Fetal risk from ACE inhibitors in the first trimesterBMJ 2011; 343 doi: https://doi.org/10.1136/bmj.d6667 (Published 18 October 2011) Cite this as: BMJ 2011;343:d6667
As in the general population, management of hypertension in pregnant women is complicated by factors that may be difficult to control (such as diabetes, obesity, and smoking). However, the choice of antihypertensive drug is uniquely complicated in pregnancy, because the clinician not only has to consider the comparative safety and efficacy of various drugs from the mother’s perspective, but also consider the effects on the fetus. Rising rates of hypertension related to obesity and diabetes heighten this concern. Furthermore, therapeutic choices cannot wait until pregnancy is recognised—because about half of pregnancies (at least in the United States) are unplanned, fetal exposure early in the first trimester is a distinct possibility. Thus, fetal concerns should be taken into account when prescribing antihypertensives to all women of childbearing potential—a considerable clinical population. In the linked retrospective cohort study (doi: 10.1136/bmj.d5931), Li and colleagues assess the association between the use of angiotensin converting enzyme (ACE) inhibitors in mothers during the first trimester and the risk of malformations in their offspring.1
Few studies have been large and rigorous enough to provide useful information on the fetal safety of most antihypertensives. Although it is accepted that ACE inhibitors cause fetal harm when exposure occurs in the later stages of pregnancy,2 a widely cited 2006 report that used US Tennessee Medicaid data found that exposure in the first trimester was also associated with an increased risk of cardiac malformations and neural tube defects; no increased risks were seen for other classes of antihypertensive drug.3 Where clinicians might previously have felt comfortable using ACE inhibitors until a woman became pregnant, switching to another drug before the second trimester, this finding suggested that to avoid inadvertent first trimester exposure, prescribers should not use ACE inhibitors in women of childbearing potential.
Li and colleagues tested the hypothesis in a larger and more diverse database—the Kaiser Permanente Northern California member population of women, with established linkages to pharmacy data, malformation diagnoses, and certain potential confounding factors.1 They estimated risks in pregnant women who received only ACE inhibitors in the first trimester, and separately, women who received antihypertensive drugs other than ACE inhibitors. These women were compared with two unexposed groups—those with a diagnosis of hypertension who received no antihypertensive drugs in the first trimester, and women without hypertension during pregnancy who did not receive antihypertensive drugs. They also considered factors that could modify the observed effects, including diabetes and obesity (unfortunately, cohorts based on medical records can rarely control for the potentially important effects of perinatal consumption of non-prescription multivitamins containing folic acid). When compared with the “normal” pregnant population, women taking ACE inhibitors had a modestly increased risk of defects overall and of cardiac defects (but not neural tube defects—other specific defects were not considered). Similar increases were seen for women taking other antihypertensive drugs. However, when the two exposed groups were compared with women with untreated hypertension, the risks were lower and approached the null hypothesis. This finding suggests that it was the underlying hypertension (treated or not) that increased the risks of the studied defects.
Li and colleagues’ findings are similar to those from a much smaller Swedish cohort, which compared users of ACE inhibitors with users of other antihypertensives and found no differences in cardiovascular defects between the two groups.4 They are also similar to those from a large US case-control study, which had the power to consider specific cardiac defects and also included a comparison involving women with untreated hypertension.5 On the basis of all these findings, it is reasonable to conclude that exposure to ACE inhibitors during the first trimester poses no greater risk of birth defects than exposure to other antihypertensives.
Given the limitations of these studies, it is possible that ACE inhibitors (and other antihypertensives) may be associated, if modestly, with one or another specific defect, but the greater concern is that the underlying hypertension itself places the fetus at risk.
But what is the definition of “hypertension” and “untreated hypertension”? It is reasonable to assume that untreated hypertension is less severe than treated hypertension, but observational studies have lacked data on crucial variables related to hypertension in pregnancy, including its causes, severity, duration, and especially the level of adherence and control associated with drug treatment. Under these circumstances, a randomised trial might seem like the answer, but the ethics of withholding drug treatment are daunting. Thus, we will probably have to continue to rely on observational studies, however imperfect they may be.
Some challenges that warrant consideration in future studies include not only providing answers to the questions above, but also to whether there is a “pre-hypertensive” condition that may affect the fetus before an increase in maternal blood pressure is detected, or even detectable. Are there physiological changes that might affect fetal development before they manifest as increased maternal blood pressure? Although clinicians must certainly identify and control hypertension, particularly in pregnancy, much is left to learn about how hypertension can cause birth defects.
Cite this as: BMJ 2011;343:d6667
Competing interests: The author has completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declares: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Commissioned; not externally peer reviewed.