Associate Professor in Maternal Fetal Medicine, Associate Program Director, Maternal Fetal Medicine Fellowship, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
Sickle cell disease (SCD) is the most commonly inherited autosomal recessive genetic hemoglobinopathy in the United States, characterized by homozygous or heterozygous inheritance of two abnormal hemoglobin genes, at least one of which is hemoglobin S.1 In the United States, people with SCD account for only 0.1% of all deliveries, but approximately 1% of maternal deaths, a 10-fold increased risk.2 SCD encompasses many distinct genotypes. Those that lead to the near-exclusive production of hemoglobin S (hemoglobin SS and hemoglobin Sβ0 thalassemia) are called sickle cell anemia. The most common compound heterozygous forms are hemoglobin SC and hemoglobin Sβ+ thalassemia, but there are many other disease-causing combinations.3,4
SCD is associated with chronic end-organ damage to the brain, lungs, kidneys, and bones that accumulates with time, and the disease course may be punctuated by acute complications, including painful crises and acute chest syndrome.1 Pregnancy in people with SCD is at high risk for maternal and fetal complications, including hypertensive diseases of pregnancy, preterm birth, placental abruption, and intrauterine fetal growth restriction.5-7
Preconception and Prenatal Care
In preconception management in persons with SCD, it is crucial to discuss partner testing for hemoglobinopathy traits by ethnicity-based testing (as recommended by the American College of Obstetricians and Gynecologists [ACOG]), as well as genetic risk to the fetus.8,9 During this time, couples at high risk for SCD should be counseled on their choices, including pre-implantation genetic diagnosis and prenatal diagnosis.
Renal and cardiopulmonary complications, such as urinary tract infections, chronic kidney disease, pulmonary hypertension, and heart failure, occur in many people with SCD during their lifetime, and the physiologic changes of pregnancy aggravate these complications.10 Hence, assessment of renal and cardiovascular function prior to pregnancy in people with SCD is important, since optimization of organ function prior to pregnancy has been shown to improve maternal outcomes.5 A screening renal function test (with at least a comprehensive panel) and screening cardiac testing (with electrocardiogram ± maternal echocardiography) are recommended prior to pregnancy.
Medication review is critical prior to conception, since people with SCD on hydroxycarbamide should discontinue pre-conceptually, because this drug has been demonstrated to be teratogenic in animals.11,12 A clinical trial (NCT04093986) currently is collecting retrospective data on hydroxycarbamide exposure during pregnancy. New medications for SCD, including crizanlizumab, L-glutamine, voxelotor, and stem-cell therapies, do not have pharmacokinetic and safety data in pregnancy, so they should be discontinued prior to conception.13
During prenatal care, it is important to co-manage people with SCD with the hematology team to maintain hemoglobin concentrations as optimally as possible, usually between 7 mg/dL to 10 mg/dL. Blood transfusion sometimes can be indicated to correct severe anemia and reduce sickle-related complications during pregnancy. Although there is increasing evidence that prophylactic blood transfusion might be beneficial in people with SCD during pregnancy, including its benefits in the reduction of cardiopulmonary complications, the best approach to transfusion (“prophylactic simple” vs. “prophylactic exchange” blood transfusion protocols) remains unknown.
In the only published randomized trial in 72 pregnant people with SCD receiving standard care (transfusion for symptomatic anemia) vs. prophylactic transfusion (prophylactic simple or prophylactic exchange), there was a significant reduction in the incidence of vaso-occlusive crises in the prophylactic transfusion arm but no differences in other secondary outcomes.14
A Phase II randomized clinical trial (NCT03975894) currently is investigating the role of serial prophylactic simple compared to prophylactic exchange transfusion in pregnant people with SCD (TAPS-2), and as such, there is insufficient evidence to recommend prophylactic transfusion during pregnancy at this time. Folic acid supplementation is reasonable in pregnant people with SCD.15 Iron therapy typically is not recommended in people with SCD during pregnancy unless there is rare laboratory evidence of iron deficiency anemia.
Risks During Pregnancy
Pregnant people with SCD have an increased risk of hypertensive diseases of pregnancy (gestational hypertension, preeclampsia, and eclampsia).2 Although the definition of hypertension in pregnancy in non-SCD pregnant people is blood pressure readings > 140/90 mmHg, recent evidence from the American Society of Hematology (ASH) demonstrates that a target blood pressure of < 130/80 mmHg is optimal for pregnant people with SCD. The ASH recommends that blood pressures > 130/80 mmHg should be considered hypertension in pregnant people with SCD.16
Although there is no specific evidence that aspirin decreases the risk of preeclampsia in people with SCD, it is reasonable to commence a daily low dose (81 mg) of aspirin from 12 weeks of gestation until delivery to mitigate the risk of preeclampsia. Management of sickle pain crisis remains the most common indication for obstetric triage visits and antepartum admissions in people with SCD during pregnancy in the United States. Although there are no good studies to guide pain control options in people with SCD during pregnancy, treatment of acute pain crises in pregnant people with SCD should follow ACOG pharmacologic pain control recommendations (analgesic ladder) in nonpregnant people, but with modifications to therapy where there are specific maternal or fetal safety concerns.17 Other management strategies for acute pain crises include bed rest and intravenous hydration. Thromboprophylaxis is recommended during antepartum admissions for acute pain crises.5
Delivery and Postpartum
Although there are no evidence-level I or II studies to guide optimal timing of delivery in people with SCD, recent studies demonstrate increased fetal mortalities in people with SCD when deliveries occur in the late-term and post-term periods.18 However, delivery in people with SCD typically occurs between 37w0d and 40w0d, and usually is the result of complications such as gestational hypertension, preeclampsia, or fetal complications. Vaginal delivery is the favored mode of delivery, with cesarean delivery reserved for obstetric indications.
Although there is no evidence to guide the optimal hemoglobin concentrations prior to cesarean delivery, people with SCD with marked anemia (< 7 mg/dL) at the time of delivery may benefit from preoperative transfusion prior to cesarean delivery. One randomized controlled trial that evaluated whether complication rates in nonpregnant people with SCD would be altered by preoperative transfusion demonstrated a reduction in postoperative sickle complications when preoperative hemoglobin was > 9 mg/dL.19 More studies are needed in pregnancy.
Postpartum contraception is recommended in people with SCD. The contraceptive choice should consider the patient’s previous complications with contraception, preference, and adherence. Progestin-only contraception typically is preferred, but copper intrauterine devices (IUDs) also have been used with increasing frequency. The copper IUD is classified as World Health Organization (WHO) medical eligibility criteria for contraceptive use (MEC) category 2 because of concern about the potential increased risk of blood loss, but it still is considered in people with SCD because its benefits outweigh its risks.20
Barrier methods are safe in people with SCD, but generally are less effective when compared to other forms of contraception. Although there is theoretical concern that estrogen-containing hormonal contraceptives might increase the risk of thrombosis in people with SCD, the most recent WHO MEC guideline classifies combined oral contraceptives as category 2, where the advantages outweigh the theoretical risks.20
REFERENCES
- Pecker LH, Lanzkron S. Sickle cell disease. Ann Intern Med 2021;174:ITC1-ITC16.
- Villers MS, Jamison MG, De Castro LM, James AH. Morbidity associated with sickle cell disease in pregnancy. Am J Obstet Gynecol 2008;199:125.e1-5.
- Koshy M. Sickle cell disease and pregnancy. Blood Rev 1995;9:157-164.
- Silva FAC, Ferreira AL, Hazin-Costa MF, et al. Adverse clinical and obstetric outcomes among pregnant women with different sickle cell disease genotypes. Int J Gynaecol Obstet 2018;143:89-93.
- Jain D, Atmapoojya P, Colah R, Lodha P. Sickle cell disease and pregnancy. Mediterr J Hematol Infect Dis 2019;11:e2019040.
- Oteng-Ntim E, Meeks D, Seed PT, et al. Adverse maternal and perinatal outcomes in pregnant women with sickle cell disease: Systematic review and meta-analysis. Blood 2015;125:3316-3325.
- Smith-Whitley K. Complications in pregnant women with sickle cell disease. Hematology Am Soc Hematol Educ Program 2019;2019:359-366.
- ACOG Committee on Obstetrics. ACOG practice bulletin no. 78: Hemoglobinopathies in pregnancy. Obstet Gynecol 2007;109:229-237.
- [No authors listed]. Committee opinion no. 691: Carrier screening for genetic conditions. Obstet Gynecol 2017;129:e41-e55.
- Eke AC. An update on the physiologic changes during pregnancy and their impact on drug pharmacokinetics and pharmacogenomics. J Basic Clin Physiol Pharmacol 2021; Dec 8. doi:10.1515/jbcpp-2021-0312. [Online ahead of print].
- Chaube S, Murphy ML. The effects of hydroxyurea and related compounds on the rat fetus. Cancer Res 1966;26:1448-1457.
- Woo G-H, Bak E-J, Nakayama H, Doi K. Hydroxyurea (HU)-induced apoptosis in the mouse fetal lung. Exp Mol Pathol 2005;79:59-67.
- Ali MA, Ahmad A, Chaudry H, et al. Efficacy and safety of recently approved drugs for sickle cell disease: A review of clinical trials. Exp Hematol 2020;92:11-18.e1.
- Koshy M, Burd L, Wallace D, et al. Prophylactic red-cell transfusions in pregnant patients with sickle cell disease. A randomized cooperative study. N Engl J Med 1988;319:1447-1452.
- Dixit R, Nettem S, Madan SS, et al. Folate supplementation in people with sickle cell disease. Cochrane Database Syst Rev 2016;2:CD011130.
- Liem RI, Lanzkron S, Coates TD, et al. American Society of Hematology 2019 guidelines for sickle cell disease: Cardiopulmonary and kidney disease. Blood Adv 2019;3:3867-3897.
- American College of Obstetricians and Gynecologists' Committee on Clinical Consensus–Obstetrics. Pharmacologic stepwise multimodal approach for postpartum pain management: ACOG clinical consensus no. 1. Obstet Gynecol 2021;138:507-517.
- Boafor TK, Olayemi E, Galadanci N, et al. Pregnancy outcomes in women with sickle-cell disease in low and high income countries: A systematic review and meta-analysis. BJOG 2016;123:691-698.
- Howard J, Malfroy M, Llewelyn C, et al. The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: A randomised, controlled, multicentre clinical trial. Lancet 2013;381:930-938.
- De Sanctis V, Soliman AT, Daar S, et al. Current issues and options for hormonal contraception in adolescents and young adult women with sickle cell disease: An update for health care professionals. Mediterr J Hematol Infect Dis 2020;12:e2020032.
Sickle cell disease (SCD) is the most commonly inherited autosomal recessive genetic hemoglobinopathy in the United States. People with SCD account for only 0.1% of all deliveries, but approximately 1% of maternal deaths, a 10-fold increased risk.
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