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 2

Department of Obstetrics and Gynecology, American University of Beirut Medical Center, Beirut, Lebanon 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 five women with TI were studied. Six pregnancies resulted in live newborns; two were complicated by firsttrimester 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 first 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 necessary in some patients. Am. J. Hematol. 81:499502, 2006. VVC 2006 Wiley-Liss, Inc. 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 classified 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 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

American Journal of Hematology 81:499502 (2006) VVC 2006 Wiley-Liss, Inc.

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 identified 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 immunodeficiency 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 defined as a birth weight less than the 10th percentile for gestational age with abnormal Doppler flow 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 five women with TI. One woman had three pregnancies and two women had two pregnancies. Six pregnancies (67%) resulted in live newborns; 2 (22%) were complicated by first-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 29.65.5 years with a median parity of 1 [13]. The mean lowest hemoglobin level was 5.22.0 g/dl and the mean number of transfusions received was 8.05.2 units. Three patients had received transfusions before pregnancy, and two required them for the first time during pregnancy. Both patients who received their first 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 978935 mg/L (130-2,366 mg/L). Cesarean delivery was performed in 42.9% of cases. The mean gestational age at delivery was 36.73.1 weeks. The mean birth weight was 2282589 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 larg500 Nassar et al. American Journal of Hematology DOI 10.1002/ajh

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 benefit 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 fluid 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 first and second trimesters, to increase again in the third trimester [10]. The two patients in our series who received transfusions for the first 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 benefits 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 findings 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 fulfilled 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. HowTABLE I. Patients Characteristics and Obstetric Data Patient Mutation Hb F (%) No. of preg. First transfusion Splenectomy IUGR Outcome 1 IVSI-5/IVSI-5 80.1 1 None Intact _ Cesarean delivery, full term 2 IVSI-6/IVSI-6 94.8 1 Index preg. Postpartum _ Cesarean delivery at 31 weeks 3 IVSI-6/IVSI-6 60.0 2 5 years Prior to pregnancy _ 1st preg.: Cesarean delivery, full term 2nd preg.: 1st-trimester abortion 4 cd29/cd29 17.1 3 2nd preg. Postpartum (after 2nd delivery) 1st preg.: vaginal delivery, full term 2nd preg.: vaginal delivery, full term 3rd preg.: vaginal delivery at 36 weeks 5 IVSI-110/IVSI-6 17.4 2 13 years Prior to pregnancy 1st preg.: 1st-trimester abortion 2nd preg.: IUFD at 36 weeks, vaginal delivery Note: Preg., pregnancy; IUGR, intrauterine growth restriction; IUFD, intrauterine fetal death.

Pregnancy Outcome of Thalassemia Intermedia Patients 501 American Journal of Hematology DOI 10.1002/ajh

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 field is needed since no safety issues from the few published cases can be concluded. It remains to be determined whether TI patients would benefit 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 confirm these findings. 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.

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 influence 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.

502 Nassar et al. American Journal of Hematology DOI 10.1002/ajh