Pregnancy in β‐thalassemia intermedia at two tertiary care centers in Lebanon and Italy: A follow‐up report on fetal and maternal outcomes
Authors: Joseph E. Roumi, Hassan M. Moukhadder, Giovanna Graziadei, Martina Pennisi, Maria Domenica Cappellini, Ali T. Taher
Journal: American Journal of Hematology (2017)

According to clinical severity, thalassemia is a spectrum of syndromes spanning patients who are asymptomatic carriers (α- or β-thalassemia minor) to those who have transfusion-dependent thalassemia (TDT), with a group of nontransfusion-dependent thalassemia (NTDT) patients existing in between these two extreme ends. The pathophysiology of the NTDT syndromes, similar to that of the other thalassemias, is believed to stem from hemoglobin chain imbalance and secondary oxidative damage.1 Pregnancy complications, for example, are most directly related to increased susceptibility to oxidative stress from overt siderosis in the mother, thrombotic events, and placental hypoxia associated with maternal anemia.2 A series by Nassar et al.3 one of the largest of its kind for pregnant women with β-thalassemia intermedia (TI), a subtype of NTDT, demonstrated a significant association between pregnancy in TI and intrauterine growth restriction (IUGR). On the other hand, the literature continues to be lacking in data on pregnancy outcomes in TI females. Our present study is an update of the pregnancy registry in TI that was published in 2008,4 whereby we comment on the maternal-fetal outcomes of 85 new pregnancies in patients with TI followed at two tertiary care centers, the Chronic Care Center in Beirut, Lebanon and the Hereditary Anemia Center in Milan, Italy. A total of 48 women, all with a documented genetic diagnosis of β-thalassemia intermedia, were identified. They had 85 pregnancies altogether, 37 from Lebanon, and 48 from Italy (Table 1). The most common four genotypes were cd39/cd39 (31.25%), cd29/cd29 (12.5%), IVSI-6/IVSI-6 (12.5%), and IVSI-110/IVSI-110 (10.41%). The most prevalent genotype in the Lebanese cohort was cd29/cd 29 (30%), while the most common genotype in the Italian cohort was cd39/cd39 (42.8%). These 85 pregnancies resulted in 79 live births (92.95%) and 6 spontaneous abortions (7.05%). The mean gestational age at delivery was 37 ± 2.4 weeks, and the mean birth weight was 2820 ± 0.697 g. Preterm delivery was noted in 2.53% of the reported pregnancies, and the incidence of delivery by Cesarean section was 59.49%. Only one pregnancy was complicated by IUGR, and no reports of intrauterine fetal demise (IUFD) were made. All patients received aspirin during pregnancy, and patients who had a history of recurrent miscarriages or recurrent deep vein thrombotic events and those who suffered from thromboembolic complications during gestation received heparin products while pregnant. However, placental thrombosis and deep vein thrombosis were observed in one and five pregnancies, respectively. In total, 73.5% of the patients had normal pregnancies and puerperia with no maternal or fetal adversities. However, three women suffered from postpartum hemorrhage requiring blood transfusion. One case of placental abruption occurring at 34 weeks of gestation and necessitating emergency delivery was reported from the Italian cohort. One Italian patient was diagnosed with TI and essential thrombocytosis during pregnancy but delivered a healthy baby at 35 weeks. The average age at the time of the first pregnancy was 29.2 ± 4.27 years and 29.7 ± 5.4 years in Lebanon and Italy, respectively. Eight patients were frequently transfused, and 10 patients were never transfused. Twenty-seven patients were transfused during pregnancy. The mean hemoglobin concentration was 8.91 g/dL before conception and 7.96 g/dL after delivery. On the other hand, mean serum ferritin increased from 605 ng/mL before pregnancy to 887.2 ng/mL after delivery. One of the main culprits of pregnancy-related adversities in TI females is iron overload. In NTDT, where the levels of hepcidin—the main regulator of iron balance—are abnormally low, excess iron is absorbed into the system and thereafter released into the circulation, depleting macrophage iron and leading to preferential portal and hepatocyte iron loading.5 This culminates in an inevitable increase in free iron in the bloodstream, which results in end-organ damage including pregnancy complications. For example, IUGR was observed in approximately 57.1% of pregnancies in TI women, added to the increased risk of spontaneous abortions and thromboembolic phenomena in light of the hypercoagulable state pervasive in these patients secondary to TI per se.3 Cappellini et al. reported an incidence of more than 30% of venous thromboembolic events in TI patients in general, reflecting the hypercoagulable state driven by endothelial damage secondary to iron-mediated free radical formation.6 However, pregnancy in TI was not shown to increase in the risk of thromboembolic complications compared to nonpregnant TI women,3 which is especially interesting provided the classical association of pregnancy with blood hypercoagulability. Anemia of TI is confounded by the physiologic anemia of pregnancy, whereby pregnancy is normally characterized by hemodynamic and cardiovascular changes that lead to anemia as a result of the increase in total circulatory volume and ensuing hemodilution.2 In addition, the demand for hemoglobin is increased in pregnancy due to the elevated oxygen requirement needed for normal fetal growth and development. While a significant proportion of pregnancies in TI women were complicated by IUGR in a Lebanese study, blood transfusions during pregnancy did decrease the risk of IUGR as well as other complications.3 Data from nonthalassemic cohorts suggests that hemoglobin levels above 10 g/dL during gestation are recommended for optimal fetal growth and preclusion of preterm delivery.7 However, targeting the 10 g/dL cutoff proved to be of clinical benefit to only 78% of the pregnant NTDT patients and their fetuses in an Italian case series, where the fetuses of the other 22% suffered from IUGR.8 This suggests that, apart from the absolute hemoglobin concentration, transfusion therapy in pregnant TI women should be tailored to the cardiac function and general condition of the mother and the growth status of the fetus.8 In NTDT, there exist no solid cutoffs for giving blood transfusions, and the only determining factor herein is the clinical status of the patient in hand.9 As such, our patients were transfused as per their obstetrician's judgment, which was primed by fetal growth and maternal cardiac status and overall well-being, and after consulting with the patients' treating hematologist. While 30 of the 48 women in our study (62.5%) received at least one blood transfusion during pregnancy, routine transfusions are not recommended in pregnant patients with TI. Blood transfusions can increase the risk of developing alloimmune antibodies that would exacerbate any preexisting hemolytic anemia, such as thalassemia. Four of our patients developed alloimmune hemolytic anemia that necessitated postpartum splenectomy in two of them. It is important to note that the incidence of spontaneous abortions decreased from 20.5% in the 2008 cohort to 7.05% in our present study.4 Moreover, the incidence of live births increased from 77 to 92%, while the incidence of IUGR decreased from 24.2 to 1.26%, suggesting better pregnancy outcomes overall. Preterm births also dropped by almost one-half (from 5.8 to 2.53%), and the average newborn birth weight increased by 0.27 kg. The rates of thromboembolic events in both cohorts are similar at approximately 7%. The high rate of Cesarean deliveries in our patients in comparison to the general population (47% versus 10–15%, respectively) can be explained by cephalopelvic disproportion in TI women as a result of their short stature and other skeletal abnormalities.9, 10 In conclusion, and to the best of our knowledge, this is the largest study to date on pregnancy outcomes in TI women, where our results reflect advances in the management of pregnancy in TI over the years. For example, only 2 out of our 85 described gestations (2.35%) were achieved by assisted reproductive technology (ART), in contradistinction to 8.33% reported by Voskaridou et al.11 Optimization of antenatal iron levels and achievement of a hemoglobin concentration ≥8 g/dL prior to conception are among the most significant practices in preparation for an uncomplicated pregnancy in a TI patient.9 Although our results suggest pregnancy outcomes in TI that approximate with those observed in the general population, pregnancy in TI women remains to be considered high-risk. Low-molecular-weight heparin should be given as anticoagulant prophylaxis in the peripartum to all pregnant women with TI and as anticoagulant treatment all throughout gestation in pregnant TI women who have had recurrent abortions or are at risk of thromboembolic events during pregnancy.9 Routine obstetrical care during pregnancy and after delivery is strongly recommended. The safety of iron chelation during pregnancy remains to be speculated, and, in light of our relatively small population size, an international registry tracking all pregnancies in women with TI reported in the literature to date and incorporating additional accounts in the next few years might be especially useful in outlining pathophysiological trends and management guidelines unique to this special population of pregnant women.