β-Blocker Use in Pregnancy and the Risk for Congenital Malformations: An International Cohort Study

Abstract

Background: β-Blockers are a class of antihypertensive medications that are commonly used in pregnancy.

Objective: To estimate the risks for major congenital malformations associated with first-trimester exposure to β-blockers.

Design: Cohort study.

Setting: Health registries in the 5 Nordic countries and the U.S. Medicaid database.

Patients: Pregnant women with a diagnosis of hypertension and their offspring.

Measurements: First-trimester exposure to β-blockers was assessed. Outcomes were any major congenital malformation, cardiac malformations, cleft lip or palate, and central nervous system (CNS) malformations. Propensity score stratification was used to control for potential confounders.

Results: Of 3577 women with hypertensive pregnancies in the Nordic cohort and 14 900 in the U.S. cohort, 682 (19.1%) and 1668 (11.2%), respectively, were exposed to β-blockers in the first trimester. The pooled adjusted relative risk (RR) and risk difference per 1000 persons exposed (RD1000) associated with β-blockers were 1.07 (95% CI, 0.89 to 1.30) and 3.0 (CI, -6.6 to 12.6), respectively, for any major malformation; 1.12 (CI, 0.83 to 1.51) and 2.1 (CI, -4.3 to 8.4) for any cardiac malformation; and 1.97 (CI, 0.74 to 5.25) and 1.0 (CI, -0.9 to 3.0) for cleft lip or palate. For CNS malformations, the adjusted RR was 1.37 (CI, 0.58 to 3.25) and the RD1000 was 1.0 (CI, -2.0 to 4.0) (based on U.S. cohort data only).

Limitation: Analysis was restricted to live births, exposure was based on dispensed medication, and cleft lip or palate and CNS malformations had few outcomes.

Conclusion: The results suggest that maternal use of β-blockers in the first trimester is not associated with a large increase in the risk for overall malformations or cardiac malformations, independent of measured confounders.

Primary funding source: The Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Söderström König Foundation.

Appendix Figure 1.

Histograms Showing the Distribution of the Propensity Score (PS) in the β-Blocker Exposed and Unexposed in the First Trimester of Pregnancy

Appendix Figure 1.

Histograms Showing the Distribution of the Propensity Score (PS) in the β-Blocker Exposed and Unexposed in the First Trimester of Pregnancy

Appendix Figure 2.

Impact of restriction to livebirths.

Appendix Figure 2.

Impact of restriction to livebirths.

Appendix Figure 2.

Impact of restriction to livebirths.

Appendix Figure 2.

Impact of restriction to livebirths.

Figure 1.. Nordic and US MAX cohort selection.

ATC = Anatomical Therapeutic Chemical; LMP = last menstrual period; US MAX = U.S. Medicaid Analytic eXtract. * From 30 d before LMP through first trimester. These included wafarin, antineoplastic agents (actinomycin, busulfan, chlorambucil, colchicine, cyclophosphamide, doxorubicin, mercaptopurine, methotrexate, vinblastine, and vincristine), lithium, isotretinoin, misoprostol, and thalidomide for the US MAX cohort and retinoids, antineoplastic agents, and immunosuppressants (ATC codes D05BB, L01, and L04) for the Nordic cohort. † From 90 d before LMP through first trimester (ATC codes C02, C03, C04, C05, C08, and C09), or (for US MAX) a Beta-blocker in the 90 d before LMP but not in the first trimester. ‡ Excluded because of missing data on parity, i.e., the checkbox for parity on the maternity record had not been filled in.

Figure 2.. Meta-analytic pooled estimates for the Nordic and US MAX cohorts.

Risk for congenital malformations after exposure to β-blockers in the first trimester of pregnancy, adjusted RR (95% CI), and adjusted RD₁₀₀₀ (95% CI). Cell sizes <11 cannot be presented for the US MAX data because of restrictions on reporting small numbers. RD₁₀₀₀ = risk difference per 1000 persons exposed; RR = relative risk; US MAX = U.S. Medicaid Analytic eXtract.