Perinatal outcomes after in-utero exposure to beta-blockers in women with heart disease: Data from the ESC EORP registry of pregnancy and cardiac disease (ROPAC).

Beta-blockers are commonly used drugs during pregnancy, especially in women with heart disease, and are regarded as relatively safe although evidence is sparse. Differences between beta-blockers are not well-studied. In the Registry of Pregnancy And Cardiac disease (ROPAC, n = 5739), a prospective global registry of pregnancies in women with structural heart disease, perinatal outcomes (small for gestational age (SGA), birth weight, neonatal congenital heart disease (nCHD) and perinatal mortality) were compared between women with and without beta-blocker exposure, and between different beta-blockers. Multivariable regression analysis was used for the effect of beta-blockers on birth weight, SGA and nCHD (after adjustment for maternal and perinatal confounders). Beta-blockers were used in 875 (15.2%) ROPAC pregnancies, with metoprolol (n = 323, 37%) and bisoprolol (n = 261, 30%) being the most frequent. Women with beta-blocker exposure had more SGA infants (15.3% vs 9.3%, p < 0.001) and nCHD (4.7% vs 2.7%, p = 0.001). Perinatal mortality rates were not different (1.4% vs 1.9%, p = 0.272). The adjusted mean difference in birth weight was -177 g (-5.8%), the adjusted OR for SGA was 1.7 (95% CI 1.3-2.1) and for nCHD 2.3 (1.6-3.5). With metoprolol as reference, labetalol (0.2, 0.1-0.4) was the least likely to cause SGA, and atenolol (2.3, 1.1-4.9) the most. In women with heart disease an association was found between maternal beta-blocker use and perinatal outcomes. Labetalol seems to be associated with the lowest risk of developing SGA, while atenolol should be avoided.

Ramlakhan KP ，Roos-Hesselink JW ，Basso T ，Greenslade J ，Flint RB ，Krieger EV ，Shotan A ，Budts W ，De Backer J ，Hall R ，Johnson MR ，Parsonage WA ，ROPAC Investigators ... -  《-》

Treatment with oral beta-blockers during pregnancy complicated by maternal heart disease increases the risk of fetal growth restriction.

To investigate the effect on fetal growth of treatment with oral beta-blockers during pregnancy in women with congenital or acquired heart disease. Historical matched cohort study. Centre for Pregnant Women with Heart Disease, Copenhagen University Hospital, Denmark. A cohort of 175 women with heart disease, grouped according to beta-blocker treatment, and a cohort of 627 women from the overall population matched on seven birthweight-determining factors. Differences between groups were tested by simple descriptive statistics and assessed using standard hypothesis tests. Associations were estimated by correlational analysis and multivariable regression. Proportion of infants born small for gestational age (SGA). More of the infants exposed to beta-blockers were SGA compared with non-exposed infants (29.4 versus 15.3%; P < 0.05). After adjustment for birthweight-determining factors, beta-blocker treatment and maternal body mass index (BMI) were the only factors independently associated with SGA (the relative difference in expected birthweight was -8.6%; 95% CI -13.3 to -3.9%; P = 0.0004). After adjustment for BMI, beta-blocker treatment was associated with an increased risk of SGA (OR 2.65; 95% CI 1.15-6.10; P = 0.02). In a subgroup with isolated tachyarrhythmias, SGA infants were more frequent in the beta-blocker exposed group compared with the non-exposed group (31 versus 10%; P < 0.005). Beta-blocker treatment was the only independent predictor of SGA, adjusting for several factors influencing fetal growth (the relative difference in expected birthweight was -12.2%; 95% CI -19.9 to -3.9%; P = 0.001). In a historical cohort of pregnancies complicated by maternal heart disease, treatment with beta-blockers was found to be independently associated with an increased risk of delivering an SGA infant.

Ersbøll AS ，Hedegaard M ，Søndergaard L ，Ersbøll M ，Johansen M ... -  《-》

Beta-blocker subtypes and risk of low birth weight in newborns.

Beta-blockers are one of the most commonly prescribed classes of antihypertensive medications during pregnancy. Previous studies reported an association between beta-blocker exposure and intrauterine growth restriction. Whether some beta-blocker subtypes may be associated with higher risk is not known. This is a retrospective cohort study of pregnant women exposed to beta-blockers in the Kaiser Permanente Southern California Region between 2003 and 2014. Logistic regression models were used to evaluate association between exposure to different beta-blocker agents and risk of low fetal birth weights. In a cohort of 379 238 singleton pregnancies, 4847 (1.3%) were exposed to beta-blockers. The four most commonly prescribed beta-blockers were labetalol (n = 3357), atenolol (n = 638), propranolol (n = 489), and metoprolol (n = 324). Mean birth weight and % low birth weight (<2500 g) were 2926 ± 841 g and 24.4% for labetalol, 3058 ± 748 g and 18.0% for atenolol, 3163 ± 702 g and 13.3% for metoprolol, 3286 ± 651 g and 7.6% for propranolol, and 3353 ± 554 g and 5.2% for non-exposed controls. Exposure to atenolol and labetalol were associated with increased risks of infant born small for gestational age (SGA) (atenolol: adjusted OR 2.4, 95% CI: 1.7-3.3; labetalol: adjusted OR 2.9, 95% CI: 2.6-3.2). Risk of SGA associated with metoprolol or propranolol exposure was not significantly different from the non-exposed group (metoprolol: adjusted OR 1.5, 95% CI: 0.9-2.3; propranolol: adjusted OR 1.3, 95% CI: 0.9-1.9). Association between beta-blocker exposure and SGA does not appear to be a class effect. Variations in pharmacodynamics and confounding by indication may explain these findings.

Duan L ，Ng A ，Chen W ，Spencer HT ，Lee MS ... -  《-》

Diuretics in pregnancy: Data from the ESC Registry of Pregnancy and Cardiac disease (ROPAC).

Data on diuretic use in pregnancy are limited and inconsistent, and consequently it remains unclear whether they can be used safely. Our study aims to evaluate the perinatal outcomes after in-utero diuretic exposure. The Registry Of Pregnancy And Cardiac disease (ROPAC) is a prospective, global registry of pregnancies in women with heart disease. Outcomes were compared between women who used diuretics during pregnancy versus those who did not. Multivariable regression analysis was used to assess the impact of diuretic use on the occurrence of congenital anomalies and foetal growth. Diuretics were used in 382 (6.7%) of the 5739 ROPAC pregnancies, most often furosemide (86%). Age >35 years (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2-2.0), other cardiac medication use (OR 5.4, 95% CI 4.2-6.9), signs of heart failure (OR 1.7, 95% CI 1.2-2.2), estimated left ventricular ejection fraction <40% (OR 2.9, 95% CI 2.0-4.2), New York Heart Association class >II (OR 3.4, 95% CI 2.3-5.1), valvular heart disease (OR 6.3, 95% CI 4.7-8.3) and cardiomyopathy (OR 3.9, 95% CI 2.6-5.7) were associated with diuretic use during pregnancy. In multivariable analysis, diuretic use during the first trimester was not significantly associated with foetal or neonatal congenital anomalies (OR 1.3, 95% CI 0.7-2.6), and diuretic use during pregnancy was also not significantly associated with small for gestational age (OR 1.4, 95% CI 1.0-1.9). Our study does not conclusively establish an association between diuretic use during pregnancy and adverse foetal outcomes. Given these findings, it is essential to assess the risk-benefit ratio on an individual basis to guide clinical decisions.

van der Zande JA ，Greutmann M ，Tobler D ，Ramlakhan KP ，Cornette JMJ ，Ladouceur M ，Collins N ，Adamson D ，Paruchuri VP ，Hall R ，Johnson MR ，Roos-Hesselink JW ， on behalf of the ROPAC Investigators Group ... -  《-》

ACE Inhibitor and Angiotensin Receptor Blocker Use During Pregnancy: Data From the ESC Registry Of Pregnancy and Cardiac Disease (ROPAC).

Angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) are not recommended during the second and third trimester because of the significant risk of congenital anomalies associated with their use. However, data are scarce, especially regarding their use in the first trimester and about the impact of stopping just before pregnancy. Our study illustrates the profile of the women who used ACE-Is or ARBs during pregnancy and evaluates the impact on perinatal outcomes. The Registry of Pregnancy and Cardiac Disease is a prospective, global registry of pregnancies in women with structural heart disease. Outcomes were compared between women who used ACE-Is or ARBs and those who did not. Multivariable regression analysis was performed to assess the effect of ACE-I or ARB use on the occurrence of congenital anomalies. ACE-Is (n = 35) and/or ARBs (n = 8) were used in 42 (0.7%) of the 5,739 Registry of Pregnancy and Cardiac Disease pregnancies. Women who used ACE-Is or ARBs more often came from a low-or-middle-income country (57% vs 40%, p = 0.021), had chronic hypertension (31% vs 6%, p <0.001), or a left ventricular ejection fraction <40% (33% vs 4%, p <0.001). In the multivariable analysis, ACE-I use during the first trimester was associated with an increased risk of congenital anomaly (odds ratio 3.2, 95% confidence interval 1.0 to 9.6). Therefore, ACE-Is should be avoided during pregnancy, also in the first trimester, because of a higher risk of congenital anomalies. However, there is no need to stop long before pregnancy. Preconception counseling is crucial to discuss the potential risks of these medications, to evaluate the clinical condition and, if possible, to change or stop the medication.

van der Zande JA ，Ramlakhan KP ，Prokselj K ，Muñoz-Ortiz E ，Baroutidou A ，Lipczynska M ，Nagy E ，Rutz T ，Franx A ，Hall R ，Johnson MR ，Roos-Hesselink JW ，ROPAC investigators ... -  《-》