Angiotensin-Converting Enzyme Inhibitors

TERATOLOGY 50399409 (1994)

Teratogen Update: Angiotensin-Converting Enzyme Inhibitors

MASON BARR, JR. Departments of Pediatrics, Pathology, and Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan 48109

Angiotensin-converting enzyme (ACE) inhibitors import such drug recirculation might have on fetal (ACEI) were developed from a serendipitous discovery physiology has not been assessed. that a Brazilian snake venom contained a bradykinin- USE OF ACEIs potentiating factor with vasodilating properties (Fer- reira, '65). The physiological significance of this was Since their introduction, ACEIs have come to be re- established by demonstrating inhibition of ACE by the garded as a major advance in the treatment of hyper- peptide mixture from the snake venom (Bakhle, '68). tension (Thurston, '92; Rodicio and Ruilope, '93; Mat- The first clinically usable ACEI, captopril, was synthe- erson and Preston, '94). It has been observed that most sized in 1975 (Cushman and Ondetti, '91). In the types of hypertension respond favorably to ACEI ther- United States, captopril (Capoten") was approved for apy, with or without the addition of diuretics (Sassano clinical use in 1981, followed by enalapril (Vasotec@)in et al., '87; Garay et al., '94). Antihypertensives such as 1985, lisinopril (Prinivil@,Zestriln) in 1987, benazepril beta-adrenergic receptor blockers and diuretics tend to (Lotensin@),fosinopril (MonopriP), and ramipril (Al- increase peripheral resistance and have side effects on tacea) in 1991, and quinapril (Accupril@) in 1992. the metabolism of electrolytes, glucose, and lipids. In Other ACEIs discussed in the literature but not cur- contrast, ACEIs decrease vascular resistance, improve rently marketed in the United States include abu- glucose handling, control left ventricular mass, and of- tapril, alacepril, ceronapril, cilazepril, delapril, fer a degree of myocardial protection (Williams, '88; idrapril, imidapril, moexipril, pentopril, perindopril, Gavras, '88; Materson and Preston, '94). In the absence rentiapril, spirapril, temocapril, trandolapril, zabicip- of heart failure, ACEIs produce little change in heart ril, and zofenapril. rate, cardiac output, or pulmonary wedge pressure in Two of the currently available ACEIs, captopril and normal or hypertensive people (Vidt et al., '82; Todd lisinopril, are in the active form; the others are proac- and Heel, '86; Gomez et al., '87). They have also been tive drugs that are deesterified in the liver to the active found to contribute to an improved quality of life for form (designated by the suffix -prat) and were devel- the hypertensive patient, particularly when compared oped to enhance absorption or prolong activity or both. to beta-blockers (Materson and Preston, '94). Captopril binds the enzyme by means of a sulfhydryl A use for ACEIs that has excited considerable inter- group, fosinopril by a phosphodyl group, and the others est stems from the demonstration that they impede the by a carboxyl (Materson and Preston, '94). ACEIs are progression of nephropathy associated with diabetes mainly excreted through the kidney, although up to mellitus, both type 1 and type 2 (Ravid et al., '93; 50% of ramipril and fosinopril is excreted in the feces Bakris, '93; Viberti et al., '94). The ACEIs reduce mi- (Williams, '88; manufacturers' literature). croalbuminuria, preserve renal function, and increase Placental passage of the various ACEIs appears to be insulin sensitivity; these effects are believed to be in- both species and drug dependent. In common labora- dependent of the antihypertensive action of these drugs tory animals there may be little passage of some ACEIs (Ravid et al., '93). through the placenta (Endo et al., '92). However, in Guthrie ('93) reported that prescriptions for ACEIs humans it is established from measurements in ex- increased nearly 250% between 1986 and 1990, testi- posed newborns that enalapril, captopril, and lisinopril fying to their popularity in clinical use, and many ar- do cross the placenta in pharmacologically significant ticles have appeared extolling their use as first line amounts, and it is assumed that the other available agents in the treatment of hypertension. The use of ACEIs also cross the human placenta (Schubiger et al., '88; Pryde et al., '93). Once in the fetus, it may be pre- Received October 3, 1994; accepted October 3, 1994. sumed that an ACEI will be renally excreted (provided Address reprint requests to Mason Barr, Jr., M.D., Pediatric Genet- there is urine production) largely as the active drug, ics-Teratology Unit, D1109 MPB 0718, University of Michigan Med- which may then be swallowed and recirculated. What ical Center, Ann Arbor, MI 48109-0718.

0 1994 WILEY-LISS, INC. 400 M.BARR

ACEIs for myocardial protection poses little concern to al. (Piper et al., '92'; Thorpe-Beeston et al., '93), and I the teratologist, since the vast majority of such use will have received at least partial reports of five others from be in patients beyond the childbearing years. However, medical colleagues and attorneys. It appears that the their use for mild or essential hypertension, and in bulk of ACEI fetopathy cases have ensued after enal- such conditions as the autoimmune diseases and dia- april exposure, but cases associated with captopril and betes mellitus, could expose a considerable number of lisinopril are recorded (Hanssens et al., '91; Pryde et women in the childbearing years, not a few of whom al., '93). As pointed out by Brent and Beckman ('gl), will be pregnant. The use of ACEIs for the manage- there is no reason to assume that the other ACEIs are ment of pregnancy-induced hypertension, by defini- incapable of producing the same result. Similarly, tion, creates a certain and identifiable fetal exposure. many of the cases have involved coexposure to other The actual number of pregnancies exposed to ACEIs antihypertensive agents, and while combination ther- cannot be determined from available data. Piper et al. apy may pose more risk to the fetus, monotherapy with ('92) reported that of 106,813 Tennessee Medicaid pa- an ACEI has produced the full-blown fetopathy. tients who delivered a live or stillborn infant during The most commonly reported adverse effect of ACEI 1983-1988, 19 were exposed to an ACEI. Given the exposure of the fetus is that of second to third trimester expansion of use of these agents to the current time, it onset of oligohydramnios and growth restriction, fol- would be reasonable to expect that the number of fetal lowed by delivery of an infant whose neonatal course is exposures will increase. complicated by prolonged and often profound hypotension and anuria (Rosa et a]., '89). The presentation may also include the oligohydramnios deformation se- ADVERSE EFFECTS quence and its lethal component, pulmonary hypopla- In the enthusiasm to employ ACEIs as first line sia (Guignard et al., '81; Mehta and Modi, '89; Cunniff agents for treatment of hypertension and to retard de- et al., '90; Pryde et al., '93). Although studies of the velopment of diabetic nephropathy, their safety some- histology of the kidneys in ACEI-exposed fetuses and times seems to be overstated. As wonderful as they infants are few in number, they are consistent in their seem, ACEIs are not without adverse effects. As de- demonstration of renal tubular dysgenesis (Knott et scribed below, because they suppress aldosterone secre- al., '89; Cunniff et al., '90; Pryde et al., '93). Delayed tion, they are liable to produce hyperkalemia, particu- development of the calvaria has been noted in enough larly in the face of sodium restriction, heart failure, cases to consider it a part of the syndrome. Postnatal diabetes, and coadministration of potassium-sparing persistence of a patent ductus arteriosus (PDA) has diuretics and nonsteroidal anti-inflammatory drugs also been suggested to be part of the syndrome, but it is (Williams, '88; Schlueter et al., '94). Their use in cer- hard to determine if this finding is an effect of ACEI tain circumstances, such as bilateral renal artery ste- exposure. nosis, can contribute to, not ameliorate, renal dysfunc- The true rates of adverse fetal effects from ACEI use tion (Hricik et al., '83; Cooke and Debesse, '94). In some in human pregnancy cannot be determined from avail- cases the dysfunction may be reversible (Wood et al., able information. Certainly, a number of exposed preg- '91) and in others irreversible (Devoy et al., '92). Per- nancies have resulted in no measurable adverse effect haps the most common side effect of the ACEIs is an (Ducret et al., '85; Kreft-Jais et al., '88; Piper et al., irritating cough, which ironically has generated more '92). In the largest published series there were 31 preg- literature than has the possibility of fetal damage. nancies exposed either to captopril (n = 22) or enala- As early as 1980, there were reports of fetal wastage pril (n = 9) (Kreft-Jais et al., '88). The reported adverse in ACEI-exposed experimental animals (Broughton- outcomes included nine cases of intrauterine growth Pipkin et al., '80, '82; Ferris and Weir, '82). In 1981, the restriction, three intrauterine deaths, and two infants first adverse outcome in a human pregnancy was re- with PDA, of which one ultimately required ligation. ported (Duminy and Burger, '81). This was followed in The 22 other cases in this report were presumably un- short order by other cases implicating both captopril affected. and enalapril as potential fetotoxins (Guignard, '82; The adverse developmental effects of ACEIs are pur- Boutroy et al., '84; Caraman et al., '84; Fiocchi et al., posely designated ACEI fetopathy because as yet there '84; Rothberg and Lorenz, '84). Warnings about the use is no convincing evidence that they cause harm in the of ACEIs in human pregnancy appeared in the litera- first trimester of human gestation or its equivalent in ture as early as 1985 (Lindheimer and Katz, '85). On laboratory animals. Studies with captopril and enala- the other hand, some recent reviews of the ACEIs make pril in rats failed to show malformations resulting from no mention of the possibility of adverse fetal effects (Materson and Preston, '94; Pinkney and Yudkin, '94). Pryde et al. ('93) recently proposed the designation "ACE inhibitor fetopathy," summarized 29 affected lone case described by Piper et al. ('921, with microcephaly and cases from the literature, and added 3 more. Two more encephalocele, was classified as an example of hypocalvaria: I believe cases have been reported since the review by Pryde et this infant's problems were probably unrelated to ACEI exposure. ACE INHIBITORS 401 high doses (Fujii et al., '85; Fujii and Nakatsuka, '85; Kininogen Angiotensinogen Robertson et al., '86; Al-Shabanah et al., '91; Al-Harbi Kaliikrein ---t 1C--, Renin et al., '92), although at the highest doses tested, fetal 1 Arachidonic, Bradykinin\/ Angiotensin I growth restriction, delayed ossification, and resorp- Acid tions were noted in conjunction with evidence of ma- I Kininase II ConvertingEnzyme ternal toxicity. In humans, the case reported by 1 ECF Expaniion Thorpe-Beeston et al. ('93) was found to have renal cystic dysplasia, a disorder distinct from the renal tu- Na+Retention bular dysgenesis found in other cases, but still likely to Prostaglandin I ? be a fetal rather than an embryonic effect. In the case 1 LAidoeterone J reported by Duminy and Burger ('81) there was a terminal transverse deficiency of a limb, again likely to be of fetal origin. The second case mentioned by Piper et al. ('92) was remarkable for microcephaly and enceph- Fig. 1. Schematic representation of the renin-angiotensin-bradyki- alocele, the latter almost certainly a problem of first nin system. ECF = extracellular fluid. trimester origin, and I am aware of an enalapril exposure-associated case of anencephaly. These few dispar- '90). Homozygotes for the deletion (DD) show the high- ate anomalies associated with ACEI exposure do not est serum levels of ACE activity, while homozygotes for constitute sufficient evidence of true teratogenicity, al- the insertion (11) have the lowest levels. The prevalence though admittedly there is insufficient evidence to be of the gene types varies in different populations (Lee, confident of safety in the first trimester. Currently, the ,941, and it has been reported that the deletion geno- recommendation is to offer reassurance of unlikely first type is less prevalent in diabetic patients with ne- trimester effects, but to avoid second and third trimes- phropathy than in those without nephropathy (Marre ter exposure, unless absolutely necessary for the moth- et al., '94). Angiotensin I1 receptors similarly have two er's well being. types: type 1 (AT,) is found in a wide variety of tissues in the adult and seems to mediate all the known effects on angiotensin I1 related to the RAS. This type of re- REVIEW OF RENIN-ANGIOTENSIN ceptor has two subtypes, ATlA and ATlB, which are SYSTEM (RAS) said to show few pharmacological differences and may Angiotensin I is a decapeptide formed from the ac- function as growth factors. While the type 2 (AT,) re- tion of renin on its precursor, angiotensinogen (Fig. 1). ceptor is the predominant type found in the gestational Angiotensin I has no known biological action in hu- day (GD) 19 rat fetus, fetal adrenal cortex and renal mans but is rapidly converted to the biologically active glomeruli express both AT,, and AT,, mRNAs (Grone octapeptide, angiotensin 11. This conversion is effected et al., '92; Shanmugam et al., '94). Their roles in fetal by ACE, a zinc metalloprotease that catalyzes the hy- development are being investigated. What effect such drolysis of carboxy-terminal dipeptides from oligopep- genetic diversity, in mother or fetus, may have on the tide substrates. The principal substrates are angioten- Occurrence of adverse fetal effects from ACEI exposure sin I and the nonapeptide, bradykinin, but other is unknown at this time, but should be explored. substrates are affected as well (Ehlers and Riordan, The RAS becomes crucially important under condi- '89). Angiotensin I1 is a potent vasoconstrictor, stimu- tions of low renal perfusion pressure (Hall et al., '77; lates aldosterone secretion from the adrenal cortex, Blythe, '83). In these conditions, which pertain to the and suppresses renin release by increasing sodium re- fetus, angiotensin 11-mediated efferent arteriolar resis- tention, whereby it closes a negative-feedback loop. A tance is essential to the maintenance of glomerular parallel system involves the formation of bradykinin filtration (GFR) and production of urine (Rudolph et and its inactivation by kininase TI (which is identical al., '71; Giugnard, '82). Activation of bradykinin by with ACE). Angiotensin I1 raises blood pressure, and suppression of angiotensin I1 can compromise GFR by bradykinin, if not inactivated by the enzyme, lowers virtue of bradykinin's vasodilatory effect on the effer- blood pressure. ent arteriole (Kon et al., '93). In the adult, ACEIs in- ACE has two catalytic sites, one near the carboxyl crease renal blood flow. Usually this occurs without terminus and one near the amino acid terminus. These modifying the GFR because vasodilation of efferent ar- sites may have specific substrates, but angiotensin I terioles exceeds that of the afferent arterioles (Wil- and bradykinin appear to be catalyzed equally at both liams, '88). In cases of renal artery stenosis, bilateral or sites (Johnston et al., '93). The ACE gene is develop- unilateral in a solitary kidney, there is an inability to mentally regulated in a tissue-specific manner and increase renal blood flow sufficiently to compensate for plays a role in the regulation of renal function and the efferent arteriolar dilation and maintain glomeru- growth (Yosipiv et al., '94). The ACE gene exhibits lar perfusion pressure (Hricik et al., '83). polymorphism, marked by the insertion or deletion of a In pregnancy-induced hypertension mean arterial 250 bp fragment in intron 16 of the gene (Rigat et al., blood pressure is correlated with serum ACE activity 402 M.BARR

(Li et al., '92) and is characterized by enhanced an- while circulating angiotensin I1 and ACE activity giotensin I1 sensitivity due to an increase in angioten- change reciprocally (Yosipiv et al., '94). It appears that sin I1 receptor number (Graves et al., '92). However, kinins and angiotensin I1 influence the development of the RAS is known to be both a circulating and a tissue ACE. It has been established that the RAS is active in hormonal system, and, of the two, tissue systems may fetal life, when it plays an essential role in maintain- be the more important (Ehlers and Riordan, '89; ing GFR under conditions of low renal perfusion pres- Johnston et al., '92). ACE is widely distributed in the sure (Jelinek et al., '86). At least in the lamb, it seems body; it has been found in soluble form in body fluids that the RAS is more active in the fetus than in the and in membrane-bound form in arterial endothelial neonate (Binder and Anderson, '92). cells within and outside the pulmonary circulation, in Angiotensin I1 may also act on the growth of its tar- epithelial cells with brush borders (placenta, kidney, get tissues. Some cells, such as those of the adrenal intestine, and choroid plexus), in neuroepithelial cells, cortex, show induction of cell division by angiotensin and in the male genital tract (testis, prostate, and ep- 11. The mechanism by which angiotensin I1 induces hy- ididymis) (Erdos and Skidgel, '87). Evidence is emerg- perplasia of its target tissues is largely unknown but ing that plasma ACE inhibition and hemodynamic re- may be from a direct action on proto-oncogene synthe- sponses are separable (Lees et al., '92). Prolonged sis or an indirect action on growth factor secretion treatment with an ACEI results in an increase of (Clauser et al., '92). As previously noted, the subtypes plasma ACE but a decrease of ACE in the renal cortex of angiotensin I1 receptors may function differentially and renal brush border (Michel et al., '93). This indi- as growth factors (Shanmugam et al., '94). cates that plasma and epithelial ACE are subject to local regulatory factors. The renal proximal convoluted ANIMAL STUDIES tubule contains angiotensinogen, ACE, and angioten- Classical studies of the ACEIs given during the pe- sin I1 receptors (Moe et al., '93; Jackson et al., '91). Moe riod of organogenesis to rats and rabbits have failed to et al. ('93) found that renin could not be found in tu- demonstrate an increased incidence of malformation. bules from normal rats, but after enalapril administra- To emphasize a point made previously, lack of terato- tion, renin was found. This was interpreted as evidence genicity does not mean lack of fetotoxicity. The admin- of a tissue RAS that could generate angiotensin I1 to istration of ACEIs to commonly used laboratory ani- locally regulate sodium absorption. mals, in late gestation and during lactation, in doses It has been suggested that in part the effects of comparable to those used in human therapy, has been ACEIs are due to a locally acting, prostaglandin-depen- associated with significant fetal and neonatal wastage. dent component to their hypotensive action. Linz et al., These are fetotoxic not teratogenic effects. However, as ('93) reported that when bradykinin degradation was described below, none of these species is an especially inhibited by ramipril, formation of the endothelial au- good model for the ACEI fetopathy seen in humans. So tacoids, nitric oxide and prostacyclin, was enhanced, far, no exploration of maternal and fetal ACEI effects which they felt contributed to the beneficial effects of and physiology seems to have been done in nonhuman the drug. Similar conclusions were reached by others primates which might be much better models of the (Vanhoutte et al., '93; Busse et al., '93). On the other effects seen in humans; the development of such models hand, Gerber et al. ('93) found that while indomethacin should be encouraged. reduced the urinary excretion of prostacyclin metabolite by more than 50%, it had no effect on the hypoten- Rabbit model sive effect of captopril or enalapril. They concluded The adult rabbit is particularly sensitive to ACEIs, that neither ACEI had a significant prostacyclin-de- showing a greater antihypertensive effect than does pendent component to its hypotensive action, and Gan- the rat or dog. As measured by blockade of the acute sevoort et al. ('94) concluded that the antiproteinuric pressor response to exogenous angiotensin 1, enalapri- and renal hemodynamic effects of ACEIs were primar- lat and captopril are of equal potency in pregnant and ily due to interference in the RAS, rather than the nonpregnant rabbits (Manson, personal communica- bradykinin system. For now, the relation of the effects tion). The administration of 2.5-5.0 mgikgiday of cap- of the ACEIs to bradykinin degradation and prosta- topril to pregnant rabbits yielded pregnancy loss rates glandin production is not resolved. These two hor- ranging from 37 to 92% (Broughton-Pipken et al., '80, mones may be acting at the tissue level without corre- '82; Ferris and Weir, '82). The ED50 values for block- lated change in blood or excretion levels. Involvement ade of the pressor response to angiotensin I by enala- of the prostaglandin system in ACEI fetopathy seems prilat in the rabbit, rat, and dog were 2.8, 5.1, and 6.4 possible, particularly given the number of reported in- mgikg, respectively. Comparable ED50 values for cap- stances of renal tubular dysgenesis (RTD)/fetal-neona- topril in these 3 species were 2.88, 26.1, and 80 mgikg, tal anuria associated with nonsteroidal anti-inflamma- respectively (Manson, personal communication). The tory agent exposure (vide infra). basis for this sensitivity in rabbits is not known. Tissue kinin generation and degradation are coordi- The late gestation rabbit fetus has been shown to be nately regulated during intrauterine development, highly sensitive to the fetotoxic effects of ACEIs. When ACE INHIBITORS 403 administered in the human therapeutic range, ACEIs sis (GD 19), have demonstrated adverse effects on ne- produce fetal deaths in mid to late gestation, with a onates (Robertson et al., '86). At high treatment levels peak effect on GD 26 (Keith et al., '82; Broughton-Pip- (approximately 30-300 mgikgiday for enalapril and kin et al., '82; Minsker et al., '90). Maternal toxicity, as lisinopril), pup deaths occurred during lactation. At evidenced by elevation of blood urea nitrogen (BUN) lower treatment levels (10 mg/kg/day), decreased pre- and creatinine, and occasionally maternal death, oc- and postweaning body weight gain was observed. Sim- curs at the same treatment levels as those causing fetal ilar findings have been obtained with other ACEIs, deaths. Fetal deaths observed in rabbits with ACEI quinapril (Dostal et al., '91) and rentiapril (Cozens et treatment may be the result of decreased placental per- al., '87). fusion commensurate with systemic hypotension in the Late gestationilactation studies, with treatment mother, rather than of a direct effect on fetal renal from GD 15 to the end of lactation, would seem to pro- perfusion (Ferris and Weir, '82; Binder et al., '89; vide the most sensitive appraisal of ACEI effects on rat Binder and Faber, '92). Captopril studies in the rabbit pups. Kidneys from weanlings whose mothers received showed no effect on amniotic fluid volume, amniotic quinapril during late gestation (GD 15 on) and/or lac- fluid electrolyte composition, or fetal plasma urea ni- tation had juxtaglomerular cell hypertrophy (Dostal et trogen, creatinine, or calcium levels (Manson, personal al., '91; Graziano et al., '93), although the latter au- communication), When plasma volume was expanded thors reported they observed no morphological changes by saline supplementation, maternal toxicity was re- in the renal tubules and no adverse effects on renal duced but fetal deaths continued, particularly at function. Early postnatal treatment with the ACEIs higher dosage levels (enalapril30 mg/kg/day) (Minsker enalapril and captopril, and the angiotensin receptor-1 et al., '90). blocker losartan, but not the angiotensin receptor-2 blocker PD-123319, in the spontaneously hypertensive Rat model rat (SHR) and the normotensive strains WKY and WR The maturation of the RAS in the fetal and neonatal produced persistent, irreversible histopathological re- rat kidney has been thoroughly studied (Ice et al., '88). nal changes in adult life, long after the treatment had Expression of the gene for the angiotensin I1 receptor stopped. These abnormalities were associated with im- was not detected in the liver of newborn rats, but in paired urine concentrating ability (Friberg et al., '94). their kidneys gene expression was 2.5 times higher This should be looked at for other ACEIs. For the most than in the adult (Iwai et al., '91). Decreasing concen- part, histopathology from such kidneys has either not trations of plasma renin from fetal, to newborn, to neo- been done or not been reported in the literature. natal rats are consistent with increased activity of the All in all, it does not appear that the rat is a suitable RAS in immature animals (Jelinek et al., '86). Renin model for predicting or understanding ACEI fetopathy was first detected by immunostaining in the kidney on in humans. The RAS develops much later in gestation GD 19, when it was located in the arcuate and inter- in rats than in humans, and in rats toxicity is mani- lobular arteries. On GD 20, renin also appeared in the fested in neonates and weanlings, while in humans the afferent arteriole. With advancing age, detectable re- major manifestations are seen prenatally and at birth. nin disappeared progressively from the arcuate and in- Also, from the available data, it appears that the rat terlobular arteries until it was restricted primarily to placenta is an effective barrier to ACEI penetration the afferent arteriole in the 20-day-old postnatal pup into the fetal compartment, although more data are and finally only to the juxtaglomerular apparatus in needed on this point. the adult kidney. A similar but more rapid progression of maturation has been observed in the mouse (re- Sheep model viewed by Ice et al., '88). Studies of the synthesis of The chronically catheterized sheep serves as an ex- renin mRNA in the rat have shown the same pattern cellent model to study the cardiovascular and renal and timing (Gomez et al., '89). changes in the maternal and fetal compartments oc- The relevance of these findings to reproductive and curring during pregnancy (Magness et al., '85; Hill and developmental toxicity studies of ACEIs in rats is that Lumbers, '88). When captopril, which crosses the sheep the RAS develops late in gestation, beyond the time placenta and blocks the fetal RAS, was administered in when treatment typically is administered in a segment late pregnancy (GD 119-133, term = 147) at 2.8-3.5 I1 rat developmental toxicity study (GD 6-17). Not sur- mgikg IV to the ewe following exogenously adminis- prisingly, then, results from these studies have uni- tered angiotensin I, maternal blood pressure was tran- formly failed to reveal any adverse effects on fetuses, siently reduced and returned to normal within 2 hr. with the exception of decrease in fetal body weight and Fetal blood pressure remained reduced for up to 2 days, ossification at treatment levels that also produce evi- and 7 of 8 lambs were stillborn (Broughton-Pipkin et dence of maternal body weight decreases. al., '82). Interestingly, results from female fertility and late In a similar model, fetal renal function was studied gestationilactation studies, in which ACEI exposure oc- in sheep given captopril (GD 123-133) at an infusion curred during the critical period of fetal renin synthe- rate of 15 mg IV for 4 days, followed by an intrafetal 404 M.BARR infusion of angiotensin I1 (6 kg/kg/hr). Fetal GFR de- used antihypertensive agents throughout pregnancy, creased from an initial 4.2 to 2.7 ml/min after maternal including one who used an ACEI. The tubular morphol- captopril administration, and 3 days later it was 1.5 ogy of these kidneys was compared with the renal tu- ml/min. When the fetuses were given angiotensin I1 bules of 20 normal controls, 13 fetuses with various intravenously, fetal GFR returned to a mean of 3.4 multiple malformation syndromes, and 6 cases of the ml/min. It was concluded that a small fall in fetal ar- twin-twin transfusion syndrome. Features of RTD were terial pressure partly contributed to the fall in fetal identified in two cases of twin-twin transfusion syn- GFR but efferent arteriolar tone fell also so that the drome, the ACEI-exposed case, and one methyldopa- filtration pressure fell further. Thus maintenance of exposed case. In trying to tie these findings and evi- fetal renal function depends on the integrity of the fetal dence from the literature together it was hypothesized RAS (Lumbers et al., '92, '93). that the primary mechanism by which ACEIs affect Enalapril has also been studied in the sheep model development of the fetal kidney is through decreased (Broughton-Pipkin and Wallace, '86). Enalapril was renal blood flow (Martin et al., '92). This hypothesis given at a dose of 1 or 2 mglkg IV at a median gesta- was supported by Landing et al. ('94), who noted that tional age of 128 days. A pressor response to exogenous RTD has been seen as a unilateral lesion in young in- angiotensin I (5 pg IV) was first established in the fants with renal artery stenosis due to arteritis or me- maternal compartment: maternally administered an- dial arterial calcinosis and resembles the renal tubular giotensin I had no effect on fetal blood pressure. Fol- atrophy of end-stage kidney diseases such as glomeru- lowing the administration of enalapril, maternal blood lonephritis, tubulointerstitial kidney disease, obstruc- pressure was decreased for 30 min, but there was no tive uropathy and pyelonephritis, graft rejection of effect on fetal heart rate, plasma renin, or ACE activ- transplanted kidneys, and the renal parenchymal ity. At the high dose of enalapril tested, there was a changes associated with protracted dialysis therapy. transient fall in fetal blood pressure, considered to be Landing et al. ('94) reported that labeled lectins that due to changes in uteroplacental blood flow rather differentially mark proximal convoluted, distal convo- than to a direct effect of the drug on the fetus. Trace luted, connecting, and collecting tubules in RTD amounts of enalapril were found in fetal plasma, and showed no distinctive differences in the staining pat- levels of its active metabolite, enalaprilat, were unde- terns of their hypoplastic renal tubules compared with tectable in three of four fetuses. One unexplained fetal those associated with postnatal renal artery obstruc- death occurred in the 2 mglkg enalapril group. It was tion or various types of end-stage renal disease. These concluded that there was minimal transfer of the drug findings suggest that the renal tubular changes seen in into the fetal compartment. Thus, the sheep model may some if not all the conditions cited, including RTD, are not be specifically informative about the effects of ex- the result of renal ischemia. posure on the human fetus for all ACEIs, for enalapril RTD, with hypoplasia especially of renal proximal does cross the human placenta and evidently acts di- convoluted tubules and clinical neonatal anuria or olig- rectly on the fetus. uria, has also been reported as a congenital familial (autosomal recessive) disease, variably with features of FEATURES OF ACEI FETOPATHY oligohydramniotic deformation and pulmonary hypoplasia (reviewed by Allanson et al., '92). According to RTD Landing et al. ('94), the microscopic appearance of the RTD is characterized by dilation of Bowman's spaces kidneys in hereditary RTD is indistinguishable from and tubules, diminished to absent differentiation of that seen in cases of renal ischemia. It must also be proximal convoluted tubules, and increased cortical noted that RTD has been reported in association with and medullary mesenchyme (and later fibrosis) (Fig. exposure to nonsteroidal anti-inflammatory agents, 2). The histological changes in the kidney strongly sug- particularly indomethacin (Simeoni et al., '89; Res- gest ischemic injury, with the added component of de- taino et al., '91; Bavoux, '92; Buderus et al., '93; Voyer ficient tubular differentiation most easily confirmed by et al., '94). Thus it would seem that RTD is not specific failure of periodic acid Schiff stain to stain the brush for ACEI exposure, but rather that ACEIs are rather border of proximal convoluted tubules. It has been my proficient at creating the conditions that lead to RTD. experience that, unless specifically looked for, the histopathological changes of RTD in the fetalheonatal kidney can be and have been missed. RTD was fully Hypocalvaria described in four cases of ACEI fetopathy (Cunniff et Apart from the renal failure and related abnormali- al., '90; Pryde et al., '93) and has been observed in a ties discussed above, six ACEI-exposed cases have had number of unreported cases. hypoplasia of the membranous bones of the skull, or To examine the specificity of this set of histopatho- hypocalvaria (Duminy and Burger, '81; Rothberg and logical findings for ACEI exposure, Martin et al. ('92) Lorenz, '84; Mehta and Moda, '89; Pryde et al., '93). In examined the kidneys of nine fetuses whose mothers this condition, the calvarial bones are found to be nor- were chronically hypertensive. Three of these mothers mal in position and shape, but greatly reduced in size ACE INHIBITORS 405

Fig. 2. RTD in four different cases of ACEI fetopathy; note particularly the ductular ectasia, dilation of Bowman's spaces, and poor to no differentiation of proximal convoluted tubules. x 20.

(Fig. 3). The sutures and fontanels are symmetrically high oxygen tension is required for their growth. The enlarged, and in severe cases, the normally developing presumed fetal hypotension produced by ACEI expo- brain is essentially unprotected by skull and liable to sure may result in hypoxic effects and thus a hypoplas- trauma during labor and delivery. Although there are tic calvaria (Barr and Cohen, '91). A more remote pos- now only a total of six cases in which this skull lesion sibility is that inhibition of angiotensin I1 may is specifically described, I believe it is more common concomitantly inhibit one of the variety of growth fac- but unrecognized; it seems that many cases may be tors involved in calvarial bone development. classified as enlarged fontanels with widely split sutures, but in instances in which hydrocephaly or mac- Intrauterine growth restriction roencephaly are not present. Lacking age-specific mor- The status of the fetal RAS in pregnancies compli- phometrics for the size of the calvarial bones, the cated by severe intrauterine growth restriction, and its distinction of hypocalvaria in milder cases is admit- possible relationship to elevated fetoplacental vascular tedly a subjective assessment. resistance, was explored by Kingdom et al. ('93). In an The cause of the hypoplastic calvaria found with intrauterine growth restriction group, cord venous an- ACEI exposure is unknown. Endochondral bone and giotensin I1 was markedly elevated compared with con- membranous bone grow and develop in entirely differ- trols, but angiotensin receptor concentration was not ent ways. Long bones develop in a low oxygen environ- significantly altered, and no changes in angiotensin ment since nutrition takes place by diffusion through receptor affinity were observed. This suggests that the cartilaginous epiphyses. Membranous bones, on the there is augmentation of'the fetal RAS in at least some other hand, have a high degree of vascularity, and a forms of intrauterine growth restriction and that re- 406 M.BARR taglandin system, which would be expected to increase prostaglandin E and prostacyclin systemically and per- haps locally, the possibility that prenatal ACEIs may inhibit ductal closure needs to be considered. Cer- tainly, more data are needed before any firm conclu- sion can be reached on this subject.

COULD IT BE THE MATERNAL DISEASE ITSELF AND NOT THE DRUG? ACEI fetopathy infants have been born to mothers whose hypertension was of widely varying etiology, including lupus erythematosus, renovascular hypertension, nephrotic syndrome, glomerulonephritis, renal transplantation, preeclampsia, and essential hypertension (Pryde et al., '93). Oligohydramnios, intrauterine growth restriction, and fetal distress are not uncom- mon complications of hypertensive pregnancies. How- Fig. 3. Hypocalvaria. In this severe example, the fibrous tissue ever, as discussed above, there is evidence that indi- comprising the fontanels and sutures has been removed, leaving only cates the oligohydramnios, hypotension, and anuria of the calvarial bone, to demonstrate the diminutive size of the bones. ACEI fetopathy are truly drug-related rather than sim- (Reproduced from Barr and Cohen, '91, with permission of Wiley- Liss.) ply phenomena of the underlying maternal disease pro- cess. The evolution of oligohydramnios followed by the delivery of a neonate with prolonged hypotension and sponsiveness of the fetoplacental vasculature to an- anuria has not been included in the well-described list giotensin I1 is not diminished as might be expected of complications of maternal hypertension and its tra- from the elevated plasma angiotensin I1 levels. An- ditional therapy, although one case of RTD has been giotensin I1 may contribute to the increased fetoplacen- observed under these circumstances (Martin et al., '92). tal vascular resistance observed in this disorder. With ACEI exposure, the probability is high that the Intrauterine growth restriction (birth weight centile oligohydramnios is in fact due to a drug-related fetal

Walls (1992) Deterioration in renal function associated with an- Guthrie, R. (1993) Fosinopril: An overview Am. J. Cardiol., 72tH22- giotensin-converting enzyme inhibitor therapy is not always re- H24. versible. J. Int. Med., 232.493-498. Hall, J.E., A.C. Guyton, T.E. Jackson, T.G. Coleman, T.E. Lohmeier, Dostal, L.A., S.N. Kim, J.L. Schardein, and J.A. Anderson (1991) and N.C. Trippodo 11977) Control of glomerular filtration rate by Fertility and perinatal/postnatal studies in rats with the angioten- renin-angiotensin system. Am. J. Physiol., 233:F366-F372. sin-converting enzyme inhibitor, quinapril. Fund. Appl. Toxicol., Hanssens, M., M.J.N.C. Keirse, F. Vankelecom, and F.A. Van Assch 17t684-695. (1991) Fetal and neonatal effects of treatment with angiotensin- Ducret, F., P.H. Pointet, B. Laurengeon, C. Jacoulet, and J. Gagnaire converting enzyme inhibitors in pregnancy. Obstet. Gynecol., 78: (1985) Grossesse sous inhibiteur de l'enzyme de conversion. Presse 128-135. Med., 143497. Hill, K., and E. Lumbers (1988) Renal function in adult and fetal Duminy, P.C., and P. du T. Burger (1981) Fetal abnormality associ- sheep. J. Dev. Physiol., 10:149-159. ated with the use of captopril during pregnancy. S. Afr. Med. J., Hricik, U.E., P.J. Browing, R. Kopelman, W.E. Goorno, N.E. Madias, 60t805. and V.J. Dzau (1983) Captopril induced functional renal insuff- Ehlers, M.W., and J.F. Riordan (1989) Angiotensin-converting en- ciency in patients with bilateral renal artery stenosis or renal ar- zyme: New concepts concerning its biological role. Biochemistry, tery stenosis in a solitary kidney. N. Engl. J. Med., 308:373-376. 28.5311-5316. Ice, K.S., K.M. Geary, R.A. Gomez, D.W. Johns, M.J. Peach, and R.M. Endo, M., Y. Yamada, M. Kohno, T. Suzuki, M. Otsuka, and 0. Ta- Carey (19881 Cell and molecular studies of renin secretion. Clin. kaiti (1992) Metabolic fate of the new angiotensin-converting en- Exp. Hypertens. Theor. Pract., A10:1169-1187. zyme inhibitor imidapril in animals. IV. Placental transfer and Iwai, N., Y. Yamano, S. Chaki, et al. (1991) Rat angiotensin I1 recep- secretion into milk in rats. Arz. Forsch./Drug Res., 42:483-489. tor: cDNA sequence and regulation of the gene expression. Bio- Erdos, E.G., and R.A. Skidgel (1987) The angiotensin I-converting chem. Biophys. Res. Commun., 177t299-304. enzyme. Lab. Invest., 56:345-348. Jackson, B., F.A.O. Mendelsohn, and C.I. Johnston (1991) Angioten- Ferreira, S.H. (1965) A bradykinin-potentiating factor (BPF)present sin-converting enzyme inhibition: Prospects for the future. J. Car- in the venom of Bothrops jararaca. Br. J. Pharmacol., 24t163-169. diovasc. Pharmacol., 18.54-58. Ferris, T.F., and E.K. Weir (1982)Effect of captopril on uterine blood Jelinek, J., R. Hackenthal, U. Hilgenfeldt, G. Schaechtelin, and E. flow and prostaglandin E synthesis in the pregnant rabbit. J. Clin. Hackenthal (1986) The renin-angiotensin system in the perinatal Invest., 71t809-815. period in rats. J. Dev. Physiol., 8t33-41. Fiocchi, R., P. Ligney, R. Fagard, J. Staessen, and A. Arnery (1984) Johnston, C.I., L.M. Burrell, R. Perich, K. Jandeleit, and B. Jackson Captopril during pregnancy. Lancet, 2:13 53. (1992) The tissue renin-angiotensin system and its functional role. Friberg, P., B. Sundelin, S.O. Bohman, et al. (1994)Renin-angiotensin Clin. Exp. Pharmacol. Physiol., Suppl. 19:l-5. system in neonatal rats: Induction of a renal abnormality in re- Johnston, C.I., B. Fabris, and K. Yoshida (1993) The cardiac renin- sponse to ACE inhibition or angiotensin-I1 antagonism. Kidney angiotensin system in heart failure. Am. Heart J., 126t756-760. Int., 45:485-492. Keith, I.M., J.A. Will, and E.K. Weir (1982) Captopril: Association Fujii, T., and T. Nakatsuka (1985) Enalapril (MK-421)oral teratoge- with fetal death and pulmonary vascular changes in the rabbit. nicity in the rat. Yakuri To Chiryo, 13529-548. Proc. SOC.Exp. Biol. Med., 170:378-383. Fujii, T., T. Nakatsuka, S. Hanada, T. Komatsu, and H. Okiyama Kingdom, J.C.P., J. McQueen, J.M.C. Connell, and M.J. Whittle (1985) Enalapril (MK-421) oral teratogenicity study in the rat. (1993)Fetal angiotensin-I1 levels and vascular (type-I) angiotensin Yakuri To Chiryo, 13519-528. receptors in pregnancies complicated by intrauterine growth retar- Gansevoort, R.T., D. Dezeeuw, and P.E. Dcjong (1994) The antipro- dation. Br. J. Obstet. Gynaecol., 100;476-482. teinuric effect of ACE inhibition mediated by interference in the Knott, P.D., S.S. Thorp, and C.A.R. Lamont (1989) Congenital renal renin-angiotensin system. Kidney Int., 459361-867. dysgenesis possibly due to captopril. Lancet,, 1,451. Garay, R., N. Senn, and J.P. Ollivier (1994) Erythrocyte ion transport Kon, V., A. Fogo, I. Ichikawa, S.E. Hellings, and T. Bills (1993) Brady- as indicator of sensitivity to antihypertensive drugs. Am. J. Med. kinin causes selective efferent arteriolar dilation during angioten- Sci., 307(Suppl. 1):S120S125. sin-I converting enzyme inhibition. Kidney Int., 44t545-550. Gavras, H. (1988) The place of angiotensin-converting enzyme inhib- Kreft-Jais, C., C. Plouin, C. Tchobroutsky, and M.J. Boutroy (1988) itors in the treatment of cardiovascular diseases. N. Engl. J. Med., Angiotensin-converting enzyme inhibitors during pregnancy: A 319t1541-1543. survey of 22 patients given captopril and nine given enalapril. Br. Gerber, J.G., G. Franca, R.L. Byyny, M. Loverde, and A.S. Nies (1993) J. Obstet. Gynaecol., 95:420-422. The hypotensive action of captopril and enalapril is not prostacyclin Landing, B.H., S.M. Ang, N. Herta, E.F. Larson, and M. Turner (1994) dependent. Clin. Pharmacol. Ther., 54.523-532. Labeled lectin studies of renal tubular dysgenesis and renal tubular Gomez, H.J., V.J. Cirillo, and F. Moncloa (1987) The clinical pharma- atrophy of postnatal renal ischemia and end-stage kidney disease. colob9 of lisinopril. J. Cardiovasc. Pharmacol., S(Supp1. 3):S27- Pediatr. Pathol., 14t87-99. s34. Lee, E.J.D. (1994) Population genetics of the angiotensin-converting Gomez, R., K. Lunch, B. Sturgill, J. Elwood, R. Chevalier, R. Carey, enzyme in Chinese. Br. J. Clin. Pharmacol., 37:212-214. and M. Peach (1989) Distribution of renin mRNA and its protein in Lees, K.R., I.B. Squire, and J.L. Reid (1992) The clinical pharmacol- the developing kidney. Am. J. Physiol.; 257:F850-F858. ogy of ACE inhibitors: Evidence for clinically relevant differences. Graves, S.W., T.J. Moore, and E.W. Seely (1992) Increased platelet Clin. Exp. Pharmacol. Physiol., Suppl. 19t49-53. angiotensin-I1 receptor number in pregnancy-induced hyperten- Li, J., H.Y. Hu, and Y.N. Zhao (1992) Serum angiotensin-converting sion. Hypertension, 20:627-632. enzyme activity in pregnancy-induced hypertension. Gynecol. Ob- Graziano, M.J., L.A. Dethloff, H.E. Griffin, and D.G. Pegg (1993) Ef- stet. Invest., 33:138-141. fects of the angiotensin-converting enzyme inhibitor quinapril on Lindheimer, M.D., and A.1. Katz (19851 Hypertension in pregnancy renal function in rats, Arch. Int. Pharmacodyn. Ther., 324t87-104. (current concepts). N. Engl. J. Med., 313:675-680. Grone, H.J., M. Simon, and E. Fuchs (1992) Autoradiographic char- Linz, W., G. Wiemer, and B.A. Scholkens (1993) Contribution of acterization of angiotensin receptor subtypes in fetal and adult hu- bradykinin to the cardiovascular effects of ramipril. J. Cardiovasc. man kidney. Am. J. Physiol., 262tF326-F331. Pharmacol., 22(Suppl. 9jrSlS8. Guignard, J.P. (1982) Renal function in the newborn infant. Pediatr. Lumbers, E.R., N.M. Kingsford, R.I. Menzies, and A.D. Stevens (1992) Clin. North Am., 29t777-790. Acute effects of captopril, an angiotensin-converting enzyme inhib- Guignard, J.P., F. Burgener, and A. Calaine (1981) Persistent anuria itor, on the pregnant ewe and fetus. Am. J. Physiol., 262tR754- in a neonate: A side effect of captopril? Int. J. Pediatr. Nephrol., R760. 2t133. Lumbers, E.R., J.H. Burrell, R.I. Menzies, and A.D. Stevens (1993) ACE INHIBITORS 409

The effects of a converting enzyme inhibitor icaptopril) and an- Rothberg, A.D., and R. Lorenz (1984) Can captopril cause fetal and giotensin-I1on fetal renal function. Br. J. Pharmacol., I IU:821-827. neonatal renal failure? Pediatr. Pharmacol., 4t189-192. Magness, R., K. Osei-Boaten, M. Mitchell, and C. Rosenfeld (1985) In Rudolph, A.M., M.A. Heyman, K.A.W. Teramo, C.T. Barrett, and vitro prostacyclin production by ovine uterine and systemic arter- N.C.R. Raiha (1971) Study on the circulation of the previable hu- ies: Effects of angiotensin 11. J. Clin. Invest., 76t2206-2212. man fetus. Pediatr. Res., 5t452-465. Marre, M., P. Bernadet, Y. Gallois, et al. (1994) Relationships be- Sassano, P., G. Chatellier, E. Billaud, F. Alhenc-Gelas, P. Corvol, and tween angiotensin I converting enzyme gene polymorphism, plasma J. Menard (1987) Treatment of mild to moderate hypertension with levels, and diabetic retinal and renal complications. Diabetes, 43: or without the converting enzyme inhibitor enalapril: Results of a 384-388. six-month double-blind trial. Am. J. Med., 83t227-235. Martin, R.A., K.L. Jones, A. Mendoza, M. Barr, and K. Benirschke Schlueter, W., T. Keilani, and D.C. Batlle (1994) Tissue renin an- (1992)Effect of ACE inhibition on the fetal kidney: Decreased renal giotensin systems: Theoretical implications for the development of blood flow. Teratology, 46r317-321. hyperkalemia using angiotensin-converting enzyme inhibitors. Materson, B.J., and R.A. Preston (1994) Angiotensin-converting en- Am. J. Med. Sci., .107~Suppl.l):S81486. zyme inhibitors in hypertension. Arch. Int. Med., I54:513-523. Schubiger, G.,G. Flury, and J. Nussberger (19881 Enalapril for preg- Mehta, N., and N. Modi (1989) ACE inhibitors in pregnancy. Lancet, nancy-induced hypertension: Acute renal failure in the neonate. 2:96. Ann. Int. Med., 108:215-216. Michel, R., D. Stephan, M. Grima, M. Barthelmebs, and J.L. Imbs Scott, A.A., and D.M. Purohit (1989) Neonatal renal failure: A com- (1993) Effects of one-hour and one-week treatment with ramipril on plication of maternal antihypertensive therapy. Am. J. Obstet. Gy- plasma and renal brush border angiotensin-converting enzyme in necol., 160t1223-1224. the rat. Eur. J. Pharmacol., 242:237-243. Shanmugam, S., C. Monnot, P. Corvol, and J.M. Gasc (1994) Distri- Minsker, D.H., W.J. Bagdon, J.S. MacDonald, R.T. Robertson, and bution of type 1angiotensin I1 receptor subtype messenger RNAs in D.L. Bokelman (1990)Maternotoxicity and fetotoxicity of an an- the rat fetus. Hypertension, 23:137-141. giotensin-converting enzyme inhibitor, enalapril, in rabbits. Fund. Simeoni, U., J. Messer, P. Weisburd, J. Haddad, and L). Willard (1989) Appl. Toxicol., 14r461-470. Neonatal renal dysfunction and intrauterine exposure to prosta- Moe, O.W., K. Ujiie, R.A. Star, et al. (1993) Renin expression in renal glandin synthesis inhibitors. Eur. J. Pediatr., I48:371-373. proximal tubule. J. Clin. Invest., 91:774-779. Tack, E.D., and J.M. Perlman 17988) Renal failure in sick hyperten- Perlman, J.M., and J.J. Volpe (1989) Neurologic complications of cap- sive premature infants receiving captopril therapy. J. Pediatr., 112: topril treatment of neonatal hypertension. Pediatrics, 83:47-52. 805-810. Pinkney, J.H., and J.S. Yudkin (1994)Antihypertensive drugs: Issues Thorpe-Beeston, J.G., N.A. Armar, M. Dancy, G.W. Cochrane, G. beyond blood pressure control. Prog. Cardiovasc. Dis., 36:397-415. Ryan, and C.H. Rodeck (19931 Pregnancy and ACE inhibitors. Rr. J. Piper, J.M., W.A. Ray, and F.W. Rosa (1992) Pregnancy outcome fol- Obstet. Gynaecol., IUU:692-693. lowing exposure to angiotensin-converting enzyme inhibitors. Ob- Thurston, H. (1992)Angiotensin-converting enzyme inhibition as 1st- stet. Gynecol., 80:429-432. line treatment for hypertension. Clin. Exp. Pharmacol. Physiol., Plouin, P.F., and C. Tchobroutsky (1985) Inhibition de l'enzyme de Suppl. 19t67-71. conversion de l'angiotensine au cows de la grossesse humaine: Todd, P.A., and R.C. Heel (1986) Enalapril: A review of its pharma- Quinze cas. Presse Med., 14t2175-2178. codynamic properties, and therapeutic use in hypertension and con- Pryde, P.G., A.B. Sedman, C.E. Nugenl, and M. Barr (1993) Angioten- gestive heart failure. Drugs, 3It198-248. sin-converting enzyme inhibitor fetopathy. d. Am. SOC.Nephrol., 3t1575-1582. Vanhoutte, P.M., C.M. Boulanger, S.C. Illiano, T. Nagao, M. Vidal, and J.V. Mombouli (1993) Endothelium-dependent effects of con- Ravid, M., H. Savin, I. Jutrin, T. Bental, B. Katz, and M. Lishner verting-enzyme inhibitors. J. Cardiovasc. Pharmacol., 2XSuppl. (1993) Long-term stabilizing effect of angiotensin-converting en- 51: SlO-Sl6. zyme inhibition on plasma creatinine and on proteinuria in normotensive type-I1 diabetic patients. Ann. Int. Med. 118.577-581. Viberti, G.,C.E. Mogensen, L.C. Groop, et al. (1994) Effect of captopril Restaino, I., B.S. Kaplan, P. Kaplan, H.K. Rosenberg, C. Witzleben, on progression to clinical proteinuria in patients with insulin-de- and N. Roberts (1991) Renal dysgenesis in a monozygotic twin: pendent diabetes-mellitus and microalbuminuria. JAMA, 271 275- Association with in utero exposure to indomethacin. Am. J. Med. 279. Genet., 39.252-257. Vidt, D.G., E.L. Bravo, and F.M. Fouad (1982) Captopril. N. Engl. J. Rigat, B., C. Hubert, F. Alhenc-Gelas, F. Cambien, P. Corvol, and F. Med., 306:214-219. Soubrier (1990) An insertion deletion polymorphism in angiotensin Voyer, L.E., R. Drut, and J.H. Mendez (1994) Fetal renal maldevel- I converting enzyme gene accounting for half the variance of serum opment with oligohydramnios following maternal use of piroxicam. enzyme levels. J. Clin. Invest., 861343-1346. Pediatr. Nephrol., 8t592-594. Robertson, R.T., D.H. Minsker, and D.L. Bokelman (1986) MK-421 Wells, T.G., T.E. Bunchman, and G.L. Kearns (1990) Treatment of (enalapril maleate): Late gestation and lactation study in rats. Jpn. neonatal hypertension with enalapril. J. Pediatr., II 7:664-667. Pharmacol. Ther., 14:43-55. Williams, G.H. (1988) Converting enzyme inhibitors in the treatment Elodicio, J.L., and L.M. Ruilope (1993) Angiotensin-converting en- of hypertension. N. Engl. J. Med., 319:1517-1524. zyme inhibitors in the treatment of mild arterial hypertension. Wood, E.G., T.E. Bunchman, and R.E. Lynch (1991) Captopril-induced Clin. Exp. Hypertens., 15:1277-1289. reversible acute renal failure in an infant with coarctation of the Rosa, F.W., L.A. Bosco, C. Fossum-Graham, J.B. Milstien, M. Dreis, aorta. Pediatrics, 88:816-818. and J. Creamer (1989) Neonatal anuria with maternal angiotensin- Yosipiv, I.V., S. Dipp, and S.S. Eldahr (1994) Ontogeny of somatic converting enzyme inhibition. Obstet. Gynecol., 74:371-374. angiotensin-converting enzyme. Hypertension, 23t369-374.