Pregnancy outcome after in utero exposure to angiotensin converting enzyme inhibitors or angiotensin receptor blockers

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Abstract

Objective

To examine first trimester safety of angiotensin-converting-enzyme-inhibitors (ACEIs) or angiotensin-receptor-blockers (ARBs).

Study design

Prospective observational cohort regarding pregnancy ACEI/ARBs-exposure including contacts to two Teratology Information Services in Israel (1994–2007) and Italy (1990–2008), with two comparison groups: (1) exposed to other antihypertensives (OAH) (2) after non-teratogenic exposure (NTE) in similar time frames.

Results

252 ACEI/ARBs-exposed, 256 OAH-exposed and 495 NTE-exposed pregnancies were followed-up. The rate of major congenital anomalies was comparable between the groups (8/190, 4.2%, ACEI/ARB; 9/212, 4.2%, OAH; 18/471, 3.8% NTE; p = 0.954) among first trimester exposed pregnancies. The median gestational age at delivery was two weeks earlier, rate of preterm deliveries more than 2-fold higher, and median birth weight more than 200 g lower in the ACEI/ARB and OAH groups compared to the NTE group.

Conclusion

The present study suggests that ACEI/ARBs are not major teratogens when used in the first trimester, and can reassure women with similar exposures.

Introduction

Angiotensin converting enzyme inhibitors (ACEIs) are a group of compounds used in the management of hypertension [1] and in diabetic nephropathy [2]. In vitro studies have shown that ACEIs cross the sheep [3] and human [4] placentae. There is evidence from animal studies that administration of ACEIs during pregnancy is associated with fetal toxicity and an increase in still-births [5], [6]. The use of ACEIs in humans during late pregnancy has been associated with a characteristic fetopathy including renal dysplasia, oligohydramnios, hypocalvaria, limb contractures, pulmonary hypoplasia and intrauterine growth restriction [7], [8], [9], [10]. The fetal effects are thought to be direct consequences of anuria and oligohydramnios resulting from ACEI-induced fetal hypotension and resultant fetal impairment.

The use of angiotensin II receptor antagonists, also known as angiotensin receptor blockers (ARBs), in the second and third trimesters of pregnancy has also been associated with a similar fetotoxicity [11], [12].

Most available data on the use of ACEIs, limited to the first trimester of pregnancy, to date, did not support an increased risk of congenital malformations [13], [14], [15], [16], [17], [18], [19], [20], [21]. Contrary to the above, one recent study [22] found an increased risk of cardiovascular and central nervous system malformations in infants whose mothers were prescribed an ACEI during the first trimester. The study raised a debate whether it adequately controlled for maternal diabetes mellitus and for obesity [23], [24], [25]. A Finnish study also found an increased risk of malformations associated with first trimester exposure to ACEIs which could be explained by maternal diabetes mellitus [26]. An increase in cardiovascular defects was noted among infants born to mothers who had used ACEIs or other antihypertensives in early pregnancy in a Swedish study [27]. The available data on first trimester use of ARBs are very limited and do not support a clear teratogenic effect [11], [27].

The primary objective of the present study was to prospectively evaluate the rate of major congenital anomalies after pregnancy exposure to ACEI/ARBs in the first trimester of pregnancy compared to the rate in a comparison group exposed to other antihypertensives (OAHs) in an attempt to control for the underlying diseases, and in a comparison group exposed to non-teratogens. Secondary endpoints of interest were pregnancy outcome, neonatal birth weight, gestational age at delivery and neonatal complications.

Section snippets

Data collection

Our prospective observational study enrolled pregnant women who contacted the Israeli Teratology Information Service (TIS), (Jerusalem, Israel) or Servizio di Informazione Teratologica (Padova, Italy) in regard to gestational exposure to ACE/ARBs between the years 1994 and 2007 (Israel), and 1990 and 2008 (Italy). The two services are members of the European Network of Teratology Information Services (ENTIS), an organization of counseling services in regard to environmental exposures during

Results

A total of 252 ACEI/ARBs exposed pregnancies were prospectively followed-up in the present study (171 from Israel and 81 from Italy). The majority of the women were exposed to ACEIs (224/252, 88.9%), while 11.1% (28/252) were exposed to ARBs. The distribution of the various ACEIs and ARBs in the exposed group is presented in Table 1. The exposure was at least in the first trimester of pregnancy in 99.2% of the ACEI/ARB group. In most of the cases (90.5%) the medication was discontinued during

Discussion

In the present prospective observational comparative cohort study, 252 ACEI/ARBs-exposed pregnancies were followed-up. The rate of major anomalies was within the expected baseline risk in the general population. The results of the present study are consistent with most previous reports, not associating first trimester ACEI-exposure with a teratogenic risk in humans [13], [14], [15], [16], [17], [18], [19], [20], [21]. This study supports that ACEI/ARBs in the first trimester of pregnancy do not

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    Previous presentation of data at the 23rd International Conference of the Organization of Teratology Information Specialists (OTIS), Louisville, Kentucky, June 28th, 2010.

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    Served as partial requirement for the MD degree of the Hebrew University.

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