Abstract
This population-based cohort study examines the risk of fetal cardiac malformations associated with maternal β-blocker exposure.
β-Blockers are the most commonly used class of medication for treating cardiac conditions in pregnant women. Despite the common use of this class of medication, data that support its safety are limited.
β-Blockers cross the placenta and potentially can cause physiological changes in the fetus. β-Blocker exposure has been shown to cause bradycardia and hypoglycemia in the neonate. A recent meta-analysis reported an association between β-blocker exposure and fetal congenital cardiovascular defects, raising a concern regarding potential teratogenic effects of this class of medication. This study examines the risk of fetal cardiac malformations in association with maternal β-blocker exposure.
Methods
This is a retrospective population-based cohort study that included births in the Kaiser Permanente Southern California (KPSC) Region between January 1, 2003, and December 31, 2014. Only singleton pregnancies were included. Pregnant women exposed to β-blockers during pregnancy were identified using pharmacy dispensing records. Maternal comorbidities and fetal congenital anomalies were identified by searching electronic medical records using ICD-9-CM codes. Fetal birth weights were obtained from California birth certificates. Logistic regression analyses were used to estimate odds ratios (ORs) with 95% CIs. Multivariable logistic regression models were constructed by including factors that have been shown in other studies to affect fetal congenital anomalies. The research protocol used in this study was reviewed and approved by the Kaiser Permanente institutional review board. The need for written informed consent was waived owing to the retrospective nature of the study.
Results
In a cohort of 379 238 pregnancies, 4847 (1.3%) were exposed to β-blockers. Among this group, 2628 (0.7%) were exposed to β-blockers during the first trimester of pregnancy. The 4 most commonly prescribed β-blockers were labetalol (n = 3357), atenolol (n = 638), propranolol (n = 489), and metoprolol (n = 324). Table 1 shows the baseline maternal characteristics of the study population. Women exposed to β-blockers were older, and had higher body mass indices. Diagnoses of hypertension, preeclampsia, eclampsia, hyperlipidemia, diabetes, heart failure, and a history of arrhythmia were more common among patients exposed to β-blockers. Gestational age at delivery was lower in the β-blocker–exposed group (mean [SD] weeks, β-blocker group 37.4 [3.0] vs 38.9 [1.9] in the unexposed group).
Table 1. Baseline Characteristics of Pregnant Women by Status of β-Blocker Exposure During Pregnancy.
| Characteristic | Unexposed (n = 374 391) | Exposed Anytime During Pregnancy (n = 4847) | P Valuea | Exposed During First Trimester (n = 2628) | P Valuea |
|---|---|---|---|---|---|
| Age, mean (SD), y | 29.7 (5.9) | 33.1 (5.7) | <.001 | 34.0 (5.9) | <.001 |
| Race/ethnicity, No. (%) | <.001 | <.001 | |||
| White | 92 030 (24.6) | 1302 (26.9) | 690 (26.3) | ||
| Black | 31 910 (8.5) | 784 (16.2) | 452 (17.2) | ||
| Hispanic | 194 660 (52.0) | 2007 (41.4) | 1066 (40.6) | ||
| Asian | 46 266 (12.4) | 606 (12.5) | 340 (12.9) | ||
| Other | 9525 (2.5) | 148 (3.1) | 80 (3.0) | ||
| BMI, mean (SD) | 26.2 (6.1) | 31.6 (8.0) | <.001 | 31.8 (8.0) | <.001 |
| HTN, No. (%) | 25 823 (6.9) | 3698 (75.3) | <.001 | 2239 (85.2) | <.001 |
| HLD, No. (%) | 36 535 (9.8) | 1362 (28.1) | <.001 | 871 (33.1) | <.001 |
| DM, No. (%) | 14 812 (4.0) | 849 (17.5) | <.001 | 537 (4.1) | <.001 |
| CHF, No. (%) | 1066 (0.3) | 144 (3.0) | <.001 | 87 (3.3) | <.001 |
| Arrhythmia, No. (%) | 16 022 (4.3) | 989 (19.4) | <.001 | 505 (19.2) | <.001 |
| CKD, No. (%) | 1866 (0.5) | 246 (5.1) | <.001 | 157 (6.0) | <.001 |
| Gravida, No. (%) | <.001 | <.001 | |||
| 1 | 110 836 (29.6) | 1104 (22.8) | 522 (19.9) | ||
| 2 | 105 243 (28.1) | 1223 (25.2) | 659 (25.1) | ||
| ≥3 | 158 312 (42.3) | 2520 (52.0) | 1447 (55.0) | ||
| Gestational age at delivery, mean (SD), weeks | 38.9 (1.9) | 37.4 (3.0) | <.001 | 37.5 (2.9) | <.001 |
| Preeclampsia, No. (%) | 2330 (0.6) | 94 (1.9) | <.001 | 37 (1.4) | <.001 |
| Eclampsia, No. (%) | 287 (0.1) | 24 (0.5) | <.001 | 10 (0.4) | <.001 |
| Fetal birthweight, mean (SD), g | 3353 (554) | 2996 (811) | <.001 | 3028 (777) | <.001 |
| Delivery method, No. (%) | <.001 | <.001 | |||
| Vaginal (spontaneous) | 261 819 (70) | 2301 (47.4) | 1237 (47.1) | ||
| Vaginal (assisted) | 8233 (2.2) | 91 (1.9) | 56 (2.1) | ||
| Cesarean | 104 203 (27.8) | 2455 (50.6) | 1335 (50.8) |
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CHF, congestive heart failure; CKD, chronic kidney disease; DM, diabetes; HLD, hyperlipidemia; HTN, hypertension.
Compared with unexposed; t-tests for continuous variables, Fisher exact for categorical variables.
Table 2 summarizes the unadjusted and adjusted associations between β-blocker exposure and congenital cardiac anomalies in the infants. In unadjusted analyses, maternal β-blocker exposure was associated with significantly increased odds of fetal congenital cardiac anomalies. However, after adjusting for maternal age, maternal body mass index, and maternal comorbidities, there was no longer an association between β-blocker exposure and fetal congenital cardiac anomalies. These results suggest that the associations seen in the unadjusted analysis were caused by confounders rather than effects conferred by β-blocker exposure itself.
Table 2. Association of β-Blocker Exposure With Fetal Congenital Cardiac Anomalies.
| Congenital Cardiac Anomalies | 374 391 Unexposed, No. (%) | 4847 Exposed to β-Blocker Anytime During Pregnancy | 2628 Exposed to β-Blocker During the First Trimester | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| No. (%) | Univariable Analysis | Multivariable Analysisa | No. (%) | Univariable Analysis | Multivariable Analysisa | ||||||
| Unadjusted Odds Ratio (95% CI) | P Value | Adjusted Odds Ratio (95% CI) | P Value | Unadjusted Odds Ratio (95% CI) | P Value | Adjusted Odds Ratio (95% CI) | P Value | ||||
| Any cardiac anomalies | 7231 (1.9) | 247 (5.1) | 2.7 (2.4-3.1) | <.001 | 1.1 (0.9-1.3) | .32 | 128 (4.9) | 2.5 (2.2-3.1) | <.001 | 1.0 (0.8-1.3) | .93 |
| ASD | 2643 (0.7) | 82 (1.7) | 2.4 (1.9-3.0) | <.001 | 1.1 (0.8-1.4) | .57 | 44 (1.7) | 2.4 (1.8-3.2) | <.001 | 1.0 (0.7-1.5) | .84 |
| VSD | 2751 (0.7) | 52 (1.1) | 1.5 (1.1-2.0) | .001 | 0.9 (0.7-1.3) | .60 | 30 (1.1) | 1.6 (1.1-2.2) | .02 | 0.9 (0.6-1.4) | .64 |
| Conotruncal defectsb | 393 (0.1) | 11 (0.2) | 2.2 (1.2-3.9) | .01 | 0.8 (0.4-1.8) | .64 | 9 (0.3) | 3.3 (1.7-6.3) | <.001 | 1.0 (0.4-2.7) | .98 |
| Single ventricle physiologyc | 166 (0.04) | 8 (0.2) | 3.7 (1.8-7.6) | <.01 | 1.1 (0.4-2.6) | .94 | 5 (0.2) | 4.2 (1.7-10.3) | .001 | 1.3 (0.4-3.9) | .70 |
| PDA | 4087 (1.1) | 185 (3.8) | 3.6 (3.1-4.2) | <.001 | 1.2 (0.99-1.5) | .06 | 92 (3.5) | 3.2 (2.6-4.0) | <.001 | 1.0 (0.8-1.4) | .77 |
| Coarctation | 218 (0.06) | 5 (0.1) | 1.8 (0.7-4.3) | .21 | 0.5 (0.2-1.8) | .33 | 5 (0.2) | 3.3 (1.4-8.0) | .01 | 1.2 (0.3-4.3) | .75 |
Abbreviations: ASD, atrial septal defect; PDA, patent ductus arteriosus; VSD, ventricular septal defect.
Adjusted for maternal age, gestational age at delivery, white race, body mass index (BMI, calculated as weight in kilograms divided by height in meters squared), maternal comorbidities (hypertension, hyperlipidemia, diabetes, congenital heart disease, heart failure, coronary artery disease, stroke, arrhythmia, chronic kidney disease). Multivariable analyses included patients from 2007-2014 because BMI information was only available in patients from 2007 onwards.
Conotruncal defects include tetralogy of Fallot, transposition of the aorta, and truncus arteriosus.
Single ventricle physiology includes hypoplastic left ventricle and common ventricle.
Discussion
In this large population-based cohort study in California, we found that β-blocker exposure was not associated with increased risks of fetal congenital cardiac anomalies after adjustment for maternal comorbidities. The previously reported association between β-blocker use and fetal cardiac anomalies in other studies may be attributed to confounding.
One limitation of our study is that β-blocker exposure was based on pharmacy dispensing information, and it was not possible to ascertain if the pregnant women actually took the medication (ie, misclassification owing to noncompliance). On the other hand, because pharmacy dispensing information was used, we were able to avoid any recall bias that might be associated with studies using surveys to determine medication exposure.
While these findings do not definitively rule out the possibility of fetal congenital defects in association with β-blocker use, these results do provide reassurance regarding the use of this class of medication for the treatment of cardiac conditions in pregnant women.
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