short report

Aplastic anaemia in pregnancy – a single centre, North

American series

Kelly E. McGowan,1 Ann K.

Summary
Malinowski,2,3 Andre C. Schuh,4,5
Wendy Whittle2 and Nadine Shehata6,7 Aplastic anaemia (AA) is infrequently observed in pregnancy. We describe 19 preg-
nancies in 9 women at a tertiary care centre over a period of 30 years. Spontaneous
1
University of Toronto, 2Department of Obstet- resolution of AA did not occur postpartum in the five pregnancies where AA was
rics & Gynecology, Division of Maternal-Fetal first diagnosed in pregnancy. In the remaining pregnancies, although haematological
Medicine, Mount Sinai Hospital, 3Department of indices declined and transfusion support was needed in 35% of pregnancies,
Medicine, Lunenfeld-Tanenbaum Research relapses were not observed. There were no deaths, but complications occurred in
Institute, Mount Sinai Hospital, University of 79% of pregnancies. Preterm delivery and postpartum haemorrhage were observed
Toronto, 4Department of Medicine, University of in 21% and 26% of pregnancies, respectively.
Toronto, 5Division of Medical Oncology and
Keywords: aplastic anaemia, pregnancy.
Hematology, Princess Margaret Cancer Centre,
University Health Network, 6Departments of
Medicine, Pathology and Laboratory Medicine,
University of Toronto, and 7Division of Hema-
tology, Mount Sinai Hospital, Toronto, Ontario,
Canada

Received 19 July 2018; accepted for publication

11 September 2018
Correspondence: Nadine Shehata, Mount Sinai
Hospital, 600 University Avenue, Toronto,
Ontario M5G 1X8, Canada.
E-mail: nadine.shehata@sinaihealthsystem.ca

Aplastic anaemia (AA) is an acquired bone marrow failure syn-
drome characterised by the immune-mediated destruction of
haematopoietic stem cells. Scarce data are available on the clin-
ical presentation, management and treatment of AA in preg-
nancy. We reviewed the clinical outcomes of these patients at
Mount Sinai Hospital, a tertiary care university-affiliated cen-
tre specializing in Maternal-Fetal Medicine in Toronto,
Canada, from 1 January 1990 to 31 January 2018. The Research
Ethics Board at Mount Sinai Hospital approved the study.
In this interval, 24 pregnancies were identified in 12
women with AA. Among these, three women (5 pregnancies)
were excluded from subsequent analysis due to incomplete
records. Among the 19 pregnancies in 9 women, six had at
least one subsequent pregnancy during the study period. The
majority of women had severe (n = 6) or very severe AA
(n = 1) at the time of diagnosis (Camitta et al, 1975).
The initial diagnosis of AA occurred during pregnancy in
five of the 19 pregnancies. The median age at diagnosis of
AA and of pregnancy was 21 and 27 years, respectively. Only
two pregnancies occurred in nulliparous women. Four of the
five pregnancies were diagnosed with AA in the first trime-
ster, while one was diagnosed with AA at 24 weeks’ gesta-
tion. Initial symptoms included fatigue (n = 1), chest pain
due to severe anaemia (n = 1), petechiae (n = 1), hae-
matemesis (n = 1) and, in one pregnancy, the diagnosis was
made following a full blood count performed for routine
prenatal care revealed cytopenias. At the time of diagnosis,
the median haemoglobin concentration was 67 g/l, median
white blood cell count was 3
6 9 109/l and median platelet
count was 26 9 109/l. Two pregnancies had a paroxysmal
nocturnal haemoglobinuria (PNH) clone. Three pregnancies
were treated antenatally with ciclosporin and one with pred-
nisone alone, all without a response (Table I). Transfusion
support was required in all pregnancies.
There were no spontaneous remissions of AA postpartum.
Following delivery, three women underwent allogeneic bone
marrow transplant (alloBMT) and two had uncomplicated
outcomes with resolution of cytopenias. Following alloBMT,
the third transplanted patient developed disseminated nocar-
diosis (brain and lung), renal dysfunction secondary to

ª 2018 British Society for Haematology and John Wiley & Sons Ltd doi: 10.1111/bjh.15654
Short Report

Table I. Definitions of response.

Response category Definition

Complete response Haemoglobin concentration >120 g/l, neutrophil count ≥1
5 9 109/l, platelet count ≥150 9 109/l and no need for
transfusion
Partial response Not fulfilling haematological criteria for complete response but did not require transfusion and had no evidence of
paroxysmal nocturnal haemoglobinuria or myelodysplastic syndrome
Relapse Decrease in blood counts to a platelet count <20 9 109/l or to counts necessitating regular red blood cell or platelet
transfusion. Patients who needed transfusions only during delivery and had sustained platelet counts >20 9 109/l were
not considered to have relapsed

ciclosporin, acute graft-versus-host disease of the gastroin- Table II. Adverse events and outcomes of 19 pregnancies with aplas-
testinal tract and liver, pericarditis, iron overload and trans- tic anaemia.
fusion dependency. Pregnancies
Of the 14 pregnancies with a prior diagnosis of AA, four preg- Adverse event (n)
nancies occurred after an alloBMT. At the time of pregnancy,
four were in complete remission (CR), six were in partial remis- Secondary to infection
Febrile neutropenia 1
sion (PR), two had a PNH clone, one was not in remission and
Klebsiella bacteraemia 1
the status of AA was missing in one pregnancy. A PR was
Severe genital HSV 1
achieved prior to two pregnancies with ciclosporin, which was Secondary to medications
maintained throughout pregnancy. One pregnancy was treated CsA-induced gingival hyperplasia 2
with a one-month trial of prednisone (1 mg/kg) in the third tri- CsA-associated hepatotoxicity 1
mester, along with 4 days of IVIG, without a response. The med- Corticosteroid-induced hyperglycaemia 1
ian haemoglobin concentration, leucocyte count and platelet Avascular necrosis of the hip secondary 2
count in the first trimester were 118 g/l, 3
8 9 109/l and to corticosteroids
92 9 109/l, respectively. Transfusion support was required in five Acute kidney injury secondary to CsA 2
(35%) of these pregnancies. Relapses were not observed among Secondary to thrombocytopenia
the 10 pregnancies in CR or PR at the onset of pregnancy. Epistaxis 2
Postpartum haemorrhage 4
There were no maternal deaths, yet there were consider-
Thrombosis
able morbidities in 15 of the 19 (79%) pregnancies
Cerebral vein thrombosis 1*
(Table II). The four pregnancies that were uncomplicated Hepatic vein thrombosis 1*
were in PR or CR at the time of conception. Most of the Superficial vein thrombosis 1
pregnancies experienced declining haematological parameters. Secondary to transfusion
Several adverse events were secondary to ciclosporin or corti- Iron overload 7
costeroid use (Table II). Postpartum haemorrhage (PPH) Platelet refractoriness 3
(n = 2), thrombosis (n = 2) and infection (bacteraemia) Serious transfusion reaction 1
occurred in four pregnancies with AA and PNH. Allo-immunisation 2
One pregnancy with PPH required uterine artery emboli- Maternal-fetal
sation. Fever developed following platelet transfusion intra- Pre-eclampsia 1
Preterm birth (<37 weeks) 5
partum in an additional pregnancy followed by non-
Spontaneous abortion 1
reassuring fetal status necessitating an emergency Caesarean
section. Of the four patients who had an alloBMT, one had CsA, ciclosporin; HSV, Herpes simplex virus.
genital herpes simplex virus that required hospitalization for *paroxysmal nocturnal haemoglobinuria clone present.
intravenous antiviral therapy, one had a superficial vein
thrombosis and one had a missed abortion of a twin preg- shown in an earlier study (Tichelli et al, 2002) whereas there
nancy. Additionally, a spontaneous abortion occurred in a were no relapses in this series. In the study reported by
pregnancy treated with valganciclovir for reactivation of cyto- Tichelli et al (2002), three of the seven relapsed patients
megalovirus following alloBMT. recovered following pregnancy and three required additional
This large case series provides a comprehensive description immune suppressive therapy, suggesting that CR or PR does
of the outcomes and treatment regimens of pregnant patients not necessarily protect from exacerbation of AA.
with AA at a tertiary care institution in North America. Nonetheless, pregnancy in these patients is not without
Spontaneous resolution of AA did not occur postpartum in complication. A considerable proportion of pregnancies
the five pregnancies where AA was first diagnosed in preg- require transfusion support. Although supportive care is the
nancy, unlike patients previously described (Kwon et al, mainstay of therapy for pregnant patients with AA (Kwon
2006). A relapse rate of 20% in patients with CR or PR was et al, 2006), cytopenias and transfusion are also associated

2 ª 2018 British Society for Haematology and John Wiley & Sons Ltd
 Short Report

with risks that may result in poorer pregnancy outcomes.
The degree of thrombocytopenia has been associated with
poorer obstetrical outcomes, odds ratio 6
8 (95% confidence
interval 2
1–21
8) (Shin et al, 2014) and maternal non-
response to therapy (Chen et al, 2017).
Ciclosporin is considered to be a potential intervention
antenatally (Killick et al, 2016), though it is not the primary
treatment-option in non-pregnant individuals with AA
(Scheinberg & Young, 2012). The safety of ciclosporin during
pregnancy has been established from patients undergoing
solid organ transplantation (Armenti et al, 1994). In our case
series, three pregnancies with newly diagnosed AA did not
respond to ciclosporin and two pregnancies with a previous
partial response to ciclosporin did not require transfusion
support until delivery. Whether ciclosporin maintained the
response cannot be definitely determined. Of the seven
patients reported at other centres who were treated with
ciclosporin, one did not have a response, two continued to
require transfusion support and two were maintained on
ciclosporin and did not require transfusion (Ohba et al, 1999;
Choudhry et al, 2002; Tichelli et al, 2002). A neonate of one
mother treated with ciclosporin who delivered at 31 weeks
developed sepsis. The lack of efficacy of ciclosporin during
pregnancy that we observed may be secondary to a shorter
duration of use i.e. inadequate time to assess response. The
risks of ciclosporin, however, warrant consideration if use is
contemplated during pregnancy, particularly as a considerable
proportion may be managed with supportive care during
pregnancy (Kwon et al, 2006; Shin et al, 2014; Bo et al, 2016;
Jakiel et al, 2016). Discontinuing ciclosporin, however, may
result in reduction in platelet counts (Tichelli et al, 2002).
The PNH clone appears to confer risk in pregnancy
(Tichelli et al, 2002). Complications associated with PNH
previously observed in four patients with clinical PNH
include relapse, increased transfusion dependency, pre-
eclampsia and death following cerebral thrombosis 1 month
after delivery (Tichelli et al, 2002). The presence of a PNH
clone was also associated with morbidities during pregnancy
in our cohort. Eculizumab, which has been observed to
reduce maternal mortality and improve fetal outcomes for
patients with PNH (Kelly et al, 2015) may be an option for
AA with a PNH clone.
The obstetrical complications that occurred in our series
were pre-eclampsia, preterm delivery and spontaneous
abortion. Pre-eclampsia has been described to occur in 2%
to 30% of pregnant patients with AA - the wide range may
reflect differences in classification of this disorder (Tichelli
et al, 2002; Kwon et al, 2006; Shin et al, 2014; Bo et al,
2016; Chen et al, 2017). Our preterm delivery rate of 26%
was comparable to other reports (5–41%) (Tichelli et al,
2002; Kwon et al, 2006; Shin et al, 2014; Bo et al, 2016;
Chen et al, 2017). The variability in rates may reflect
heterogeneity of criteria used to determine need for deliv-
ery.
The use of thrombopoietin mimetics, specifically eltrom-
bopag, has shown promise for non-pregnant patients with
AA. In a pivotal study of 25 patients, 36% patients treated
with eltrombopag no longer required platelet transfusion
support and its use was associated with a median rise in the
platelet count of 44 9 109/l in those who responded, as well
as improvement in other haematological parameters (Olnes
et al, 2012). In rats, eltrombopag, 60 mg/kg/day, was associ-
ated with embryopathy and fetal loss (Nieto et al, 2011).
There are a limited number of pregnant women described
who have been exposed to eltrombopag antenatally, thus
there remains the potential for fetal harm and it is not con-
sidered a standard intervention during pregnancy presently.
The infrequency of patients with AA pursuing pregnancy
supports the need for registries for these patients, as larger
sample sizes are required to clarify the natural history of AA
in pregnancy and best approach to management in order to
reduce the risk of adverse pregnancy outcomes. Equally
important is the need for a multidisciplinary (obstetricians,
haematologists, anesthesiologists, transfusion medicine spe-
cialists) approach with frequent assessments to optimize the
care for these patients.
Author contributions
KS, NS, AKM, designed the study. KS performed the research
and analysed the data. ACS and WW contributed to the
design and data acquisition. KS wrote the first draft of the
paper and all other authors critically reviewed and approved
the final version.
Competing interests
The authors have no competing interests.

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