy’ (http://depts.washing-
ton.edu/druginfo/Formulary/Pregnancy.pdf). One study iden-
tified 153 pregnancies associated with maternal rituximab
exposure for varied indications, with known outcomes, from
which there were 90 live births; of these, there were 22 pre-
mature births, one neonatal death (6 weeks), 11 haematolog-
ical abnormalities (no infections), and two congenital
malformations (clubfoot in one twin, and cardiac malforma-
tion in a singleton) (Chakravarty et al, 2011). One maternal
death from pre-existing autoimmune thrombocytopenia
occurred. It is difficult to draw firm conclusions from this
review as the maternal conditions were serious and likely to
have an adverse effect on pregnancy outcome. There are sev-
eral reports of good outcome when rituximab was used for
ITP in the 2nd/3rd trimesters of pregnancy (Gall et al, 2010;
Schmid et al, 2011).
Rituximab crosses the placenta and may cause a delay in
neonatal B-lymphocyte maturation. This seems to normalize
at between 4 and 6 months postpartum, and the reports to
date have not described any significant clinical consequences
(Klink et al, 2008; Gall et al, 2010).
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Thrombopoietin receptor agonists. There is no clinical infor-
mation in pregnancy about the new thrombopoietin receptor
agonists, romiplostim and eltrombopag. Animal studies have
shown evidence of thrombocytosis, post-implantation losses,
and an increase in mortality with romiplostim (http://www.
medicines.org.uk/emc/medicine/23117/SPC#PREGNANCY).
Both drugs are classified as category C in pregnancy (see
above).
ITP and venous thromboembolism (VTE) pro-
phylaxis
There are a number of studies that suggest that ITP confers a
prothrombotic state, (Severinsen et al, 2011). Thrombopro-
phylaxis risk assessment should be carried out as normal,
and thromboprophylaxis considered unless the platelet count
is <50 9 109
/l or there is bleeding (Provan et al, 2010).
Below this level, discussion with a haematologist with experi-
ence in this area should be sought regarding thrombopro-
phylaxis.
Pre-pregnancy counselling
Women with an established diagnosis of ITP who wish to
become pregnant should be offered pre-pregnancy counsel-
ling. Table IV summarizes the relevant issues that should be
addressed. In general, pregnancy should not be discouraged,
but the risks of possible relapse or worsening of ITP, possible
need for treatment, risks of haemorrhage and neonatal
thrombocytopenia should be discussed.
Hypertensive and microangiopathic disorders
of pregnancy: thrombocytopenia + micro-
angiopathy
These include the hypertensive disorders pre-eclampsia,
HELLP (Haemolysis, Elevated Liver enzymes, and Low Plate-
lets) syndrome (see below), haemolytic uraemic syndrome
(HUS) and thrombotic thrombocytopenic purpura (TTP).
There is overlap between these conditions with the common
features of thrombocytopenia and microangiopathy, which
may cause considerable diagnostic difficulties. Typical charac-
teristics of each are shown in Table V, which may help dis-
tinguish between them. Diagnosis can be especially
problematic post-natally, because all the conditions may
present in the immediate postnatal period. However, delay in
diagnosis, especially in TTP, is rapidly life-threatening, and
so where there is diagnostic uncertainty, immediate referral
to a centre with expertise is advised, for consideration of
plasma exchange (PEX).
Pre-eclampsia/toxaemia (PET)
PET affects 6% of all first pregnancies. Criteria for the diag-
nosis include: new-onset hypertension with ! 140 mmHg
systolic or ! 90 mmHg diastolic after 20 weeks’ gestation
together with proteinuria (ACOG Committee on Practice
Bulletins–Obstetrics, 2002). It is characterized by multisystem
involvement, with systemic endothelial dysfunction affecting
many organ systems, especially the kidney (Mirza & Cleary,
2009), together with activation of the coagulation system.
Thrombocytopenia is the commonest abnormality, occurring
in up to 50% of women with pre-eclampsia, and the severity
parallels the PET. The hypercoagulability of normal preg-
nancy is accentuated, even when platelet counts appear nor-
mal. PET also affects the liver, with elevated aspartate
aminotransferase and lactic dehydrogenase levels, although
increments are small, except when the HELLP syndrome su-
pervenes. The pathogenesis is thought to be due to inade-
quate placentation. Elevated levels of various growth factors
are present in ‘pre-eclamptic’ placentae from late first trimes-
ter, characterized as vascular endothelial growth factor recep-
tor type1 (Maynard et al, 2005) and endoglin, a tumour
growth factor-b receptor derived from the endothelium
(Venkatesha et al, 2006). There is decreased nitric oxide pro-
duction and endothelial dysfunction as a result of interaction
of these with placental growth factor (Myatt & Webster,
2009).
Due to the other well recognized features of this condi-
tion, thrombocytopenia in PET is unlikely to be confused
with the previously described conditions. However, there
may be overlap with the HELLP syndrome.
HELLP syndrome
The HELLP syndrome is a serious complication specific to
pregnancy characterized by: Haemolysis, Elevated Liver
enzymes, and Low Platelets. It occurs in about 0·5–0·9% of
pregnancies and in 10–20% of cases with severe pre-eclamp-
sia (Kirkpatrick, 2010). A 70% of cases develop antenatally,
usually in the third trimester, and the remainder within 48 h
Table IV. Key points in pre-pregnancy counselling for women with
immune thrombocytopenia (ITP).
1. Explain that ITP may worsen or relapse during pregnancy
2. Up to one-third of women require treatment in pregnancy,
especially peri-natally
3. Detail treatments for ITP, their side-effects and risks to mother
and baby
4. Explain increased risk of bleeding, but this risk is small, even
with a very low platelet count
5. Epidural analgesia/anaesthesia may not be possible, but anaesthetic
review will be arranged to discuss alternatives
6. Serious adverse maternal outcomes are very rare
7. Maternal platelet count is not predictive of the baby’s platelet
count
8. The risk of severe haemorrhage, such as intracranial haemorrhage,
for the fetus/neonate is very low and is not reduced by caesarean
section
9. Explain measures that are put in place to minimize trauma to
baby’s head at delivery
Review

after delivery. The syndrome can occur without proteinuria
(25%) or hypertension (40%), and the diagnosis may then
be missed. Presenting features are often vague, with nausea,
malaise and upper abdominal pain. There should be a low
threshold for checking blood count and liver function. The
pathophysiology is similar to that of pre-eclampsia, with
endothelial damage and release of tissue factor and coagula-
tion activation. A recent study identified mutations in genes
that regulate the alternative complement system in four of 11
patients with HELLP, suggesting that excessive complement
activation may be involved in the pathogenesis (Fakhouri
et al, 2008), similar to atypical HUS. Haemolytic anaemia,
thrombocytopenia and red cell fragments are characteristic,
secondary to the endothelial damage. Liver function shows
raised liver enzymes, and disseminated intravascular coagula-
tion (DIC) complicates >80% severe cases. This is a progres-
sive condition and serious complications are frequent.
Abdominal pain reflects obstructed blood flow in hepatic
sinusoids, with the development of hepatic necrosis. Medical
stabilization, with blood products, followed by delivery, is
indicated if HELLP occurs after the 34th week or the fetal
and/or maternal conditions deteriorate. Vaginal delivery is
preferable. Conservative management for very early HELLP is
controversial, with need for risk-benefit assessment between
gaining extra time for the baby versus maternal risks. Close
surveillance of the mother should be continued for at least
48 h after delivery, as the process may worsen before
improvement occurs.
The severity and frequency of complications for mother
and infant was shown in a study by Celik et al (2003), who
reported 36% incidence of acute renal failure, 17% placental
abruption, 6% DIC, one case of adult respiratory distress
syndrome, and two (of 36) patients died. Intrauterine death
occurred in 19% and 30% of birth-weights were below
1·5 kg. Five of 11 babies died in the neonatal period. Several
studies have reported the rarer complications of hepatic rup-
ture and liver transplantation (Zarrinpar et al 2007; Smyth,
2011). These emphasize the need for prompt recognition of
HELLP syndrome, close observation and transfer to obstetric
centres with expertise in this field, and a multidisciplinary
approach to improve materno-fetal prognosis.
Thrombotic thrombocytopenic purpura (TTP)
The reader is referred to the newly updated British Commit-
tee for standardization in Haematology (BCSH) TTP guide-
line (Scully et al, 2012) for detailed diagnostic and
management information.
TTP is a life-threatening condition characterized by micro-
angiopathic haemolytic anaemia, thrombocytopenia, fever,
neurological abnormalities and renal dysfunction, due to a
deficiency of VWF cleaving protein, ADAMTS13. The coagu-
lation screen is normal in TTP, and may help to differentiate
it from other microangiopathies. TTP is more common in
women (3:2), and nearly 50% cases occur in women of child
bearing age. TTP occurs in approximately one in 25 000
pregnancies. Unlike HELLP, it is not specific to pregnancy,
but occurs with increased frequency in association with preg-
nancy, in 5–25% of cases (Vesely et al, 2004; Scully et al,
2008). In one series, 55% of cases occurred in the second
trimester (Sadler, 2008). There is a risk of relapse during
subsequent pregnancies, although women with normal levels
of ADAMTS13 pre-pregnancy have a lower risk of relapse
(Ducloy-Bouthors et al, 2003; Scully et al, 2006).
There is a normal drift down of ADAMTS13 levels in the
2nd and 3rd trimesters of pregnancy, resolving post-partum
(Sanchez-Luceros et al, 2004).
Management of TTP in pregnancy
Any delay in treatment for TTP is life-threatening for mother
and baby; treatment with PEX should be commenced with-
out delay. Regular PEX may enable pregnancy to continue
successfully (Scully et al, 2006). The optimal frequency of
Table V. Hypertensive and microangiopathic disorders of pregnancy: usual characteristics.
Characteristic TTP HUS HELLP Pre-eclampsia AFLP APS SLE
Onset Any time Postpartum Third trimester Third trimester Third trimester Any time Any time
Hypertension No No +/À +++ +/À ± ±
MAHA +++ ++ ++ +/À + À/± ±/+++
Thrombocytopenia +++ ++ ++ +/À +/± + +
DIC No +/À ++ +/À +++ ± ±
Liver disease +/À +/À +++ +/À +++ À ±
Renal disease +/À +++ + + ± ± +/++
CNS disease +++ +/À +/À +/À ± + +
Management Plasma
exchange
Supportive Deliver fetus,
blood
products
Deliver fetus Correct metabolic
defect
Deliver fetus
LMWH
Aspirin
Aspirin
(LMWH)
(Hydroxy-chloroquine)
AFLP, acute fatty liver of pregnancy; APS, antiphospholipid syndrome; CNS, central nervous system; DIC, disseminated intravascular coagulation;
HELLP, haemolysis, elevated liver enzymes and low platelet count syndrome; HUS, haemolytic uraemic syndrome; MAHA, microangiopathic hae-
molytic anaemia; SLE, systemic lupus erythematosus; TTP, thrombotic thrombocytopenic purpura.
Reproduced with permission from Myers (2009).
Review

PEX during pregnancy is unknown. Where possible, delivery
is the treatment of choice for pregnancy-associated microan-
giopathies, however delivery does not guarantee remission
(Hovinga & Meyer, 2008).
The recommendations for pregnancy management from
the 2012 guideline are:
1 If a thrombotic microangiopathy (TMA) cannot be
explained by a non-TTP pregnancy-related TMA, then the
diagnosis of TTP must be considered and PEX started.
2 Mothers with congenital TTP should attend a specialist
centre and receive ADAMTS13 supplementation regularly
throughout pregnancy and post-partum.
3 Close liaison with an obstetrician with a special interest in
feto-maternal medicine is required in mothers with TTP.
Serial fetal monitoring with uterine artery dopplers should
be used to assess fetal growth and placental blood flow.
4 In mothers with acquired TTP, ADAMTS13 activity
should be monitored throughout pregnancy to help pre-
dict the need for adjuvant therapy and outcome.
5 Pre-conceptual counselling is advised for subsequent preg-
nancies.
Counselling women – risk of recurrence
The rarity of the condition and possible reporting bias makes
precise advice difficult. In one study, following a pregnancy-
associated event, the risk of recurrence was 50%, with a live
birth rate of 67% (Vesely et al, 2004). Prophylactic treatment
with PEX in subsequent pregnancies may be appropriate, on
a fortnightly basis. The baseline ADAMTS13 level in early
pregnancy may be useful in predicting likelihood of relapse,
and hence help to guide use of PEX. Reduction in ADAM-
TS13 activity (<10%) in early pregnancy may require elective
therapy.
Supportive therapy: This is a prothrombotic condition
and thromboprophylaxis with low molecular weight heparin
(LMWH) is recommended once the platelet count is
>50 9 109
/l (Yarranton et al, 2003). Red cell transfusions
and folate supplementation are required during active hae-
moylsis. The clinical efficacy of antiplatelet agents in TTP is
unproven in terms of response rate in recent trials (Bobbio-
Pallavicini et al, 1997) but it is relatively safe, and may help
to reduce placental thrombosis.
Haemolytic uraemic syndrome (HUS)
HUS is a microangiopathy similar to TTP, but with predom-
inant renal involvement. An atypical form is usually seen in
association with pregnancy, with no evidence of infection.
Although most patients with HUS have renal insufficiency as
the prominent component, there is still considerable overlap
with TTP. The levels of ADAMTS13 are generally not
severely reduced, but management decisions must usually be
made before this result is available. A useful clinical feature
distinguishing atypical HUS from TTP is the timing of onset:
most cases of HUS occur several weeks postpartum. There
are recently published guidelines on the diagnosis and man-
agement of atypical HUS and the reader is referred to this
text for more detailed discussion (Taylor et al, 2010).
In one retrospective study of 100 women with atypical
HUS, 21% had experienced pregnancy-associated HUS symp-
toms, of which 79% occurred postpartum. Complement
abnormalities were detected in 90% of the cases with preg-
nancy-related disease. A 76% developed end-stage renal dis-
ease (Fakhouri et al, 2010). The poor outcome in this study
underlines the gravity of this syndrome. There is poor
response to PEX, although a trial of PEX should be under-
taken, especially as the diagnosis may be uncertain between
atypical HUS (aHUS) and TTP. Anticoagulants and antiplat-
elet agents are not beneficial.
Eculizumab, a terminal complement inhibitor, appears a
promising agent for aHUS (Nurnberger et al, 2009). The
most recent study reports sustained normalization of 13/15
aHUS patients with thrombocytopenia and four of five
patients became dialysis-free (Greenbaum et al, 2011).
Eculizumab is approved for use in aHUS in the USA and
reports of eculizumab in pregnancy (in PNH) support its
safety in this setting (Kelly et al, 2010).
Acute fatty liver of pregnancy (AFLP)
AFLP is a rare, serious disorder that presents in the third tri-
mester or postpartum with nausea, vomiting, right upper
quadrant pain and cholestatic liver function. It occurs in
1:7000–1:20 000 deliveries, and still has a maternal mortality
rate of around 15%. Laboratory findings include low platelet
count, prothrombin time, low fibrinogen, and low anti-
thrombin levels in addition to raised bilirubin levels. This
results in a clinical picture similar to DIC; however, in AFLP,
the values are abnormal not due to consumption of the clot-
ting factors but rather to decreased production by the dam-
aged liver. Treatment requires intensive supportive care with
blood product support for the coagulopathy (McCrae, 2006).
Neonatal outcome in microangiopathies
The prognosis for the baby in all the microangiopathies
described is poor, because of extensive placental ischaemia.
Miscellaneous causes of thrombocytopenia not
specific to pregnancy
Disseminated intravascular coagulation (DIC)
Pregnancy-related DIC often presents a dramatic clinical
picture. The obstetric events associated with DIC include pla-
cental abruption, amniotic fluid embolism, and uterine rup-
ture, where there is profound activation of the clotting
system and severe consumption of clotting factors. DIC may,
Review

however, develop more gradually in the case of retained fetal
products, and thrombocytopenia may be the presenting fea-
ture (McCrae & Cines, 1997).
Antiphospholipid syndrome (APS)
A detailed account is presented elsewhere (Myers & Pavord,
2011). Immune thrombocytopenia may be associated with
APS, usually mild, or moderate in degree. In those with pri-
mary or secondary APS, standard management in pregnancy
is to give LMWH and aspirin, which improves neonatal out-
come. Occasionally, the degree of thrombocytopenia may
make this treatment more difficult to achieve. In this circum-
stance, steroids may be required to boost the platelet count,
as the mechanism of the thrombocytopenia in APS is the
same as in ITP. See also Table V.
Familial thrombocytopenias
Inherited thrombocytopenias, such as the May–Hegglin
anomaly, may first come to light in pregnancy. These condi-
tions are usually due to defective platelet production, and,
depending on the level may require platelet transfusion (or
on standby) for delivery. Patients with a bleeding history
should receive tranexamic acid (see below) postpartum. As
there is a risk of neonatal thrombocytopenia, traumatic deliv-
ery should be avoided, and a cord sample taken at birth.
Type 2B von Willebrand disease (type 2B VWD)
This is a rare subtype of VWD, with increased affinity for
platelet receptor glycoprotein 1b, which binds to platelets
inducing spontaneous platelet aggregation, accelerating plate-
let clearance and hence causing thrombocytopenia.
During pregnancy, the abnormal VWF increases and throm-
bocytopenia may become evident or more pronounced, with
the platelet count occasionally falling as low as 20–30 9 109
/l.
Women with type 2B VWD (and other types) should be man-
aged by a multidisciplinary team at a haemophilia centre.
There is variability of response of VWD to pregnancy, and reg-
ular monitoring of the VWF, factor VIII (FVIII) level, and
platelet count is essential. These should be taken at booking,
before invasive procedures, and at 28 and 34 weeks.
Levels of VWF and FVIII should be increased to >50 iu/
dl, to cover any surgical procedures, spontaneous miscar-
riage, and delivery. For delivery, infusion should start at the
onset of established labour, with the aim of maintaining lev-
els >50 iu/dl for ! 3 d after vaginal delivery and ! 5 d after
caesarean section. Platelet transfusions may be required if the
platelet count falls to <20 9 109
/l antenatally, prior to inva-
sive procedures, if bleeding, or if <50 9 109
/l at delivery,
together with the factor replacement. Epidural anaesthesia is
not recommended, as fully normalized coagulation cannot be
guaranteed, even with treatment. Whilst normal vaginal
delivery is the aim, prolonged second stage should be
avoided (as judged by obstetricians), with early recourse to
caesarean section if necessary, to reduce risk of trauma to
mother and baby. Fetal scalp monitoring/sampling, ventouse
and rotational forceps should be avoided. Postpartum, ensure
surgical haemostasis and uterine contraction. Prophylactic
tranexamic acid should be given (Pavord, 2010).
Malignant haematological disorders
These are very rare, and include infiltrative marrow disor-
ders, such as metastatic disease, and bone marrow syn-
dromes, such as myelodysplasia. In some, platelet counts
may also be dysfunctional, making bleeding risk more likely
for any given platelet count. This is one of the few indica-
tions for a bone marrow during pregnancy to clarify the
diagnosis and plan appropriate management. The manage-
ment plan will depend on the exact diagnosis and stage of
pregnancy, and the risk to the mother of delay in treatment
if deferred until after delivery. Neonates may also be at risk
of low platelet counts.
Nutritional deficiencies
Severe deficiency of either folic acid or vitamin B12 may
cause low platelet counts, usually accompanied by a low red
and white cell count. However, both are rare in pregnancy.
Folic acid supplementation preconceptually and in early
pregnancy is recommended to reduce risk of neural tube de-
formatities, and has reduced the deficiency as a cause of FBC
changes. Vitamin B12 deficiency is rare in pregnancy because
those with established B12 deficiency are subfertile. B12 levels
may be difficult to interpret in pregnancy; in standard labo-
ratory testing, the levels fall during pregnancy due to changes
in protein binding.
Medication
Although there is less use of drugs in pregnancy, medication
should always be considered as a possible cause of thrombo-
cytopenia.
Heparin-induced thrombocytopenia (HIT) has been
described, very rarely, in pregnancy. Greer and Nelson-Piercy
(2005) reviewed prophylactic dose of LMWH use during
2777 pregnancies and identified no cases of HIT, and only
one possible case was reported in another three studies
(Warkentin et al, 2008); therefore routine monitoring is not
recommended for prophylactic doses in pregnancy. The
BCSH guideline recommends monitoring when therapeutic
doses are used, or when unfractionated heparin is used. In
this case the occurrence of HIT is still uncommon (0·1–1%:
Lee & Warkentin, 2007). HIT is an intensely thrombotic pro-
cess, despite the low platelet count and, after stopping hepa-
rin, alternative anticoagulation is needed to avoid thrombotic
risk. The alternative drugs used for HIT include lepirudin,
danaparoid and more recently, fondaparinux. Danaparoid
Review

sodium is a heparinoid, distinct from heparin and thus has
little cross-reactivity. It does not cross the placenta and is
not secreted in breast milk. There are anecdotal reports of its
use in pregnancy (Myers et al, 2003; Gerhardt et al, 2009).
Fondaparinux is not licensed for use in HIT, but due to the
ease of use and favourable outcomes of its use in HIT out-
side pregnancy, there are occasional reports of use in preg-
nancy, for women with allergy to LMWHs and, in one case
of HIT, following use of unfractionated heparin in pregnancy
(Ciurzynski et al, 2011). Lepirudin is a synthetic direct
thrombin inhibitor. It crosses the placenta, and should be
avoided in pregnancy, although there are a few case reports
of its use in pregnancy, in the second and third trimesters
(Harenberg et al, 2005).
Tranexamic acid
Tranexamic acid is an antifibrinolytic that is regularly used
outside pregnancy to stabilize clotting in bleeding disorders,
including thrombocytopenia. It crosses the placenta, but has
been used to treat bleeding during pregnancy in a limited
number of cases of type 2B VWD and other bleeding disor-
ders without reported adverse fetal effects (Lindoff et al,
1993). There are no adequate well-controlled trials of its use
in pregnancy and its systemic use should be considered only
in refractory patients with ongoing symptoms after the 1st
trimester. It is a category B drug (Pregnancy Category B –
Animal reproduction studies have failed to demonstrate a
risk to the fetus but there are no adequate and well-con-
trolled studies in pregnant women).
A recent meta-analysis concluded it is safe (with respect to
thrombotic risk) and effective in pregnancy-associated use
(Peitsidis & Kadir, 2011)..
Conclusion
In conclusion, there are a large number of causes of throm-
bocytopenia in pregnancy. By far the most common causes
are mild, but awareness of the complex disorders in which
thrombocytopenia occurs is essential to ensure prompt diag-
nosis and referral into a centre with expertise in these rare
conditions, to optimize outcome for mother and baby.
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