A successful twin pregnancy in a patient with HbE-β-thalassemia in western India.

Improvements in medical facilities have helped a large number of clinically severe hemoglobin E (HbE)-β-thalassemia patients reach adulthood. Consequently, there is a new challenge, that of managing women with HbE-β-thalassemia during pregnancy. In particular, they have a high risk of abortion, preterm delivery, intrauterine growth restriction, and thromboembolism. A 27-year-old HbE-β-thalassemia patient on regular transfusion, who was splenectomized and heptatitis C (HCV)-positive, conceived for the first time without any infertility treatment. However, there was incomplete abortion with heavy bleeding at 3 months of gestation, which required bilateral uterine artery angiography. The angiogram showed the left uterine artery to be moderately hypertrophied. This was embolized with 300-500 micron polyvinyl alcohol (PVA) to stop the bleeding. Soon after, she conceived again with a twin pregnancy, and at 33.3 weeks of gestation, there was a normal delivery of twin girls without any postpartum hemorrhage or perineal tear. Both babies were given prematurity care. The mother and children were both normal up till the last follow-up 18 months after delivery, and both the girls are HbE heterozygous. Thorough monitoring of endocrine functions along with proper management of transfusions and iron overload can help in reducing the complications related to pregnancy in these patients.

Introduction

Hemoglobin E (HbE)-β-thalassemia cases behave clinically as thalassemia intermedia or thalassemia major. Untreated patients exhibit hepatosplenomegaly, severe anemia, hypersplenism, and skeletal disease.[1] Hydroxyurea has been used in patients with different hemoglobinopathies in India with some success.[234] With increasing awareness about the disease and improvement in medical facilities in urban areas, many patients receive proper management and reach adulthood. Still, we face another challenge, that of managing women during pregnancy and delivery. Here we present a case of severe HbE-β-thalassemia with spontaneous pregnancy and highlight the various complications encountered during the pregnancy.

Case Report

A 27-year-old woman from Aurangabad, Maharashtra in western India with HbE-β-thalassemia [HbE+codon41/42(-CTTT)] had been receiving regular blood transfusions from 5 years of age. She was splenectomized at 8 years of age; however, the transfusion requirements persisted. At the age of 16, hepatitis C (HCV) antibodies were noted in her blood. She was heterozygous for the Gγ-gene polymorphism-158(C→T) [Xmn-I (±)] and had normal α-genotype (αα/αα). She was on regular folic acid, calcium, and deferiprone. She was started on hydroxyurea therapy at 10 mg/kg/day at 22 years of age, which was increased to 20 mg/kg/day. After 6 months on hydroxyurea therapy, her transfusion requirements decreased, but she could not maintain hemoglobin levels above 7.5 g/dL for more than 45 days.

She got married at 23 years to a man without any hemoglobinopathy. Before planning pregnancy, genetic counseling regarding the inheritance of either HbE or β-thalassemia and the risk of vertical transmission of HCV was given. Hydroxyurea was stopped and the regular blood transfusion regimen was restarted.

She first conceived at 24 years of age. She had normal endocrine function and did not undergo any kind of fertility treatment. Iron chelation was immediately stopped. Unfortunately, the pregnancy was complicated by incomplete abortion with heavy bleeding at 3 months, requiring dilation and curettage. She continued to have irregular, heavy bleeding even after evacuation of the abortus. A bilateral uterine artery angiogram showed the left uterine artery to be moderately hypertrophied. There was a dilated, tortuous branch supplying a focal area of hypervascularity, which demonstrated an early venous drainage suggestive of a small slow-flow arteriovenous fistula formation. It was embolized with 300-500 micron polyvinyl alcohol (PVA) particles by an interventional radiologist, and the patient stopped bleeding. Digital subtraction angiography revealed complete obliteration of hypervascularity with stasis of contrast in the left uterine artery.

One year after the abortion, she again had a normal conception. Ultrasonography (USG) confirmed it to be a diamniotic monochorionic twin pregnancy. Her serum ferritin level before pregnancy was 417 ng/mL and at full term was 1196 ng/mL. Her cardiac function was monitored by a cardiologist and remained stable throughout the pregnancy.

At 33.3 weeks of gestation, she had a normal delivery wherein twin girls were born without any postpartum hemorrhage or perineal tear. She required transfusion for blood loss. The two babies weighed 1.62 kg and 1.59 kg, which were appropriate for 33 weeks of gestation. Both babies were shifted to the nenonatal intensive care unit (NICU) for prematurity care. The girls are now 18 months of age and are both HbE heterozygous.

Discussion

The majority of patients with β-thalassemia are growth-retarded, and their puberty is delayed due to endocrine complications. A major issue in female patients has been hypogonadotropic hypogonadism, which is due to iron deposition in the pituitary gonadotroph cells and the hypothalamus.[5] Successful pregnancies in β-thalassemia patients have been reported after treatment for amenorrhea and gonadotropin-induced ovulation; however, this has resulted in twin or triplet pregnancies. There is a high risk of abortion, preterm delivery, intrauterine growth restriction as a consequence of ovarian hyperstimulation syndrome, cephalopelvic disproportion, hypersplenic crises and worsening heart function during gestation, and thromboembolism in pregnant women with thalassemia intermedia.[6789] There are few reports of pregnancies in clinically severe HbE-β-thalassemia patients from Thailand and no reports of pregnancy in clinically severe HbE-β-thalassemia patients from India. Singleton pregnancies reported in 54 women from Thailand with β-thal/HbE disease had increased risks of fetal growth restriction, preterm birth (37.40 ± 2.6 weeks), and low birth weight.[10] Das and Sengupta reported HbE homozygous women to have more live births in spite of having more spontaneous abortions.[11]

Pregnancy in a thalassemia patient requires multidisciplinary support in patient care and monitoring. Iron chelators need to be discontinued after conception due to their possible teratogenic effects on the fetus.[12] Serum ferritin increases in the initial trimester of pregnancy and needs to be monitored. Chelation with desferoxamine can be restarted after delivery during breastfeeding as it is not secreted in breast milk. However, there are no data available on any similar effects with deferasirox. Discontinuation of hydroxyurea is also recommended, however, we had earlier reported two of our clinically severe sickle-β-thalassemia patients conceiving while still on hydroxyurea therapy, and they delivered healthy babies.[13] Anemia is common during pregnancy and the transfusion requirement is increased with the preferred hemoglobin level of 10-11 gm/dL. Blood should be readily available at the time of labor. Cardiac function is closely monitored, as an already compromised heart (due to anemia and cardiac siderosis) can go into cardiac failure especially during labor and in the postpartum period. Endocrine complications such as diabetes and hypothyroidism are more common in thalassemia patients and may worsen, needing to be addressed appropriately. Bisphosphonates used for the treatment of osteoporosis in thalassemia is contraindicated in pregnancy and breastfeeding, but vitamin D and calcium should be continued. Thalassemia is a prothrombotic state and along with pregnancy, the risk of thrombosis and subsequent embolism is increased, which needs monitoring.[14]

The vertical transmission risk in hepatitis C is 4.3%. Risk of transmission is directly related to maternal viral load, and coinfection with human immunodeficiency virus (HIV) increases this risk by fivefold. Modes of delivery do not have any protective effect, and routine cesarean delivery is not recommended.[14]

It has been reported that out of the 62% of the women with β-thalassemia major who start breastfeeding, only 20.7% continue for more than 3 months due to resumption of chelation therapy or perhaps due to the belief that breastfeeding enhances the risk of transmitting viral hepatitis.[15] Our patient continued to breastfeed her babies for 1 year. Though the HCV virus may be present in breast milk, the risk of contraction through breastfeeding is minimal and breastfeeding is recommended.

Conclusion

Pregnancy in thalassemia is rare and with complications. Its management requires the team effort of the obstetrician, the endocrinologist, the radiologist, the cardiologist, the hematologist, the primary pediatrician, and good laboratory support. Watchful expectancy and timed intervention could be rewarding in high-risk cases. This case report underscores the importance of coordinated and team efforts required in managing a pregnancy involving HbE-β-thalassemia.