Antihypertensive drugs and pregnancy: an update

About 1-5% of women develop hypertensive disorders in pregnancy and some of them are treated with antihypertensive drugs.1 Gestational hypertension increases the risk of preeclampsia1 and has been associated to negative outcomes in pregnancy, like spontaneous abortion, intrauterine growth restriction and premature delivery.2

Are these outcomes due to hypertension or drugs?

It is still under discussion if some of the cited outcomes could be associated to hypertension itself, more than to the drugs used for its treatment, or to both.3 A retrospective cohort study published in 2013 evaluated a group of hypertensive pregnant women treated or not with antihypertensive drugs. During the study – conducted on 100,029 registered pregnancies - 1,964 women developed chronic hypertension and about 620 infants were exposed at least once to an antihypertensive drug (atenolol and methyldopa).
In respect to pregnant women with normal blood pressure who were not treated with antihypertensive drugs, hypertensive women exposed to antihypertensive had a higher risk of intrauterine growth restriction (7.2% vs 2.1%, adjusted odds ratio 4.27, p A similar risk was even found even for hypertensive not-treated women were compared with not-treated women with normal blood pressure. The authors conclude that chronic hypertension is an independent risk factor for important perinatal adverse events.

ACE inhibitors, sartans, beta blockers and calcium antagonists

Exposure to ACE inhibitors (and perhaps to sartans too)4 in pregnancy, especially in the third trimester, has been associated to a foetopathy characterized by foetal hypotension, anuria-oligohydramnios, growth restriction, renal tubular dysplasia and hypoplasia of cranial bones.5 Even though in the past ACE-inhibitors usage during the first trimester was not associated with congenital anomalies, a study published in 2006 noticed that exposure to ACE inhibitors during the first trimester was associated to a risk of malformation which was 2.7 times higher in respect to the not-exposed control group (see Focus n. 46, August 2006).6
Another comparative study7 on enalapril limited to the first trimester of pregnancy with a control group treated with enalapril for the whole pregnancy, identified a three times higher risk for congenital anomalies for the patients who kept using the drug beyond the first trimester. A more recent study did not identify particular risks associated with ACE inhibitors or sartans use during the initial phase of pregnancy.8 Therefore at present it is difficult to assess the safety of ACE inhibitors usage during specific gestational ages because data are lacking or conflicting.
A British cohort study in 20139 evaluated the prevalence of congenital anomalies among children whose mothers (n=341) were exposed to antihypertensive drugs in the early phases of pregnancy, comparing the risk of congenital anomalies for different drugs users and women not exposed to antihypertensive drugs in the first trimester (n=682). The prevalence of congenital anomalies among the exposed women was 23.5 on thousand pregnancies in respect to 20.9 for the women not exposed (relative risk: 3.8; 95% confidence interval: 0.4–2.2). Exposure to ACE inhibitors (relative risk: 3.8; 95% confidence interval: 0.9–16.0), beta blockers (relative risk: 2.8; 95% confidence interval: 0.7-11.9) and calcium antagonists (relative risk: 1.3; 95% confidence interval: 0.1–12.4) does not increase the risk of congenital anomalies in a statistically significant way. Considering the study results and its limitations, the authors’ advice is against the use of ACE inhibitors during the first trimester of pregnancy. Calcium antagonists use has been correlated to limbs defects in animals,10 whilst a study on a very small group of women exposed to calcium antagonists did not identify particular risks.11
Some authors12 identified a potential risk of reduced oxygen extraction at cerebral level for a very small group of preterm infants (n=49) born from women exposed to labetanol and/or magnesium sulfate during pregnancy. The same effect has been observed for nifedipine. It is unknown if this damage could lead to subsequent ailments.