First Trimester Hypertension, Not ACE Inhibitors, Linked to Birth Defects

Although the teratogenic properties of ACE inhibitors in the second and third trimesters are well-documented, the effect of ACE inhibitors on infants born to women taking ACE inhibitors in the first trimester has been unclear, so don’t order a diaper cake yet. Now a new study suggests that hypertension itself, rather than ACE inhibitors or other antihypertensive drugs, is the likely cause of an increased risk for birth defects in this population.

In a paper published in BMJ, De-Kun Li and colleagues analyzed Kaiser Permanente data from 465,754 mother-infant pairs in Northern California from 1995 to 2008. After adjusting for other risk factors, ACE inhibitor use was associated with an increased risk of congenital heart defects only when compared with normal controls without hypertension or use of other antihypertensives. No significant elevation in risk was observed when ACE inhibitor use was compared to other antihypertensives or to hypertensive controls.

The authors concluded:

Maternal use of ACE inhibitors in the first trimester has a risk profile similar to the use of other antihypertensives regarding malformations in live born offspring. The apparent increased risk of malformations associated with use of ACE inhibitors (and other antihypertensives) in the first trimester is likely due to the underlying hypertension rather than the medications.

In an accompanying editorial, Allen Mitchell writes that on the basis of this and previous studies “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.” He also discusses the implications of the finding that  hypertension can cause birth defects, and wonders if there are “physiological changes that might affect fetal development before they manifest as increased maternal blood pressure.”

Here is the press release from BMJ:

High blood pressure in early pregnancy raises risk of birth defects, irrespective of medication

Research: Maternal exposure to angiotensin-converting enzyme inhibitors in the first trimester and risk of malformations in offspring: a retrospective cohort study
Editorial: Fetal risk from ACE inhibitors in the first trimester

Women with high blood pressure (hypertension) in the early stages of pregnancy are more likely to have babies with birth defects, irrespective of commonly prescribed medicines for their condition, finds new research published on bmj.com today.

The finding suggests that it is the underlying hypertension, rather than the use of antihypertensive drugs in early pregnancy, that increases the risk of birth defects.

Angiotensin-converting enzyme (ACE) inhibitors are a type of antihypertensive medication commonly prescribed to tackle hypertension. It is already known that they have a toxic effect on fetuses in the second or third trimesters, but their effects on a fetus during the mother’s first trimester is still unclear.

So researchers led by Dr De-Kun Li of the Kaiser Foundation Research Institute in California, set out to see if there was an association between using ACE inhibitors during a woman’s first trimester and birth defects.

They studied data on 465,754 mother-infant pairs from the Kaiser Permanente Northern Californian region between 1995 and 2008. Data was also available on which medications had been prescribed and dispensed to these women.

Analysis showed that women who used ACE inhibitors in their first trimester were more likely to have a baby with some form of birth defect compared with women who did not have hypertension or who had not used any form of antihypertensive medication.

However, a similar elevated risk was found among women who used other antihypertensive drugs and those with hypertension who did not take any antihypertensive medication. 

The researchers conclude: “Our finding suggests that it is likely the underlying hypertension rather than use of antihypertensive drugs in the first trimester that increases the risk of birth defects in offspring.”

In an accompanying editorial, Professor Allen Mitchell from Boston University says that – based on the available studies – it would appear reasonable to conclude that first-trimester exposure to ACE inhibitors poses no greater risk of birth defects than other antihiypertensives, and that it is the underlying hypertension that places the fetus at risk. 

He believes that, while clinicians must certainly identify and control hypertension, particularly in pregnancy, “we have much to learn about how hypertension can cause birth defects.”

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