American Journal of Hematology 81:499502 (2006)

Pregnancy In Patients with b-Thalassemia Intermedia:

Outcome of Mothers and Newborns
Anwar H. Nassar,1* Ihab M. Usta,1 Johnny B. Rechdan,1 Suzanne Koussa,2
Adlette Inati,2 and Ali T. Taher2,3
1

Department of Obstetrics and Gynecology, American University of Beirut Medical Center, Beirut, Lebanon
2
Chronic Care Center, Beirut, Lebanon
3
Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon

Little is known about the outcome of pregnancy in women with b-thalassemia intermedia
(TI). Over 10 years, maternal and neonatal outcomes of women with TI followed at a single
thalassemia center were reviewed. Nine spontaneous pregnancies in ve women with TI
were studied. Six pregnancies resulted in live newborns; two were complicated by rsttrimester abortions and one by an unexplained intrauterine fetal death at 36 weeks gestation. Two patients had splenectomy before pregnancy: one required cesarean delivery and
splenectomy at 312/7 weeks gestation for worsening hemolytic anemia and thrombocytopenia and another had splenectomy 8 weeks postpartum for symptomatic hypersplenism. Two
patients had received transfusions before pregnancy, and two required them for the rst
time during pregnancy and developed antibodies, which contributed to worsening of their
anemia and repeated transfusions. The mean number of transfusions received during pregnancy was 8.0 5.2 units. The mean lowest hemoglobin level in pregnancy was 5.2 2.0 g/dl.
Cesarean delivery was performed in 42.9% of cases. Mean gestational age at delivery was
36.7 3.1 weeks with intrauterine growth restriction (IUGR) complicating 57.1% of cases. In
conclusion, IUGR complicates more than half of pregnancies with TI. Transfusions are needed
in most cases, even in non-transfusion-dependent patients. Postpartum splenectomy might be
C 2006 Wiley-Liss, Inc.
necessary in some patients. Am. J. Hematol. 81:499502, 2006. V
Key words: b-thalassemia intermedia; obstetric complications; neonatal outcome

INTRODUCTION

Transfusion-independent thalassemic patients suffering from anemia with hemoglobin levels (Hb) of
710 g/dl and variable degrees of splenomegaly are
classied as b-thalassemia intermedia (TI) [1,2].
Patients with TI have, in general, a milder clinical
phenotype than those with thalassemia major. At
the severe end of the clinical spectrum of TI,
patients are usually diagnosed between the ages of 2
and 6 years old. Although they survive without regular transfusions, growth and development are retarded. At the other end of the spectrum, there are
patients who are completely asymptomatic until
adulthood, when they present with anemia and splenomegaly often found by chance during hematological examinations or family studies [1,2].
Although fertility is compromised in patients with
transfusion-dependent thalassemia major, pregnancy
is possible in the majority of patients with TI. This is
particularly true with the availability of assisted
C 2006 Wiley-Liss, Inc.
V

reproductive techniques and as medical advances

continue to increase the life expectancy of these
patients who can now reach adulthood and attain
reproductive capacity. A handful of pregnant women
with b-thalassemia have been reported in the medical
literature, a few having TI. The chronic anemia associated with these conditions can cause an increase in

Presented at the 25th Annual Meeting of the Society for Maternal Fetal Medicine in Reno, Nevada, Feb 712, 2005.
*Correspondence to: Anwar H. Nassar, Department of Obstetrics and Gynecology, American University of Beirut Medical
Center, P.O. Box 113-6044/B36, Beirut, Lebanon.
E-mail: an21@aub.edu.lb
Received for publication 2 August 2005; Accepted 18 December
2005
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI: 10.1002/ajh.20654

500

Nassar et al.

spontaneous abortions, preterm labor, and intrauterine growth restriction (IUGR) [3,4]. In Lebanon,
approximately one third of thalassemia patients have
TI [5]. A study that analyzed the molecular basis of
TI has shown that the most contributing factor in
this population is the b-genotype where 68% of
patients have a mild b mutation (IVSI-6, cd29,

88, or
87), while 26% are positive for the XmnI
polymorphism associated with increased production
of fetal hemoglobin (HbF), which shows strong linkage to certain mutations (IVSII-1, cd8, and cd30) [5].
The purpose of this study is to review the maternal
and fetal outcome of patients with TI followed up in
a single center with standard protocols.
MATERIALS AND METHODS

All pregnant patients with the diagnosis of TI were

identied from the Chronic Care Center database. This
is the only thalassemia center in Lebanon that cares
for approximately 450 patients with b-thalassemia, one
third of whom have TI. Patients with TI are followed
up regularly with viral screen (hepatitis B and C and
human immunodeciency virus), ferritin levels, liver
function evaluation, endocrine tests, and echocardiography prior to pregnancy. Endocrine evaluation includes
screening for hypothyroidism and diabetes mellitus.
Generally, those patients are counseled to plan a pregnancy if their Hb levels exceed 8.0 g/dl. During gestation, patients are followed up every 2 weeks for maternal weight gain, blood pressure measurement, and fetal
heart rate documentation. Hb levels are assessed routinely every 2 weeks, serum ferritin every 4 weeks,
and ultrasonographic evaluation of fetal growth every
4 weeks starting at 2426 weeks. IUGR was dened as
a birth weight less than the 10th percentile for gestational age with abnormal Doppler ow studies.
After obtaining informed written consent, the
maternal records were reviewed for maternal age, parity, smoking history, need for transfusion, baseline
Hb, Hb electrophoresis results, b-globin gene mutation, presence of splenomegaly, and hepatitis status.
In addition, obstetric complications like placenta previa, abruptio placentae, preterm labor, previous cesarean, and hypertensive disorders of pregnancy, the
mode of delivery, and postpartum complications like
endomyometritis and hemorrhage were recorded. The
neonatal records were reviewed for birth weight,
Apgar scores at 1 and 5 min, IUGR, gender, congenital malformations, and nursery stay.
RESULTS

During the 10 years, nine spontaneous pregnancies,

all planned, occurred in ve women with TI. One
American Journal of Hematology DOI 10.1002/ajh

woman had three pregnancies and two women had

two pregnancies. Six pregnancies (67%) resulted in live
newborns; 2 (22%) were complicated by rst-trimester
abortions and one (11%) by an unexplained intrauterine fetal death (IUFD) at 36 weeks gestation. This
patient had an uncomplicated antenatal course with a
reactive non-stress test 1 week prior to presentation
with decreased fetal movement. She never received
transfusions and her Hb was maintained at 9.0 g/dl.
None of the patients had thyroid dysfunction or
pregestational or gestational diabetes mellitus. Since
all pregnancies were planned, none of the patients was
on iron chelation at conception. The four patients
who were receiving deferoxamine had it interrupted
27 months prior to conception. Patients characteristics and obstetric data are summarized in Table I.
The mean maternal age was 29.6 5.5 years with a
median parity of 1 [13]. The mean lowest hemoglobin
level was 5.2 2.0 g/dl and the mean number of
transfusions received was 8.0 5.2 units. Three patients had received transfusions before pregnancy, and
two required them for the rst time during pregnancy.
Both patients who received their rst transfusion in
pregnancy developed alloantibodies, which contributed
to worsening of their anemia and repeated transfusions ante- and intrapartum. This eventually necessitated splenectomy postpartum: one at 312/7 weeks gestation following cesarean delivery and the other about
8 weeks postpartum for worsening anemia, thrombocytopenia, and a persistently positive Coombs test.
Both patients who had splenectomy prior to pregnancy never received hydroxyurea (HU). None of the
patients had hemodynamic abnormalities. The mean
ferritin level was 978 935 mg/L (130-2,366 mg/L).
Cesarean delivery was performed in 42.9% of cases.
The mean gestational age at delivery was 36.7 3.1
weeks. The mean birth weight was 2282 589 g with
IUGR complicating 57.1% of cases. No congenital
malformations were observed in our series. We noted
that the two cases of spontaneous abortions and
three of four IUGR cases occurred in splenectomized
patients.
DISCUSSION

Several small studies and case series have demonstrated favorable obstetrical and fetal outcome in
patients with b-thalassemia major when close followup and intensive treatment are instituted [69]. Less is
known about pregnancy performance in patients with
TI [6,8]. This entity encompasses a wide clinical spectrum. These patients usually have a disease the
severity of which is somewhere between the mild manifestations of thalassemia trait and the severe symptoms of thalassemia major. Our series, one of the larg-

Pregnancy Outcome of Thalassemia Intermedia Patients

501

TABLE I. Patients Characteristics and Obstetric Data

Patient

Mutation

Hb F
(%)

No. of
preg.

First
transfusion

Splenectomy

IUGR

Outcome
Cesarean delivery, full term
Cesarean delivery at 31 weeks
1st preg.: Cesarean delivery, full term
2nd preg.: 1st-trimester abortion
1st preg.: vaginal delivery, full term
2nd preg.: vaginal delivery, full term
3rd preg.: vaginal delivery at 36 weeks
1st preg.: 1st-trimester abortion
2nd preg.: IUFD at 36 weeks, vaginal delivery

1
2
3

IVSI-5/IVSI-5
IVSI-6/IVSI-6
IVSI-6/IVSI-6

80.1
94.8
60.0

1
1
2

None
Index preg.
5 years

Intact
Postpartum
Prior to pregnancy

cd29/cd29

17.1

2nd preg.

Postpartum (after 2nd delivery)

IVSI-110/IVSI-6

17.4

13 years

Prior to pregnancy

Note: Preg., pregnancy; IUGR, intrauterine growth restriction; IUFD, intrauterine fetal death.

est of patients with TI, shows that these pregnancies

may have complicated antepartum and postpartum
courses. IUGR complicates 57.1% of pregnancies.
Transfusions, with their potential complications, are
needed in most cases, and splenectomy may be indicated postpartum in a few patients.
Transfusion therapy is not currently a routine treatment approach for patients with TI. Initiating regular
blood transfusions in such patients remains a hard
decision because of the heterogeneity of the disease.
Patients who would benet from such a measure
include those with delayed growth, recurrent infections,
and hypersplenism [2,3]. When given, blood transfusions should be leukocyte-poor to avoid sensitization,
keeping in mind that such patients might become
transfusion-dependent in the future. The physiologic
anemia of pregnancy secondary to the increase in the
uid component of the blood is aggravated in patients
with TI. Also, the greater demand for hemoglobin for
normal growth and development of the fetus might
necessitate initiating transfusion or increasing the number of transfusions in those already requiring it. A
study published in the late 1980s found that Hb levels
in patients with TI gradually decrease in the rst and
second trimesters, to increase again in the third trimester [10]. The two patients in our series who received
transfusions for the rst time during pregnancy were
asymptomatic with Hb levels of 8.6 and 8.4 g/dl.
Avoiding transfusion could have prevented the development of alloantibodies, which led to severe hemolytic anemia refractory to high steroid doses, a close
dependency on transfusions, and need for splenectomy
thereafter. On the other hand, some attempt at maintaining Hb levels above 10g/dl because chronic maternal anemia can lead to a state of hypoxia, which is
associated with growth restriction, preterm birth, and
intrauterine demise [8,11]. Therefore, the benets of
frequent transfusion to the mother and infant (i.e., prevention of growth restriction) should be weighed
against its negative effects (antibody development).
Administration of erythropoietin in combination with

iron and folic acid has been previously proposed and if

proven effective might be an alternative to blood transfusion in such patients [12,13]. HU may be administered in TI patients to minimize or even obviate the
need for regular transfusions and concomitant iron
overload [14]. In animal models, HU has been proven
to play an important role in the development of
anomalies [15].
Splenomegaly and hyperactivity of the spleen in
removing the abnormal red blood cells associated
with thalassemia, common ndings in b-thalassemia
intermedia, lead to hemolytic anemia and hypersplenism. Splenectomy is usually reserved to patients who
develop severe hypersplenism, considerable decrease
in the hemoglobin levels, symptomatic thrombocytopenia, and leukopenia [16]. Both our patients fullled
criteria for splenectomy, which was postponed till the
postpartum period, thus avoiding potential complications of this procedure during pregnancy.
Patients with TI have an increased risk of thrombosis compared with the general population [16]. Cappellini et al. [17] reported that 30% of patients with TI
that were followed up for 10 years experienced venous
thromboembolic events, suggesting the presence of a
chronic hypercoagulable state [18]. Pregnancy is expected to further increase these risks; however, none
of our patients had such complications.
Pregnancy is associated with physiologic hemodynamic changes that might cause deterioration of
already impaired cardiovascular system commonly
seen in association with thalassemia. However, all our
patients had a normal baseline echocardiographic evaluation and they seemed to tolerate pregnancy rather
well cardiac-wise. In fact, one patient had three successful pregnancies at a 3-year interval.
Iron overload is a potential complication of TI,
even in non-transfusion-dependent patients [19]. This
results from excessive dietary iron absorption, a consequence of ineffective erythropoiesis, and a rapid
turnover of plasma iron. Iron chelating agents have
potential side effects including teratogenicity. HowAmerican Journal of Hematology DOI 10.1002/ajh

502

Nassar et al.

ever, Singer and Vichinsky, in a review of over 40

cases exposed to deferoxamine during pregnancy, did
not document any toxic or teratogenic effect [20].
This was not an issue in our patients, who were not
receiving any of these medications. More research in
this eld is needed since no safety issues from the few
published cases can be concluded. It remains to be
determined whether TI patients would benet from
aggressive chelation prior to conception to improve
their obstetrical performance. Cardiac and endocrine
problems have not been previously reported in these
pregnancies [6,8], and none of our patients suffered
from such complications.
More than 50% of our patients tolerated vaginal
delivery, which seems to be a suitable approach under epidural anesthesia. Even Aessopos et al., who
performed cesarean delivery on all their patients,
advocated individualizing the mode of delivery in
these patients since vaginal delivery might be possible
in many patients [5].
TI has been associated with an increased incidence
of obstetrical complications [3]. Two studies, on the
other hand, that included a total of nine pregnancies
in patients with TI did not report evidence of an
increased risk for ante-, intra-, or postpartum complications [6,8]. Our patients had a high incidence of
IUGR and IUFD complicated one pregnancy. Since
IUGR complicates more than half of pregnancies with
TI, the need for close antenatal follow-up and frequent
sonographic assessment of fetal growth cannot be
overemphasized. A trend toward a poorer obstetrical
outcome was observed in the two patients with low
HbF levels (Table 1). Increasing the synthesis of HbF
can help alleviate anemia and therefore improve the
clinical status of patients with TI [21]. However, this
observation is limited by the small sample size and
larger studies are needed to conrm these ndings.
In conclusion, b-thalassemia intermedia during pregnancy can present unique management challenges and
requires close maternal and fetal surveillance. Management of those patients should be individualized until
more clinical trials evaluate the role of routine blood
transfusions, preconceptional chelation, splenectomy,
and thromboprophylaxis requirements in such patients
that might impact their obstetric outcome. Care for
such pregnancies should be multidisciplinary, incorporating a maternal-fetal medicine specialist, a genetic
counselor, and a hematologist. Although our patients
did not experience cardiac, hemodynamic, hepatic, or
kidney deterioration during pregnancy, other complications can occur, which stresses the need for careful
monitoring throughout pregnancy.

American Journal of Hematology DOI 10.1002/ajh

REFERENCES
1. Camaschella C, Cappellini MD. Thalassemia intermedia. Haematologica 1995;80:5868.
2. Olivieri NF. The beta-thalassemias. N Engl J Med 1999;341:99
109.
3. Karagiorga-Lagana M. Fertility in thalassemia: the Greek experience. J Pediatr Endocrinol Metab 1998;11(Suppl 3):945951.
4. Skordis N, Christou S, Koliou M, Pavlides N, Angastiniotis M.
Fertility in female patients with thalassemia. J Pediatr Endocrinol Metab 1998;11(Suppl 3):935943.
5. Aessopos A, Karabatsos F, Farmakis D, Katsantoni A, Hatziliami A, Youssef J, Karagiorga M. Pregnancy in patients with
well-treated beta-thalassemia: outcome for mothers and newborn infants. Am J Obstet Gynecol 1999;180:360365.
6. Daskalakis GJ, Papageorgiou IS, Antsaklis AJ, Michalas SK.
Pregnancy and homozygous beta thalassaemia major. Br J
Obstet Gynaecol 1998;105:10281032.
7. Savona-Ventura C, Bonello F. Beta-thalassemia syndromes and
pregnancy. Obstet Gynecol Surv 1994;49:129137.
8. Jensen CE, Tuck SM, Wonke B. Fertility in beta thalassemia
major: a report of 16 pregnancies, preconceptual evaluation and
a review of the literature. Br J Obstet Gynaecol 1995;102:625
629.
9. Qatanani M, Taher A, Koussa S, Naaman R, Fisher C, Rugless
M, Old J, Zahed L. b-Thalassemia intermedia in Lebanon. Eur
J Haematol 2000;64:237244.
10. Vaeurson O, Fuchareon S, Wasi P. A study of thalassemia
associated with pregnancy. Birth Defects 1988;23:295299.
11. Levy A, Fraser D, Katz M, Mazor M, Sheiner E. Maternal
anemia during pregnancy is an independent risk factor for low
birthweight and preterm delivery. Eur J Obstet Gynecol Reprod
Biol 2005;122:182186.
12. Lialios G, Makrydimas G, Tsanadis G, Lolis D, Bourantas K.
Effective treatment of beta-thalassemia intermedia during pregnancy with rHuEpo. A case report. Minerva Ginecol 2000;52:
2931.
13. Bennett M, Macri CJ, Bathgate SL. Erythropoietin use in a
pregnant Jehovahs witness with anemia and beta-thalassemia: a
case report. J Reprod Med 2005;50:135137.
14. Panigrahi I, Dixit A, Arora S, Kabra M, Mahapatra M,
Choudhry VP, Saxena R. Do alpha deletions inuence hydroxyurea response in thalassemia intermedia? Hematology 2005;10:
6163.
15. Woo GH, Katayama K, Bak EJ, Ueno M, Yamauchi H, Uetsuka K, Nakayama H, Doi K. Effects of prenatal hydroxyureatreatment on mouse offspring. Exp Toxicol Pathol 2004;56:17.
16. Moratelli S, De Sanctis V, Gemmati D, Serino ML, Mari R,
Gamberini MR, Scapoli GL. Thrombotic risk in thalassemic
patients. J Pediatr Endocrinol Metab 1998;11(Suppl 3):915921.
17. Cappellini MD, Robbiolo L, Bottasso BM, Coppola R, Fiorelli
G, Mannucci AP. Venous thromboembolism and hypercoagulability in splenectomized patients with thalassaemia intermedia.
Br J Haematol 2000;111:467473.
18. Eldor A, Rachmilewitz EA. The hypercoagulable state in thalassemia. Blood 2002;99:3643.
19. Pippard MJ, Callender ST, Warner GT, Weatherall DJ. Iron
absorption and loading in beta-thalassaemia intermedia. Lancet
1979;2:819821.
20. Singer ST, Vichinsky EP. Deferoxamine treatment during pregnancy: is it harmful? Am J Hematol 1999;60(1):2426.
21. Olivieri NF. Reactivation of fetal hemoglobin in patients with
beta-thalassemia. Semin Hematol 1996;33:2442.