Mode of Action: Angiotensin-Converting Enzyme Inhibition—Developmental Effects Associated With Exposure to ACE Inhibitors

Abstract

Relative to species tested in laboratory studies, the human fetus displays higher vulnerability to enalapril and other angiotensin-converting enzyme inhibitors (ACEI) exhibiting a malformative syndrome that does not appear to have a similar counterpart in experimental animals. An important reason for this higher vulnerability is the earlier intrauterine development of the kidney and the renin-angiotensin-aldosterone (RAS) system in humans, organ systems that are specific targets of ACEI's pharmacological effect. In humans, these systems begin developing prior to the onset of skeletal ossification at the end of the first trimester, with continuing vulnerability throughout the pregnancy. In most animal species tested, these target systems develop close to term, when the fetus is relatively more mature and less vulnerable to the effects of developmental toxicants. For this reason, animal studies that follow standard protocols and evaluate developmental toxicity only for exposures during embryogenesis will miss developmental effects arising secondary to disruption of target systems that develop after the period of major organogenesis. Thus, although the animal mode of action (MOA) for enalapril and other ACEI is plausible in humans, differences in the timing of development of critical target organ systems, particularly the renal system and RAS, explain the absence of definitive structural abnormalities in test animals.

Maternal use of antihypertensive drugs in early pregnancy and delivery outcome, notably the presence of congenital heart defects in the infants

“…In humans, hypocalvaria has been described in some cases [18][19]. Since membranous bones are highly vasculated and in need of high vascular oxygen tension during development, it has been postulated that fetal hypotension produced by ACE inhibitors could induce hypoxia thus resulting in hypocalvaria [18].…”

“…Since membranous bones are highly vasculated and in need of high vascular oxygen tension during development, it has been postulated that fetal hypotension produced by ACE inhibitors could induce hypoxia thus resulting in hypocalvaria [18]. The renal development has also been described to be affected by fetal kidney hypotension, causing renal tubular dilatation or distal tubular hypoplasia [18][19]. These effects are suggested to occur, not in the first, but in the second and third trimesters [15].…”

Does the Renin-Angiotensin System Participate in Regulation of Human Vasculogenesis and Angiogenesis?

“…ACE inhibitors have shown particular efficacy in preventing adverse cardiac events in high-risk individuals, treatment of patients with congestive heart failure, and prevention of diabetic nephropathy. However, it has also been recognized for several years that these drugs are teratogenic when developing fetuses are subjected to prolonged exposure during the second and third trimesters of pregnancy (1). Congenital abnormalities associated with fetal exposure to ACE inhibitors include neonatal renal failure, oligohydramnios, and skeletal abnormalities, all of which were presumably related to decreased amniotic fluid production (2), with the proposed pathophysiology for these congenital abnormalities being attributed to reduction in fetal renal blood flow (3).…”

The Use of Angiotensin Converting Enzyme Inhibitors during the First Trimester of Pregnancy

“…ACEIs are known to cross the placenta [9][10][11][12]. It is now known that when administered mid-late pregnancy, ACEIs can impair fetal development through inducing fetal hypotension, decreasing uterine, umbilical, and renal blood flow [13]. This can induce oligohydramnios, growth reduction, hypocalvaria, hypotension, neonatal renal failure and death [12][13][14][15].…”

“…It is now known that when administered mid-late pregnancy, ACEIs can impair fetal development through inducing fetal hypotension, decreasing uterine, umbilical, and renal blood flow [13]. This can induce oligohydramnios, growth reduction, hypocalvaria, hypotension, neonatal renal failure and death [12][13][14][15]. Since 1992, the U.S. Food and Drug Administration has required a warning on all ACEIs regarding their fetotoxic effects when used during trimesters two and three [16,17].…”