Received: 2 September 2023 | Accepted: 4 October 2023

DOI: 10.1111/bjh.19161

O R I G I N A L PA P E R

Treatment of immune thrombocytopenia during pregnancy with

thrombopoietin receptor agonists

Amihai Rottenstreich1,2,3,4 | James B. Bussel5

1
Division of Maternal-Fetal Medicine,
Department of Obstetrics and Gynecology,
Zucker School of Medicine at Hofstra/
Northwell, New York, New York, USA
2
Laboratory of Blood and Vascular Biology,
Rockefeller University, New York, New York,
USA
3
Department of Obstetrics and Gynecology,
Hadassah-Hebrew University Medical Center,
Jerusalem, Israel
4
Faculty of Medicine, Hebrew University of
Jerusalem, Jerusalem, Israel
5
Division of Hematology/Oncology,
Department of Pediatrics, Weill Cornell
Medicine, New York, New York, USA
Correspondence
Amihai Rottenstreich, Division of Maternal-
Fetal Medicine, Department of Obstetrics and
Gynecology, Zucker School of Medicine at
Hofstra/Northwell, New York, NY, USA.
Email: amichaimd@gmail.com
Summary
The introduction of thrombopoietin receptor agonists (TPO-RAs) led to a paradigm
shift in the management of immune thrombocytopenia (ITP). However, TPO-RAs
are not approved for use during pregnancy due to the absence of evidence and con-
cerns for possible effects on the fetus due to their expected transplacental transfer.
This comprehensive review examines the safety and efficacy of TPO-RA in 45 preg-
nancies of women with ITP (romiplostim n = 22; eltrombopag n = 21; both in the same
pregnancy n = 2). Mothers experienced failure of the median of three treatment lines
during pregnancy prior to TPO-RA administration. A platelet response (>30 × 109/L)
was seen in 86.7% of cases (including a complete response >100 × 109/L in 66.7%) and
was similar between eltrombopag and romiplostim (87.0% and 83.3%, p = 0.99). The
maternal safety profile was favourable, with no thromboembolic events encountered.
Neonatal thrombocytopenia was noted in one third of cases, with one case of ICH
grade 3, and neonatal thrombocytosis was observed in three cases. No other neonatal
adverse events attributable to TPO-RAs were seen. This review suggests that the use
of TPO-RA during pregnancy is associated with a high response rate and appears
safe. Nevertheless, TPO-RA should not be routinely used in pregnancy and should
be avoided in the first trimester until further evidence is accumulated.

K EY WOR DS
eltrombopag, immune thrombocytopenic purpura, ITP, pregnancy, romiplostim, thrombopoietin
receptor agonists, TPO

I N T RODUC T ION or trauma-induced bleeding, placental abruption and post-

partum haemorrhage (PPH), while newborns of pregnant
Immune thrombocytopenic purpura (ITP) is an acquired women with ITP may experience marked thrombocytope-
autoantibody-mediated disorder characterized by a de- nia in 10%–15% of cases, which rarely results in intracranial
creased platelet count,1 resulting from immune-mediated haemorrhage (ICH).6,9,10
platelet destruction and impaired platelet production.2,3 ITP commonly worsens during pregnancy 9–12; at least
Haemorrhagic manifestations in patients with ITP range one third of mothers with ITP require treatment for throm-
from mild cutaneous bleeding to severe, life-threatening bocytopenia during pregnancy, whether throughout or at a
bleeding events.4–6 point during the course of gestation.9–12 The latter is most
ITP commonly affects women of childbearing age,1,3 commonly a limited usage at the end of the third trimester
occurs in 1 per 1000–10 000 pregnancies, may precede or to provide a sufficient platelet count to ensure a safe delivery.
present during pregnancy,7 and is the most common cause As with non-pregnant patients with ITP, first-line treat-
of severe maternal thrombocytopenia (<50 × 109/L).8 ITP in ment in pregnancy includes corticosteroids and/or intra-
pregnancy is associated with maternal risks of spontaneous venous immunoglobulin (IVIG), although in pregnancy,
Abbreviations: CR, complete response; ICH, intracranial haemorrhage; ITP, immune thrombocytopenic purpura; IVIG, intravenous immunoglobulin; LBW, low birth
weight; PPH, postpartum haemorrhage; SGA, small-for-gestational age; TPO-RAs, thrombopoietin receptor agonists.

© 2023 British Society for Haematology and John Wiley & Sons Ltd.

Br J Haematol. 2023;00:1–14.  wileyonlinelibrary.com/journal/bjh | 1


2 |   
prednisone is greatly preferred over dexamethasone because
of the potential adverse effects of dexamethasone on the
fetus. One report suggests both IVIG and prednisone may be
less effective during pregnancy and may be associated with
various side effects.13
While first-line treatment is reasonably standard, if ad-
ditional treatment is required, no second-line treatment
options are universally accepted. They are either not rec-
ommended during pregnancy (e.g. rituximab, thrombopoi-
etin receptor agonists and splenectomy) or contraindicated
(mycophenolate mofetil, vinca alkaloids, danazol, cyclo-
phosphamide and fostamatinib).7,8 Specifically, rituximab
has some drawbacks, including slow platelet response and
potential risk of prolonged neonatal B lymphocytopenia,
precluding the administration of live-attenuated vaccines
in the first year of life following in utero exposure.8 Several
second-line immunosuppressive treatments are also not
thought to be teratogenic, but none have extensive use in ITP
during pregnancy. Their slow mode of action (e.g. azathio-
prine), risk of hypertension (cyclosporine) and haemolytic
anaemia (dapsone) limit their use in pregnancy, and their
safety data are mostly or almost entirely based on their uti-
lization in other diseases in pregnancy (renal transplant for
azathioprine, inflammatory bowel disease for cyclosporin,
and malaria for dapsone).7,8 Very limited data are available
regarding proceeding with splenectomy in these women,
which is associated with risks of bleeding, infections, throm-
boembolic complications and premature labour.14 Thus, it is
rarely performed and only early in the second trimester in
refractory patients.
In 2008, two thrombopoietin receptor agonists (TPO-
RAs), romiplostim and eltrombopag, were approved in
the United States for the treatment of adults with chronic
ITP by the European Medicine Association (EMA).
Subsequently, they were both approved for the treatment
of children as well. Widespread use of TPO-RAs led to a
paradigm shift in the management of ITP, with a world-
wide increase in their use.15 Despite this, TPO-RAs are
not approved for use during pregnancy by any regulators,
and no prospective studies of either agent have been un-
dertaken. Therefore, recent ITP guidelines do not endorse
their utilization in pregnancy.6,16,17 Both romiplostim, a
peptibody containing an Fc receptor, and eltrombopag, a
small molecule, were shown to cross the placenta in an-
imals, and are expected to cross the placenta in women.
Avatrombopag, another small molecule, and lusutrom-
bopag, are also expected to cross the placenta. In vitro,
thrombopoietin affects the function of decidual cells.18
In non-primate models, exposure to TPO-RA throughout
gestation, at much higher doses than clinically used, was
explored, providing reassuring data in one study,19 while
two high-dose studies reported pregnancy complications
and fetal anomalies. 20,21
Overall, many pregnant women with ITP require sec-
ond-line treatment, but there are drawbacks and/or a lack
of information for the candidates. The impetus to consider
TPO-RA has come from three sources: a Chinese study of 33
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TPO-RA IN PREGNANT WOMEN WITH ITP
pregnancies using a recombinant TPO available in China;
a multicentre retrospective conglomerate of 17 pregnancies;
and a pregnancy surveillance project sponsored by Amgen,
a manufacturer of romiplostim. Given the limitations inher-
ent in these three studies (recombinant TPO is not available
in the United States; retrospective and heterogeneous case
series; and pregnancy surveillance project missing substan-
tial data and lacking information regarding efficacy), we re-
viewed published cases to better delineate the efficacy and
safety profiles of TPO-RA in pregnant patients with ITP.
L I T E R AT U R E SE A RCH
A search of the medical literature was conducted by two
researchers (AR and JBB) to identify publications that de-
scribed the use of TPO-RA in ITP-pregnant patients. We
performed an online search of the MEDLINE (PubMed)
and Embase databases, conducted with both key words and
MESH/EMTREE terms. We also searched Google Scholar
for additional reports. Software EndNote Basic® (Thompson
Reuters, New York, NY) managed all references with the
last search on 1 June 2023. Only English-language, full-
text papers were included. Initially, titles of identified stud-
ies were screened, and abstracts of relevant studies were
read. In addition, abstracts from the American Society of
Hematology (ASH) and International Society of Thrombosis
and Haemostasis (ISTH) annual meetings were reviewed,
and one was included. The reference lists of retrieved articles
were reviewed to identify reports missed in the initial search.
DE F I N I T ION A N D OU TC OM E S
For assessment of platelet response, the International
Working Group criteria were used: complete response (CR)
was defined as a platelet count of at least 100 × 109/L and ab-
sence of bleeding; response as a platelet count greater than
30 × 109/L and an increase to at least twice baseline and ab-
sence of bleeding; and non-response as a platelet count below
30 × 109/L or less than a twofold increase in baseline platelet
count or bleeding.4 The ITP phase was divided into newly
diagnosed, persistent and chronic.4
Assessment of bleeding was performed according to the
Gruppo Italiano Malattie Ematologiche dell'Adulto ITP
Working Party22 and graded as follows: grade 0, absence
of bleeding; grade 1, petechiae; grade 2, ecchymoses and/or
nasal dripping with moderate loss of blood; grade 3, major
mucocutaneous haemorrhage with copious loss of blood
without sequelae; and grade 4, major mucocutaneous and/or
parenchymal haemorrhage with copious loss of blood with
sequelae and/or life-threatening or deadly.
Other outcomes evaluated were: time to platelet response,
adverse events in mothers and neonates, mode of delivery,
preterm birth (<37 weeks), neonatal platelet count, neonatal
bleeding and birthweight. Small-for-gestational-age (SGA)
was defined as <10th percentile (corresponding to 10%

ROTTENSTREICH and BUSSEL
SGA incidence in the general population), according to the
INTERGROWTH-21st project.23 Low birth weight (LBW)
was defined as <2500 g.
Statistical analysis
Patient characteristics are described as proportions for cat-
egorical variables and medians and interquartile ranges
for continuous variables without normal distribution. The
significance between subgroups was assessed using the chi-
square test for categorical variables. The correlation between
maternal and neonatal platelet counts was calculated by
the Spearman test with the correspondent rs and p values.
Results are reported using p-values. A two-sided p-value
<0.05 indicated statistical significance. Data were analysed
using the Software Package for Statistics and Simulation
(IBM SPSS version 25, IBM Corp, Armonk, NY).
R E SU LT S
Twenty-four relevant articles were identified describing 45
pregnancies: an international retrospective study of 15 pa-
tients (17 pregnancies: eltrombopag n = 10, romiplostim n = 7)
and 23 case reports comprising 27 mothers (28 pregnancies:
eltrombopag n = 11, romiplostim n = 15, both eltrombopag
and romiplostim in the same pregnancy n = 2).24–47
Table 1 summarizes maternal baseline characteristics:
The median age was 32 [IQR 27–34] years; the ITP phase at
the onset of pregnancy was primarily chronic (n = 32, 71.1%),
with one persistent case (2.2%) and 12 newly diagnosed cases
(26.7%), with eight of the latter diagnosed during pregnancy.
Secondary ITP with concurrent autoimmune conditions was
seen in 12/42 (28.5%). Twelve (28.5%) had previously under-
gone a splenectomy. In 15/45 pregnancies, there was prior
use of TPO-RA before pregnancy.
Data regarding pregnancy characteristics and outcomes
are described in Table 2. Bleeding prior to TPO-RA admin-
istration was observed in 29 (64.4%) cases: grade 1 (n = 7),
grade 2 (n = 16), grade 3 (n = 5) and grade 4 (n = 1). Mothers
had used a median of 3 [IQR 2–4]) ITP treatments during
pregnancy prior to TPO-RA. Concurrent treatment was
given in 37 pregnancies (82.2%), primarily corticosteroids
and IVIG. Platelet transfusion was administered in 29.4%
(10/34) pregnancies for active bleeding (n = 7) and during
caesarean section (n = 3).
Median doses of romiplostim and eltrombopag were 4 μg/
kg (range 1–10 μg/kg) and 50 mg (range 12.5–100 mg) re-
spectively. Ten women conceived while on TPO-RA (eltrom-
bopag n = 7, romiplostim n = 3); seven (eltrombopag n = 6,
romiplostim n = 1) were ‘unintended’ pregnancies. Among
these 10, TPO-RAs were used throughout gestation in 4 (#3,
#7, #10, #28b). In the remaining six, TPO-RA was withheld
in the first trimester once pregnancy was diagnosed: in two
patients (#2, #35), TPO-RAs were re-introduced (at 10 and
18 weeks gestation, respectively) for a significant platelet
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   | 3
decrease, while in the other four patients (#13, #15, #16, #18),
TPO-RAs were not resumed.
In the 35 pregnancies in which TPO-RAs were introduced
after the beginning of pregnancy, 29 women had TPO-RA
started in the third trimester, six without bleeding. Six oth-
ers started TPO-RA in the second (n = 4) and first trimesters
(n = 2). The median duration of use of TPO-RA in these 35
pregnancies was 4 weeks (IQR 1.5–8).
Median platelet nadir during pregnancy was 7 × 109/L
(IQR 3–12 × 109/L), with 38 (84.4%) mothers having a nadir
<20 × 109/L. Platelet response was observed in 39/45 (86.7%)
pregnancies, above 50 × 109/L in 38 (84.4%), with similar
response rates for eltrombopag (87.0%) and romiplostim
(83.3%); CR was seen in 30 (66.7%) pregnancies. The median
time to platelet response (in 18 cases with available data)
was 1 week (range 1–4 weeks). The six pregnancies with no
response included three with romiplostim (#12, #22, #24;
maximal dose 2, 10, 10 μg/kg), two eltrombopag (#19, #29;
maximal dose 75, 50 mg) and one with both TPO-RA (#36a;
eltrombopag 75 mg, then romiplostim 5 μg/kg), all in the
third trimester. In case #1, following failure to respond to
eltrombopag 75 mg given for 3.5 weeks, romiplostim 3 μg/kg
resulted in a CR. In #36a, following 8 weeks of eltrombopag
75 mg daily, no response was observed to romiplostim (5 μg/
kg); however, in a subsequent gestation, romiplostim was
used at a higher dose (8 μg/kg), leading to a CR.
No maternal antepartum adverse events were reported
except for a mild headache in two patients.35 No thrombo-
embolic events were reported. Primary prophylaxis using
low-molecular-weight heparin was prescribed in two cases
(cases #11, #39), in one because of super obesity (BMI >50),
while in the other, a woman with newly diagnosed ITP, no
specific reason was provided (no personal or family history of
thromboembolism). The remaining patients did not receive
thromboprophylaxis, including #28, who had triple-positive
anti-phospholipid syndrome and received TPO-RA in two
pregnancies (one with eltrombopag 50 mg, one with romi-
plostim 6 μg/kg) without thromboembolism.
There were 47 live births (45 pregnancies, two sets of
twins); no fetal losses, for example miscarriages or intrauter-
ine fetal losses, were described. The mode of delivery was
caesarean in 19 pregnancies and vaginal in 24 cases (missing
n = 2). The rate of preterm birth was 37.2% (16/43) with at
least 11 medically-indicated preterm births. Neuraxial an-
aesthesia was administered in five cases and general anaes-
thesia in five, with this type of anaesthesia reported in only
12 cases. PPH occurred in four cases—two non-responders
to TPO-RA, while the other two had normal predelivery
counts: 369 × 109/L and 160 × 109/L. TPO-RAs were contin-
ued postpartum in 16 cases. Placental infarcts were described
in two cases in which TPO-RAs were used throughout ges-
tation: #10, treated with eltrombopag 12.5 mg with platelet
counts remaining between 200 and 300 × 109/L, who had
concurrent preeclampsia; and #3, treated with romiplostim
3 μg/kg with a maximal platelet count of 60 × 109/L.
Neonatal outcomes are summarized in Table 3. Among 16
newborns with reported birthweight, 9 were LBW with 4/9
 4

TA BL E 1 Baseline characteristics of mothers with ITP treated with TPO-RA during pregnancy.
|

Age, Gravidity, Prior Exposure to TPO-RA

  

Reference (year) number of pregnancies Country Mother, n years parity ITP phase Secondary ITP splenectomy prior to pregnancy
[24] (2012), n = 1 Oman 1 34 G6P5 Newly diagnosed SLE, Evans Syn. No No
[25] (2012), n = 1 USA 2 34 G2P1 Chronic No Yes Yes
[26] (2013), n = 1 USA 3 28 G1 Chronic No No Yes
[27] (2014), n = 2 France 4 34 G2P1 Newly diagnosed Positive ANA No No
5 34 G2P0 Chronic No No No
[28] (2016), n = 1 India 6 27 G5P1LC0 Chronic No No No
[29] (2017), n = 2 USA 7 32 G2P0 Chronic MCTD/SLE Yes Yes
8 26 G1 Newly diagnosed No No No
[30] (2018), n = 1 Iran 9 22 NR Chronic SLE Yes No
[31] (2018), n = 1 Japan 10 25 G3P0 Chronic No No Yes
[32] (2018), n = 1 Portugal 11 33 G1 Chronic Sarcoidosis No No
[33] (2018), n = 1 UK 12 34 G3P0 Newly diagnosed No No No
[34] (2020), n = 1 Italy 13 22 G1 Chronic No Yes Yes
[35] (2020), n = 17 Multi 14a 33 NR Chronic No Yes No
a
14 35 NR Chronic No Yes Yes
15 30 NR Chronic No No Yes
16 36 NR Chronic No No Yes
17 29 NR Chronic No No No
18 21 NR Chronic No Yes Yes
19 29 NR Chronic No No No
20 32 NR Newly diagnosed No No No
21 32 NR Persistent Sjogren syn. No No
22 33 NR Chronic No Yes No
23 24 NR Chronic No Yes No
24 19 NR Chronic No No No
25 36 NR Newly diagnosed No No No
26 38 NR Chronic No Yes No
27 29 NR Newly diagnosed No No No
28a 34 NR Newly diagnosed SLE, triple positive anti- No No
phospholipid syn.
28a 37 NR Chronic SLE, triple positive anti- No Yes
phospholipid syn.
[36] (2020), n = 1 USA 29 35 G2P1 Chronic No No No
TPO-RA IN PREGNANT WOMEN WITH ITP

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 ROTTENSTREICH and BUSSEL

TA BL E 1 (Continued)

Age, Gravidity, Prior Exposure to TPO-RA

Reference (year) number of pregnancies Country Mother, n years parity ITP phase Secondary ITP splenectomy prior to pregnancy
[37] (2020), n = 1 China 30 33 G2P1 Newly diagnosed SLE No No
[38] (2020), n = 1 USA 31 29 G2P1 Chronic SLE No No
[39] (2020), n = 2 Australia 32 31 G1 Chronic No No No
33 27 G1 Newly diagnosed Hypothyroidism, No No
positive ANA
[40] (2020), n = 1 Spain 34 34 G2P1 Newly diagnosed No No No
[41] (2021), n = 1 Italy 35 23 G2P1LC0 Chronic DM1, UC No Yes
[42] (2021), n = 2 Australia 36a 25 G2P0 Chronic No Yes No
36a 27 G5P1 Chronic No Yes Yes
[43] (2022), n = 1 Japan 37 32 G1 Chronic No Yes Yes
[44] (2022), n = 1 Turkey 38 29 Multigravida Newly diagnosed No No No
[45] (2023), n = 2 Qatar 39 20 G2P1 Chronic No No Yesb
40 NR G1 Chronic No No Yes
[46] (2023), n = 1 Canada 41 34 G1 Chronic SLE No No
[47] (2023), n = 1 Japan 42 32 G2P0 Chronic No Yes No

Abbreviations: ANA, anti-nuclear antibodies; DM1, diabetes mellitus type 1; MCTD, mixed connective tissue disease; NR, not reported; SLE, systemic lupus erythematosus; TPO-RA, thrombopoietin receptor agonist; UC, ulcerative
colitis.
a
Second pregnancy occurred in the same mother.
b
Prior exposure to a different TPO-RA than the one used in the index pregnancy.
|   
5

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 6

TA BL E 2 Pregnancy characteristics and maternal outcomes of women with ITP treated with TPO-RA during pregnancy.
|

Platelet count Platelet

  

TPO-RA, nadir/platelet response

Reference maximal dose GA at TPO-RA initiation count after (time to GA at
(year) number Mother, Bleeding during Treatments used prior to Platelet used during (duration of use in TPO-RA prior to response, Mode of delivery, delivery,
of pregnancies n pregnancy TPO-RA transfusion pregnancy pregnancy, weeks) delivery, ×10 9/L weeks)b indication weeks PPH Comments

[24] (2012), n = 1 1 Gum bleeding, Dexamethasone, Yes Romiplostim 30 (4) 3/91 CR (1) VD, ITP 34 No Failure of
haematuria, methylprednisolone, 3 μg/kg eltrombopag
epistaxis, melena, IVIG, anti-D 75 mg
petechiae immunoglobulin,
rituximab,
cyclophosphamide
[25] (2012), n = 1 2 None IVIG No Romiplostim Initiated prior to pregnancy, 5/175 CR (NR) NR NR No
10 μg/kg stopped at 6th week,
resumed at 10th week
until delivery
[26] (2013), n = 1 3 Epistaxis Dexamethasone, IVIG No Romiplostim Initiated prior to pregnancy, 1/300 CR (NR) VD, ITP 33 + 6 No Placental
4 μg/kg used throughout pathology-
pregnancy multiple
infarcts
[27] (2014), n = 2 4 Bruises, gum bleeding Prednisone, IVIG No Romiplostim 17 (21) 4/110 CR (1) VD, spontaneous 39 + 6 No
4 μg/kg
5 Bruises, epistaxis, Prednisone, IVIG No Romiplostim 28 (10) 26/120 CR (1) VD, ITP 38 No
gum bleeding 4 μg/kg
[28] (2016), n = 1 6 Vaginal spotting, Prednisolone, Yes Eltrombopag 28 (7) 18/50 R (3) VD, NR 36 No
conjunctival azathioprine, triple 50 mg
haemorrhage, therapy for H.Pylori
petechiae
[29] (2017), n = 2 7 None Prednisone, IVIG No Romiplostim Initiated prior to pregnancy, 5/369 CR (1) VD, preeclampsia 35 + 5 Yes, late
4 μg/kg used throughout
pregnancy
8 Petechiae Prednisone, No Romiplostim 32 (5) 5/131 CR (1) VD, ITP 37 No
dexamethasone, IVIG, 1 μg/kg
rituximab
[30] (2018), n = 1 9 None Steroids No Romiplostim 3 cycles near delivery NR/164 CR (3 cycles) NR NR No
Dose-NR
[31] (2018), n = 1 10 None Prednisolone, IVIG Yes Eltrombopag Initiated prior to pregnancy, 19/60 CR (NR) CS, preeclampsia 37 NR Placental
12.5 mg used throughout pathology-
pregnancy infarct
[32] (2018), n = 1 11 Petechiae, epistaxis, Methylprednisolone, IVIG, Yes Eltrombopag 27 (3) 3/346 CR (1) VAD, 37 No LMWH primary
bruises, azathioprine 50 mg preeclampsia prophylaxis
conjunctival was used
haemorrhage,
haematuria
[33] (2018), n = 1 12 Petechiae, Prednisolone, IVIG, anti-D Yes Romiplostim 32 (1) 1/37 No response CS, ITP 34 Yes Twin pregnancy
ecchymoses, immunoglobulin, 2 μg/kg
haematuria azathioprine, PEX
[34] (2020), n = 1 13 None None No Eltrombopag Initiated prior to pregnancy, 65/150 CR (NR) VD, spontaneous 39 No
25 mg stopped at 8th week
TPO-RA IN PREGNANT WOMEN WITH ITP

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 TA BL E 2 (Continued)

Platelet count Platelet

TPO-RA, nadir/platelet response
Reference maximal dose GA at TPO-RA initiation count after (time to GA at
(year) number Mother, Bleeding during Treatments used prior to Platelet used during (duration of use in TPO-RA prior to response, Mode of delivery, delivery,
of pregnancies n pregnancy TPO-RA transfusion pregnancy pregnancy, weeks) delivery, ×10 9/L weeks)b indication weeks PPH Comments
a
[35] (2020), 14 None None No Eltrombopag 36 (4) 10/110 CR (NR) NR NR No
n = 17c 50 mg
ROTTENSTREICH and BUSSEL

14a None None No Eltrombopag 36 (2) 9/94 R (NR) NR NR No Twin pregnancy

25 mg
15 Skin+mucosa Yes NR Eltrombopag Initiated prior to pregnancy, 1/123 CR (NR) NR NR No
50 mg stopped at 12th week
16 Skin Yes NR Eltrombopag Initiated prior to pregnancy, 4/114 CR (NR) NR NR No
50 mg stopped at 9th week
17 Skin+mucosa None No Eltrombopag 33 (7) 7/169 CR (NR) NR NR No
50 mg
18 None None No Eltrombopag Initiated prior to pregnancy, 50/68 R (NR) NR NR No
75 mg stopped at 12th week
19 Skin None No Eltrombopag 34 (5) 8/23 No response NR NR No
75 mg
20 Skin None No Eltrombopag 27 (10) 4/64 R (NR) NR NR No
50 mg
21 Skin+mucosa Yes NR Eltrombopag 30 (4) 1/136 CR (NR) NR NR No
100 mg
22 Skin Yes NR Romiplostim 39 (1) 1/6 No response NR NR No
10 μg/kg
23 Skin Yes NR Romiplostim 34 (6) 12/250 CR (NR) NR NR No
10 μg/kg
24 Skin+mucosa Yes NR Romiplostim 32 (1) 2/7 No response NR NR No
10 μg/kg
25 Skin+mucosa Yes NR Romiplostim 37 (1) 5/40 R (NR) NR NR No
7.5 μg/kg
26 Skin+mucosa Yes NR Romiplostim 36 (1) 5/120 CR (NR) NR NR No
3 μg/kg
27 Skin Yes NR Romiplostim 37 (1) 17/21 CR (NR) NR NR No
4 μg/kg
28a Skin, active GI Yes NR Romiplostim 31 (3) 3/367 CR (NR) NR NR No
bleeding, 6 μg/kg
haematuria
28a None Yes NR Eltrombopag Initiated prior to pregnancy, 44/249 CR (NR) NR 39 No
50 mg used throughout
pregnancy
[36] (2020), n = 1 29 Epistaxis Steroids, IVIG Yes Eltrombopag 27 (1) 9/11 No response CS (low lying 30 Yes
50 mg placenta),
ITP
|   
7

(Continues)

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 | 8

TA BL E 2 (Continued)
  

Platelet count Platelet

TPO-RA, nadir/platelet response
Reference maximal dose GA at TPO-RA initiation count after (time to GA at
(year) number Mother, Bleeding during Treatments used prior to Platelet used during (duration of use in TPO-RA prior to response, Mode of delivery, delivery,
of pregnancies n pregnancy TPO-RA transfusion pregnancy pregnancy, weeks) delivery, ×10 9/L weeks)b indication weeks PPH Comments

[37] (2020), n = 1 30 Epistaxis, gum Prednisone, Yes Eltrombopag 31 (5) 1/65 R (4) CS (prior CS), 36 + 3 No
bleeding, dexamethasone, 50 mg ITP
ecchymoses, methylprednisolone,
haematuria IVIG, rhTPO,
cyclosporine,
hydroxychloroquine
[38] (2020), n = 1 31 Gum bleeding, Prednisone, Yes Romiplostim 19 (18) 5/250 CR (1) CS (cord 37 No
purpura dexamethasone, 5 μg/kg prolapse),
IVIG, rituximab, gestational
azathioprine hypertension
[39] (2020), n = 2 32 Epistaxis Prednisolone, IVIG No Romiplostim 30 (8) 13/50 R (2) VD, spontaneous 38 No
6 μg/kg
33 Gum bleeding, Prednisolone, IVIG Yes Romiplostim 33 (4) 8/146 CR (1) CS (failed 37 No
bruising, 3.5 μg/kg induction),
epistaxis preeclampsia
[40] (2020), n = 1 34 Petechiae, vaginal Methylprednisolone, No Romiplostim 35 (1) 16/158 CR (1) VD, ITP 36 No
bleeding prednisolone, IVIG 3 μg/kg
[41] (2021), n = 1 35 None Prednisone, IVIG No Eltrombopag Initiated prior to pregnancy, 20/214 CR (NR) CS (prior CS), 35 No
50 mg stopped at 13th week, ITP
resumed at 18th week
until delivery
[42] (2021), n = 2 36a Epistaxis, bruising, Prednisolone, IVIG, anti-D Yes Romiplostim 35 (3) 2/10 No response CS, ITP 38 No Failure of
petechiae, immunoglobulin 5 μg/kg eltrombopag
wet purpura, 75 mg
haematuria
36a None Prednisolone, IVIG, No Romiplostim 29 (8) 10/100 CR (4) CS, previous 37 No
rituximab 8 μg/kg caesarean
[43] (2022), n = 1 37 None None No Eltrombopag 11 (27) 9/123 CR (3) VD, ITP 38 No
25 mg
[44] (2022), n = 1 38 Epistaxis, petechiae Methylprednisolone, No Eltrombopag 25 (13) 3/100 CR (1) CS, ITP 38 No
dexamethasone, IVIG 50 mg
[45] (2023), n = 2 39 None Prednisolone, No Romiplostim 34 (4) 8/NR R (NR) CS, low lying 38 No LMWH primary
dexamethasone, IVIG Dose-NR placenta prophylaxis
was used
40 None Steroids, IVIG No Eltrombopag 35 (2) 13/62 R (2) VD, spontaneous 37 + 2 No
50 mg
[46] (2023), n = 1 41 None IVIG No Romiplostim 12 (24) NR/100 CR (NR) CS, NR 36 + 2 NR TIA prior to
2 μg/kg romiplostim
initiation
TPO-RA IN PREGNANT WOMEN WITH ITP

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ROTTENSTREICH and BUSSEL    | 9

SGA. Neonatal thrombocytopenia occurred in 15/44 (34.1%)

newborns (missing n = 3) and was severe (<50 × 109/L) in

Abbreviations: CS, caesarean section; GA, gestational age; IVIG, intravenous immunoglobulin; LMWH, low molecular weight heparin; NR, not reported; PEX, plasma exchange; PPH, postpartum haemorrhage; rhTPO, recombinant
Comments
13/15, who received IVIG with platelet transfusions added in
6/13. Three neonatal bleeding manifestations occurred: two
ICH, grades 1 (#33) and 3 (#3). The neonate with grade 3 ICH
(#3) had a nadir platelet count of 33 × 109/L and was born to

PPH

Yes
a primiparous woman who received romiplostim through-
out pregnancy with maternal platelet counts remaining

delivery,
200–300 × 109/L. An additional grade 1 ICH related to pre-
weeks
GA at

27 + 3
maturity (#21) was observed without evidence of neonatal
thrombocytopenia.
Mode of delivery,

CS, preeclampsia
Neonatal thrombocytosis (511, 555, 799 × 109/L) was
indication

seen in three cases (eltrombopag, n = 2, #21 [maximal dose

100 mg], #29 [50 mg]; romiplostim, n = 1, #41 [2 μg/kg]),

In the study by Michel et al. for some of the outcomes only aggregate results were reported, while individual patient data was not reported (e.g. mode of delivery, preterm delivery).
with respective maternal predelivery counts of 136, 11 and
100 × 109/L. In two cases (#21, #41), neonatal thrombocy-
response,
response
(time to
Platelet

weeks)b

tosis persisted with breastfeeding, in one for 11 months de-

CR (2)

spite breastfeeding cessation (#41). For those women using

TPO-RA at delivery (available data n = 25), there was no
TPO-RA prior to
delivery, ×10 9/L

correlation between maternal predelivery and neonatal birth

Platelet count
nadir/platelet
count after

platelet counts (rs = 0.25; p = 0.22).

Other neonatal adverse events reported were congenital
8/160

phimosis with postnatal sepsis and adrenal insufficiency fol-

lowing prolonged antenatal use of dexamethasone (n = 1, #3),
GA at TPO-RA initiation

neonatal death due to trisomy 8 (n = 1, #22) after one dose

of romiplostim at week 37, pulmonary artery stenosis (n = 1,
(duration of use in
pregnancy, weeks)

#27) and fetal supraventricular tachycardia (n = 1, #29).

These events were not attributed to TPO-RA.
human thrombopoietin; TPO-RA, thrombopoietin receptor agonist; VAD, vacuum-assisted delivery; VD, vaginal delivery.
18 (9)

DISC US SION
maximal dose

Eltrombopag
used during
pregnancy

25 mg
TPO-RA,

In 45 reported pregnancies of women with ITP using a

TPO-RA during pregnancy, 86.7% had platelet responses
with a median time to response of 1 week, which may be
transfusion

attributed to the high frequency of concomitant medi-

Platelet

cations in these pregnant women. This is comparable to

Platelet response-defined as: CR-complete response; R-response; NR-no response.
No

the almost 80% response rate in the Chinese study of re-

combinant TPO in pregnancy as well as to rates seen with
Treatments used prior to

TPO-RA outside of pregnancy in patients who failed first-

Prednisolone, IVIG

line treatment.48,49 Similar response rates were seen with

eltrombopag and romiplostim precluding drawing conclu-
sions on the better agent in terms of efficacy.
TPO-RA

The safety findings are in line with the recently pub-

lished report of the Pregnancy Surveillance Program
Second pregnancy occurred in the same mother.

(PSP) initiated by Amgen Inc., which collected data on

Bleeding during

pregnancy outcomes among 186 women with ITP exposed

to romiplostim from 20 days prior to conception until
pregnancy

the end of pregnancy. 50 Due to the retrospective nature

None

of pharmacovigilance data, the information collected by

(Continued)

the PSP was often incomplete, with known pregnancy and

Mother,

birth outcomes in 86 (46%) and 92 (49%) women respec-

42

tively. The timing of exposure to romiplostim was only

n

[47] (2023), n = 1

known to 128 (69%) women. The only adverse event with

of pregnancies
(year) number
TA BL E 2

a higher than expected rate in the PSP report was throm-

Reference

bocytopenia, which is obviously expected as all women in

the PSP had ITP by definition. There were three cases of
b
a

c
 10

TA BL E 3 Neonatal outcomes following maternal exposure to TPO-RA during pregnancy.

|

Reference (year)
number of Birthweight, Neonatal Neonatal platelet count
  

pregnancies Mother, n gram LBW, SGA thrombocytopenia nadir, ×10 9/L Neonatal bleeding Neonatal treatment Neonatal adverse events
[24] (2012), n = 1 1 NR — No Normal No No No
[25] (2012), n = 1 2 NR — No Normal No No No
[26] (2013), n = 1 3 1910 Yes, No Yes 33 ICH grade 3 (outcome-NR) IVIG, Platelets 1. Congenital phimosis
2. Postnatal sepsis and adrenal
insufficiency
[27] (2014), n = 2 4 3480 No, No No 186 No No No
5 2640 No, No Yes 90 No No No
[28] (2016), n = 1 6 1860 Yes, Yes Yes 55 No IVIG No
[29] (2017), n = 2 7 NR — No 174 No No No
8 NR — No 132 No No No
[30] (2018), n = 1 9 NR — NR NR No No No
[31] (2018), n = 1 10 1670 Yes, Yes No 416 No No No
[32] (2018), n = 1 11 2400 Yes, No No 282 No No No
[33] (2018), n = 1 12b NR — Yes in both neonates <20 in both neonates No Both-IVIG No
[34] (2020), n = 1 13 NR — No 160 No No No
[35] (2020), n = 17 14a NR — Yes 6 No IVIG, Platelets No
14a,b NR — Yes in both neonates 8 & 34 No twin A: none, twin B: No
IVIG, Platelets
15 NR — No NR No No No
16 NR — No NR No No No
17 NR — Yes 20 No IVIG No
18 NR — No NR No No No
19 NR — No NR No No No
20 NR — No NR No No No
21 NR — No NR ICH grade 1, favourable outcome, No Neonatal thrombocytosis 555 × 109/L,
no intervention, no sequela persistent (breastfeeding while on
eltrombopag)
22 NR — No NR No No Death on 7th day postnatal-trisomy 8
23 NR — No NR No No No
24 NR — Yes 4 No IVIG, Platelets No
25 NR — No NR No No No
26 NR — Yes 20 No IVIG No
27 NR — No NR No No Pulmonary artery stenosis
28a NR — No NR No No No
28a 2700 No, No No NR No No No
TPO-RA IN PREGNANT WOMEN WITH ITP

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 TA BL E 3 (Continued)
Reference (year)
ROTTENSTREICH and BUSSEL

number of Birthweight, Neonatal Neonatal platelet count

pregnancies Mother, n gram LBW, SGA thrombocytopenia nadir, ×10 9/L Neonatal bleeding Neonatal treatment Neonatal adverse events
[36] (2020), n = 1 29 1370 Yes, No No 274 No No 1. Fetal SVT, 1 week after eltrombopag
initiation
2. Neonatal thrombocytosis 511 × 109/L,
(breastfeeding-NR)
[37] (2020), n = 1 30 NR — No NR No No No
[38] (2020), n = 1 31 2885 No, No No NR No No No
[39] (2020), n = 2 32 2770 No, No No 229 No No No
33 4650 No, No Yes 6 Purpura, ICH grade 1, favourable IVIG, Platelets Cystic fibrosis
outcome, no intervention, no
sequela
[40] (2020), n = 1 34 2740 No, No No 378 No No No
[41] (2021), n = 1 35 2280 Yes, No No 198 No No No
[42] (2021), n = 2 36 a NR — Yes 2 Petechiae IVIG, Platelets, No
corticosteroids
36a NR — Yes 19 No IVIG No
[43] (2022), n = 1 37 2370 Yes, No No 173 No No No
[44] (2022), n = 1 38 2470 Yes, Yes No 230 No No No
[45] (2023), n = 2 39 NR — NR NR No No No
40 NR — NR NR No No No
[46] (2023), n = 1 41 NR — No 288 No No Neonatal thrombocytosis 799 × 109/L,
persistent even after breastfeeding
cessation
[47] (2023), n = 1 42 714 Yes, Yes Yes 33 No IVIG No

Abbreviations: ICH, intracranial haemorrhage; LBW, low birth weight; NR, not reported; SGA, small-for-gestational-age; SVT, supraventricular tachycardia; TPO-RA, thrombopoietin receptor agonist.
a
Second pregnancy occurred in the same mother.
b
Twin pregnancy.
|   
11

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12 |    TPO-RA IN PREGNANT WOMEN WITH ITP
thrombosis (details unavailable, including temporal rela-
tionship to TPO-RA), and rates of other adverse events
were comparable to those found in the general population
of pregnant women. Birth outcomes were also within the
expected range for the general population. In consider-
ation of safety, the PSP ensures that there is considerably
more information available for romiplostim at this time.
More than 70 women conceived while on romiplostim and
took it for at least several weeks during pregnancy, making
the safety data more impressive. In the current report, no
thromboembolic events occurred; however, in two cases,
placental infarcts were observed. The significance of the
latter is unclear considering its low rate and the concur-
rent occurrence of preeclampsia in one of these two cases.
Overall, the current review and the PSP report suggest
that there is no compelling evidence to suspect any fre-
quent adverse effects of TPO-RA on the mother and the
offspring. Similar safety findings were also observed in the
aforementioned prospective study in China (n = 31) using
recombinant TPO.49
The two agents described in this review are anticipated
to cross the placenta either via FcRn (romiplostim) or as a
small molecule (eltrombopag). Despite these expectations,
the effects of TPO-RA on neonatal platelet counts seem
surprisingly limited. There were only three cases of neo-
natal thrombocytosis, and neonatal thrombocytopenia
occurred in one third of cases and was severe (<50 × 109/L)
in 13 with one grade 3 ICH. In the study by Kong et al.
following maternal exposure to recombinant TPO, which
is not expected to cross the placenta, the rate of neonatal
thrombocytopenia was 16% (5/31), but no ICH or severe
thrombocytopenia (<50 × 109/L) was seen.49 Increasing the
maternal platelet count might have decreased the amount
of free anti-platelet IgG available to cross that placenta
and increased TPO-RA binding to platelets in the mother,
making it unavailable to the fetus, but these are both
speculative hypotheses.
Both romiplostim46 and eltrombopag20 have been de-
tected in breast milk, which may lead to prolonged post-
natal thrombocytosis,35,36,46 so the platelet count should
be carefully monitored in lactating mothers on TPO-RA.
Eltrombopag, if present in breast milk, would be expected
to be chelated and inactivated by the high calcium content of
breast milk, but at least one case appears to contradict this
hypothesis.
The main caveats of the current review include the
relatively small number of women, retrospective design
and heterogeneous characteristics of cases reviewed, but
especially that ‘successful’ cases are more likely to be
published. Information regarding various pregnancy and
neonatal outcomes was missing in some cases. Finally, lack
of follow-up of mothers and infants beyond the early post-
partum period limits knowledge of long-term outcomes;
only the Chinese TPO study followed mothers and espe-
cially infants for 1 year. Nevertheless, this is the largest ef-
ficacy and safety investigation of TPO-RA in pregnant ITP
patients. Despite these limitations, we believe it represents
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a valuable collation of the use of TPO-RA in pregnant
women with difficult ITP.
Especially in the third trimester, pregnant women with ITP
can lose their response to steroids and IVIG, and this creates
therapeutic dilemmas, particularly when the goal is a safe de-
livery and the provision of neuraxial anaesthesia.51 The cur-
rent review confirms that the use of TPO-RA in pregnancy
is associated with a high response rate and, in comparison to
other options such as rituximab and azathioprine, leads to a
relatively rapid increase in the platelet count. Nonetheless, due
to the limited number of cases, we cannot recommend that
TPO-RA be routinely used in pregnancy. In particular, their
use in the first trimester remains a particular concern, as it
would with any drug, although short-term use in the third
trimester to increase the platelet count for delivery appears
to be less concerning. The relative absence of thromboem-
bolic events is important. While no substantive differences
in response or safety were seen between eltrombopag and
romiplostim, there is considerably more safety information
available from the PSP report on romiplostim. Future pro-
spective studies are warranted to extend the safety and effi-
cacy profiles of TPO-RA in pregnant women with ITP.
AU T HOR C ON T R I BU T ION S
Amihai Rottenstreich and James B. Bussel reviewed the liter-
ature and wrote the paper. Amihai Rottenstreich performed
the statistical analyses for this study. Both authors read and
approved the final manuscript.
AC K N O​W L E​D G E​M E N T S
None.
F U N DI N G I N F OR M AT ION
No external funding was used in this conduct of this study.
C ON F L IC T OF I N T E R E S T S TAT E M E N T
AR: The author declare that he does not have any conflicts
of interest. JBB: consult/ad boards: Amgen, Novartis, Sobi,
Shenyang Bio, Rigel, Sanofi, Astra-Zeneca, UCB, Janssen,
Argenx.
DATA AVA I L A BI L I T Y S TAT E M E N T
The data that support the findings of this study are available
on request from the corresponding author, AR.
ORC I D
Amihai Rottenstreich https://orcid.
org/0000-0002-2472-5204
James B. Bussel https://orcid.org/0000-0002-2884-9247
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