Fetopathy associated with exposure to angiotensin converting enzyme inhibitors and angiotensin receptor antagonists

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Abstract

The renin–angiotensin system plays an important role in the regulation of blood pressure. The use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers both control hypertension by interruption of the production or action of angiotensin II, the major end-product of the renin–angiotensin system. The use of angiotensin converting enzyme inhibitors in pregnant women revealed serious and deleterious effects on fetal development including renal failure, renal dysplasia, hypotension, oligohydramnios, pulmonary hypoplasia, and hypocalvaria. The fetal effects of angiotensin converting enzyme inhibitors seem to be greatest during the 2nd and 3rd trimesters of pregnancy. The fetal effect of angiotensin converting enzyme inhibitors during the 1st trimester is controversial. These effects may represent the effect of hypoperfusion in the fetus and not a teratogenic effect. The effect of angiotensin receptor blockers is similar to converting enzyme inhibitors. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers should be avoided in all pregnant women. Alternative antihypertensive medications should be considered for use in women of childbearing years.

Introduction

The renin–angiotensin system plays an important role in the homeostasis of extracellular fluid volume and blood pressure [1]. The major effector hormone of the renin–angiotensin system is the octapeptide, angiotensin II. Angiotensin II acts directly on vascular smooth muscle to produce vasoconstriction and elevate blood pressure and stimulates aldosterone release by the adrenal cortex to retain filtered sodium and expand the extracellular fluid volume [1].

The classical renin–angiotensin system was initially described as a systemically circulating endocrine hormonal system, where the final endproduct of the cascade is angiotensin II. In this scheme (Fig. 1), circulating angiotensinogen, derived from the liver, is cleaved by renin, an aspartyl protease, to produce angiotensin I. Renin is released into circulating via the juxtaglomerular cells in the kidney in response to extracellular volume depletion. Angiotensin I, in turn, is cleaved by angiotensin converting enzyme into the very biologically active peptide hormone, angiotensin II. Angiotensin converting enzyme is present in high concentration on the vascular endothelium. Newly formed angiotensin II is then free to circulate and exert its effects on a wide range of target tissues, including the heart, brain, vascular smooth muscle, and kidney. In addition to the classical endocrine renin–angiotensin system, there is growing evidence that autonomous autocrine or paracrine renin–angiotensin systems exist and exert control in a localized tissue specific manner [1], [2]. Such an autonomous localized tissue specific renin–angiotensin system has been demonstrated to function in the kidney [2].

The renin–angiotensin system is known to be active during renal development in the fetus [3]. All components of the renin–angiotensin system have been demonstrated to exist in the developing kidney including renin and its mRNA, angiotensinogen peptide and its mRNA, proximal tubule and renal vascular angiotensin converting enzyme, angiotensin I and II, and angiotensin II receptors, including both receptors subtypes, type 1 (AT1) and type 2 (AT2) [3]. These components of the renin–angiotensin system appear in a complex and yet, consistently coordinated fashion throughout embryologic development. For example, early during embryogenesis, the AT2 receptor predominates over the AT1 receptor, particularly in the developing mesenchyme surrounding the ureteric bud. After birth, the nephron matures and AT1 receptor expression rises as the expression of the AT2 receptor falls [3]. By the end of the second week of postnatal life, AT2 mRNA is undetectable [3]. The coordination of angiotensin receptor expression throughout fetal life illustrates the importance of the role of the renin–angiotensin system in normal renal development.

Section snippets

Angiotensin converting enzyme inhibitors

The use of angiotensin converting enzyme inhibitors (ACE inhibitors) represents a major advance in the treatment of hypertension. ACE inhibitors inhibit the conversion of angiotensin I into angiotensin II, thereby preventing production of a vasoactive peptide and reducing blood pressure (Fig. 1). The first converting enzyme inhibitor to be developed was captopril. Since then, a number of longer acting analogues have been developed including, enalapril, accupril, lisinopril, ramipril,

Adverse effects of angiotensin converting enzyme inhibitors during pregnancy: animal data

Many of the studies that reported adverse effects of ACE inhibitor use during pregnancy were initially conducted in animals. A common model for study of maternal–fetal interactions is the use of pregnant sheep. Use of captopril in the maternal sheep during late pregnancy (119–133 days gestational age—term is 147 days) reduced maternal blood pressure transiently for 2 h. However, fetal blood pressure remained reduced for up to 2 days and the risk of stillbirth was significantly elevated, where 7

Adverse effects of angiotensin converting enzyme inhibitors during pregnancy: human studies

Since the wide availability of ACE inhibitors for clinical use, numerous reports on their effects during pregnancy in humans have surfaced. Although the deleterious effects of ACE inhibitors on fetal development may be dependent upon which stage of pregnancy the drugs are used, the fetal effects of their use during the first trimester of pregnancy remain somewhat controversial. In a survey of Michigan Medicaid recipients, there was no association between use of ACE inhibitors during the first

Angiotensin II receptor antagonist

Recently, a new class of antihypertensive drugs have emerged and have targeted another arm of the renin–angiotensin system. These drugs are angiotensin II receptor antagonist and competitively inhibit the binding of angiotensin II to its receptor (AT1), thereby oppose the systemic effects of angiotensin II. Commonly used angiotensin II receptor antagonist (AT1 antagonist) include losartan, candesartan, valsartan and tasosartan. AT1 antagonist are as effective as the ACE inhibitors in control of

Adverse effects of angiotensin II receptor antagonist during pregnancy

Human studies on the fetal effects of maternal use of AT1 antagonists are limited. 32 infants were identified who were born to women who took AT1 antagonists during the first trimester of their pregnancies [38]. Of these 32 infants, only 2 (6%) were noted to have major malformations. In one case, the fetus had exencephaly and in the other, had cleft palate, patent ductus arteriosus, coarctation of the aorta, and growth retardation [38]. In another study in the United Kingdom, four pregnancies

Summary and current recommendations

The ACE inhibitors and AT1 antagonists are powerful antihypertensives in the medicinal armamentarium against hypertension. Given the central role of the fetal renin–angiotensin system in normal renal development, it is not surprising that the use of ACE inhibitors or AT1 antagonists can disrupt normal organogenesis. ACE inhibitors and AT1 antagonists produce a very similar clinical outcome and includes oligohydramnios, fetal growth retardation, pulmonary hypoplasia, neonatal hypotension, renal

Key guidelines

  • The fetal renin–angiotensin system plays an important role in renal development.

  • Use of ACE inhibitors or angiotensin receptor blockers during pregnancy can cause renal abnormalities, renal failure, oligohydramnios, and pulmonary hypoplasia.

  • Fetal exposure to ACE inhibitors or angiotensin receptor blockers during the 2nd or 3rd trimesters is associated with a higher incidence of fetal anomalies.

  • ACE inhibitors or angiotensin receptor blockers should be avoided in women who may become pregnant.

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