ILLUSTRATIVE CASE

A 29 year-old woman at 24 weeks of gestation presented for a regular checkup visit to her obstetrician. She was diagnosed with β-thalassemia intermedia at 5 years of age (IVSI-6/IVSI-6) when she had presented with anemia (total hemoglobin level 9.5 g/dl) and splenomegaly. She had an uncomplicated disease course since diagnosis and receives no treatment. On routine laboratory studies, she showed a total hemoglobin level of 8 g/dl. The patient was thus started on blood transfusions to elevate the total hemoglobin level to >10 g/dl. She developed alloantibodies and worsening anemia. She underwent Caesarian section at 31 weeks of gestation for intrauterine growth restriction and non-reassuring fetal heart monitoring and had splenectomy postpartum.

CONTEXT AND EVIDENCE

Although delayed puberty may be common in NTDT patients, fertility is usually preserved. Few case series reported pregnancy outcomes in women with NTDT (β-thalassemia intermedia) [1-3]. All reported pregnancies were spontaneous [1-3]. Abortion, pre-term delivery, intrauterine growth restriction (IUGR), Caesarean section delivery, thromboembolic events, and splenectomy were generally common in such women [1-3].

Blood transfusion therapy is a common consideration in pregnant NTDT women due to intensification of anemia during gestation. The physiologic anemia of pregnancy becomes exaggerated in NTDT patients, and the increased oxygen demand by the fetus makes blood transfusion a tempting option [2]. Data from non-thalassemic cohorts suggest that keeping hemoglobin level above 10 g/dl is optimal for the development of the fetus and to avoid intrauterine growth IUGR, intrauterine fetal demise (IUFD), or preterm delivery [4]. The largest case series of pregnant β-thalassemia intermedia (83 pregnancies in 44 women) reported that 22% of patients still had IUGR despite abiding by this standard [1]. However, a recent β-thalassemia intermedia case series from Italy with trials of random transfusion regimens (1 to 1 per week, mean total hemoglobin level from 7.6 to 9.3 g/dl) in 11 out of 17 pregnancies showed that most babies (except in two cases) were appropriate for gestational age [3]. Transfusions were not only administered based on total hemoglobin level but also general and cardiac maternal status and fetal growth [3]. The main concern with administering blood transfusion during pregnancy especially to previously never- or minimally-transfused patients is alloimmunization. Such patients commonly had alloimmunization in available studies and usually had adverse outcomes (abortion, IUGR, cardiac failure, Caesarian section delivery) [1-3]. Thrombotic disease was also a common occurrence, especially in women with additional prothrombotic risk factors [1, 5]. However, in one series were all splenectomized patients received aspirin and all patients were given low-molecular-weight heparin the peripartum period, no thrombotic events occurred in any patient [3]. Splenomegaly can interfere with the enlargement of the uterus and can be complicated by hypersplenism necessitating splenectomy during gestation or after delivery [1-2].

PRACTICAL RECOMMENDATIONS

• NTDT patients planning to get pregnant need comprehensive counseling regarding the risk of having an affected child and prenatal diagnosis
• Pregnancy in NTDT patients should be considered a high-risk one, and care should be achieved through close collaboration between the hematologist, obstetrician, cardiologist, and other concerned specialists
• Introduction of blood transfusions for pregnant patients with NTDT should rely on
  • > Total hemoglobin level
  • > Maternal general and cardiac status
  • > Fetal growth status
• Pregnant women with NTDT who were previously never- or minimally-transfused, should be considered at high risk of alloimmunization if blood transfusions are to be administered during pregnancy. If blood transfusion is deemed necessary, extended genotype and antibody screening should be performed before giving any transfusion and fully-phenotyped matched blood should be given (see Chapter 2)
• Splenectomy should be considered for patients complicated with hypersplenism or splenomegaly before conception or postpartum
• Pregnant women with NTDT should receive prophylactic dose anticoagulant therapy (low-molecular-weight heparin) in the peripartum. Patients with a history of recurrent abortions or who are at increased risk of thromboembolic events (see Chapter 6) may be considered for anticoagulant therapy (low-molecular-weight heparin) all throughout pregnancy. Splenectomized patients should also be considered for aspirin therapy
• The following general monitoring and management standards should also be considered:
  • > Pre-pregnancy
    • - Assess iron overload status and ensure adequate management of iron overload (see Chapter 5)
    • - Assess cardiac status and manage accordingly (echocardiogram, , cardiac stress test, elec trocardiogram, Holter monitoring)
    • - Assess endocrine (see Chapter 9), bone (see Chapter 9), and liver function (see Chapter 8) and manage accordingly
    • - Assess viral status (hepatitis B and C, HIV, rubella) and ensure appropriate vaccinations (hepatitis B, Pneumovax, seasonal influenza)
    • - Screen for red blood cell antibodies
    • - Initiate folic acid
  • > During pregnancy
    • - Cardiac, hepatic, and thyroid monitoring
    • - Serial ultra sound to monitor growth restriction
    • - Gestational diabetes monitoring (16 and 28 weeks)
    • - Discontinue: iron chelators (deferoxamine may be used if needed in second and third trimesters, no other chelators are so far suggested), hormone replacement therapy, hydroxyurea, bisphosphonates (6 months prior), interferon/ribavirin, warfarin (switch to heparin), oral hypoglycemic (switch to insulin)
    • - May be resumed: calcium, vitamin D, penicillin in splenectomized patients
  • > During delivery
    • - Vaginal vs. Caesarian section: assessment depending on pelvic and cardiac status
    • - Epidural anesthesia in case of Caesarian section
  • > Post-delivery
    • - Restart iron chelation (post breast feeding, deferoxamine can be resumed immediately)
    • - Resume calcium and vitamin D
    • - Restart bisphosphonates (post breast feeding)
    • - Restart hormone replacement therapy (post breast feeding)
    • - Avoid breast feeding if positive for HIV, hepatitis B or C
    • - Discuss contraception
• In NTDT patients with hypogonadism, ovulation or spermatogenesis may need to be induced and should be done by an experienced fertility centre.

REFERENCES

1.

Nassar AH, Naja M, Cesaretti C, Eprassi B, Cappellini MD, Taher A. Pregnancy outcome in patients with beta-thalassemia intermedia at two tertiary care centers, in Beirut and milan. Haematologica. 2008;93(10):1586–1587. [PubMed: 18698079]

2.

Nassar AH, Usta IM, Rechdan JB, Koussa S, Inati A, Taher AT. Pregnancy in patients with beta-thalassemia intermedia: outcome of mothers and newborns. Am J Hematol. 2006;81(7):499–502. [PubMed: 16755576]

3.

Origa R, Piga A, Quarta G, Forni GL, Longo F, Melpignano A, Galanello R. Pregnancy and beta-thalassemia: an Italian multicenter experience. Haematologica. 2010;95(3):376–381. [PMC free article: PMC2833066] [PubMed: 19903676]

4.

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(2):182–186. [PubMed: 16219519]

5.

Nassar AH, Usta IM, Taher AM. Beta-thalassemia intermedia and pregnancy: should we anticoagulate? J Thromb Haemost. 2006;4(6):1413–1414. [PubMed: 16706992]