Angiotensin-Converting Peter G. Pryde, P.G Pryde, Aileen CE. B. Sedman,2 Nugent, M. Obstetrics/Gynecology, cal Center, A.B. M. M. Soc, Jr., E. Nugent, Department of Michigan of Medical Center, of Pathology, Center. Nephrol. of Jr. , Department Barr, Medical Clark Medi- Ml Jr. , Department Barr, (J. Am. Arbor, of Michigan Michigan Barr, University Ann Sedman, University Enzyme Ann Arbor, 1993; Pediatrics, Ann Arbor, University Ml of Ml 3:1575-1582) ABSTRACT Angiotensin-converting enzyme (ACE) inhibitors are widely used for controlling hypertension. Their use in women who are pregnant is not without risk to the fetus. We describe three infants exposed in utero to ACE inhibitors who had adverse outcomes. These cases, combined with other reports in the literature, suggest strongly that these drugs are fetotoxic. ACE inhibitor fetopathy is characterized by fetal hypotension, anuria-oligohydramnios, monary hypoplasia, pocalvaria. Although fetal effects has yet the debilitating and age when it occurs, ACE inhibitors not be in the second Key Words: and Kidney, oligohydramnios, growth restriction, pul- renal tubular dysplasia, and hythe true frequency of adverse to be determined, because of lethal nature of the fetal damit is our recommendation that used in pregnancy, particularly third trimesters. captopril, teratogen, enalapril, lisinopril, skull, anuria. fetotoxin I n the decade since their introduction, the angiotensin-converting enzyme (ACE) inhibitors have gained widespread acceptance in the management of hypertension. Their success (even as monotherapy) and relative paucity of side effects have contributed to this popularity (1 -3). Further, the lack of metabolic changes (such as hyperglycemia or hyperbipidemla). as well as a possible ameliorating effect on the progression of diabetic nephropathy, has prompted the suggestion that ACE inhibitors be considered first- ‘Received August 2Correspondence 0297, University 25, 1992. Accepted to Dr. A. B. Sedman, of Michigan Medical November Pediatric Center. 30. 1992. Nephrology, Ann Arbor, 1046-6673/0309-1575$03.00/0 Journal of the American society of Nephrology Copyright © 1993 by the American Society of Nephrology Journal of the American Society of Nephrology Room L2602, MI 48 109-0297. Box Inhibitor and Mason Barr, Fetopathy’ Jr. line agents in the management of hypertensive diabetics (1.3.4). As early as 1 980, there were worrisome reports of extraordinary fetal loss rates in a variety of experimental animals exposed to ACE inhibitors during gestation (5-7). In 1 98 1 the first case of adverse fetal outcome in a human pregnancy exposed to captopril was reported (8). Soon, other cases appeared Implicating both captopril and enalaprib as possible fetotoxins (9-12). The animal data, coupled with a growing list of adverse human pregnancy outcomes, prompted warnings as early as 1 985 against the use of ACE inhibitors during human gestation ( 1 3). However, in contacts with prescribing physicians, our experience has been that many are not aware of the potential danger to the fetus from ACE inhibitor exposure. We report three cases from our institution of adverse fetal outcome in hypertensive pregnancies exposed to ACE inhibitors, and we review previously reported cases (8-12,14-24). Further, we propose that sufficient evidence exists to implicate the ACE inhibitors as fetotoxins and suggest the designation “ACE inhibitor fetopathy.” , CASE Patient REPORTS I The mother was a 26-yr-old. gravida 2, para 0. with an 8-yr history of systemic bupus erythematosus. Her associated hypertension was controlled by a regimen of prednisone. 5 to 1 0 mg/day, atenobol, 1 00 mg/day, furosemide, 20 mg/day, and captopril, 1 50 mg/day. Ultrasonographic evaluation at 1 9 wk of gestation revealed oligohydramnios but no fetal structural abnormalities. Over the next several weeks, there was persistence of the oligohydramnios and evolution of mild growth restriction. At 33 wk of gestation. labor was induced because of a worsening biophysical profile. A 1 .440-g female was delivered vaginally from a breech presentation. Apgar scores were 1 and 5 at 1 and 5 mm, respectively. Despite maximal ventilator support. the infant remained hypoxic and became progressively acidotic. Her hypotenslon was unresponsive to volume and pressor therapy, and during the 14 h before death, there was no urine output. At autopsy, the hand, foot, and face deformational features of the oligohydramnios sequence were identified. The lungs were small with histologic features of pulmonary hypoplasia. A calcified thrombus in the subhepatic vena cava extended into the renal veins bilaterally. Subdiaphragmatic venous return to the 1575 ACE Inhibitor Fetopathy heart was via a well-developed, thick-walled azygous system to the superior vena cava. The kidneys were enlarged compared with gestationab age-matched controls and had histologic changes consistent with renal tubular dysplasia. The distal urinary tract, although slender and empty. was structurally normal and patent. The brain and cranial base were normal. However, the calvarial bones, although normal in shape and configuration, were remarkably small, leaving the top third of the brain unprotected by bone (Figure 1). Microscopically, these bones were thin with poor trabeculatlon and marrow development compared with those of age-matched controls (see reference 38). Patient 2 The mother was an 18-yr-old primigravida with renovascular hypertension of 10 yr duration. She had been managed on multiagent therapy with variable success until age 18, at which time llsinoprib monotherapy was initiated with the establishment of excellent control. When she became pregnant, lisinopril was continued. At 16 wk of gestation, an ultrasound examination revealed a fetus of appropriate size with a normal anatomic survey and normal amniotic fluid volume. Subsequently, there was no suspicion of problems until the onset of labor at 32 wk of gestation. After a failed trial of tocolysis, a 1 .480-g male was delivered by cesarean section. Amniotic fluid volume was not described. Apgar scores were 4 and 7 at 1 and 5 mm, respectively. The infant required 48 h of mechanical ventilation for respiratory distress. The newborn period was complicated by hypotension and anuria that failed to respond to fluid chablenge and pressor support. Ultrasound evaluation showed normal size and appearance of the kidneys and renal collecting system. Renal artery Doppler studies demonstrated bilateral flow. At 8 days of age, the infant remained anuric and peritoneab dialysis was initiated. By day 12 of life, he began to pass small amounts of urine. ACE activity increased from a day 12 value of 7.9 U/mL (normal, 20 to 50) to 22 U/mL on day 37. A kidney biopsy performed at 4 wk of age demonstrated evidence of previous ATN, patchy cortical necrosis, and lack of Figure 1. Hypocalvaria (Patient 1). The skull viewed from above, with the fibrous tissue of the fontanels to emphasize the diminutive size of the bones. Reprinted with permission from Barr and Cohen (38). 1576 Volume and sutures 3. Number removed 9 1993 Pryde Patient differentiation of the proximal convoluted tubules (Figure 2). Although his urine volume increased modestby over the next several weeks, he remained dependent on peritoneal dialysis and, at 22 months of age. received a successful kidney transplant. He mitialby suffered from intestinal malabsorption and Severe growth retardation. After the transplant. his growth remains delayed. but his cognitive function is progressing normally. At birth, his fontanels were noted to be barge and the sutures excessively wide. At 1 month of age, the cabvarlal plates were small but of appropriate shape and position. The width of the sagittal. coronal, and lambdoidab sutures measured 3, 3, and 2 cm, respectively. The anterior fontaneb was 6 cm long by 4 cm wide, and the posterior fontanel was 4 cm by 4 cm. Subsequently, considerable growth of the skull bones was noted so that by 3 months of age. the sutures had narrowed to 0.5 cm in width, with a corresponding reduction in size of the fontanebs. At 22 months of age, his anterior fontanel was still patent, but the rest of the skull examination was unremarkable. Figure 2. ACE inhibitor-exposed kidney (Patient 2) showing of differentiation between proximal and distal convoluted original magnification, x20. Journal of the American Society of Nephrology et al 3 The mother was a 30-yr-old primigravida with a 9yr history of presumed essential hypertension adequately controlled by atenobob until several months before conception. At that time, she was changed electively to enalapril, 5 mg/day. Her blood pressure was well controlled until 20 wk of gestation, when the daily dose was increased to 7.5 mg for an elevated diastolic pressure. At 30 wk. fundal height was noted to be subnormal and ultrasonography demonstrated fetal growth restriction and profound oligohydramnios. At 32 wk, a contraction stress test showed recurrent decelerations and the infant was delivered by cesarean section. The boy infant weighed only 980 g although the physical examination was appropriate for 32 wk of gestation. Apgar scores were 8 and 9 at 1 and 5 mm, respectively, but mild grunting progressed to frank respiratory distress and by 2 h of age mechanical ventilation was required. He was profoundly hypotensive (mean arterial pressure of 16 mm Hg) and remained so despite administration of dopammne, do- dilated tubules, Bowman’s spaces and tubules, and increased mesenchyme. old tubular necrosis, lack Periodic acid-Schiff stain; 1577 ACE Inhibitor Fetopathy butamine, and epmnephrmne and aggressive hydration. Hypotension and anuria persisted until initiation, on day 5 of life, of peritoneal dialysis. After 14 h of dialysis. his blood pressure rose to 40/ 1 7 mm Hg and 7 mL of urine was obtained. On day 8, the dialysate became cloudy and bowel obstruction or perforation was suspected. At laparotomy, a length of ischemic jejunum was resected. Postoperatively, he remained hypotensive despite massive pressor support and died on day 9. At autopsy, he had barge fontanebs (anterior, 5.0 x 3.5 cm: posterior, 2.0 x 1 .5 cm) and widened sutures (sagittal. 1 cm; coronals and bambdoidabs, 0.3 cm: metopic, 0.5 cm). His face was wide with a short nose and anteverted nares. His arms (150 mm) and begs (120 mm) were short in relation to his crown-rump length (285 mm). The kidneys were barge (combined weight. 16.1 g; expected, 9.0 ± 1.6 for body weight). but no other gross abnormalities of the urinary tract or renal vascular system were found. Microscopic examinations of the kidneys showed tubular dysplasia (Figure 3). The lungs, particularly the left one, were small (right, 13.7 g; left, 6.9 g; combined weight, 20.6 g; expected, scopicab features 25.4 ± 5.2) of hypoplasia. and showed the micro- DISCUSSION The ACE inhibitors are competitive inhibitors of kininase II. Their complex pharmacology has been reviewed in detail by others ( 1 -3). Most importantly. they affect both the renin-angiotensin-abdosterone and the bradykinin-prostaglandin systems. Many other antlhypertensive agents tend to increase peripherab resistance and affect the metabolism of glucose, lipids, and electrolytes. In contrast, ACE inhibitors decrease vascular resistance and have no known adverse metabolic consequences ( 1 ,3). In the absence of heart failure, they produce little change in heart rate, cardiac output, or pulmonary wedge pressure (25-27). An important effect of ACE inhibitors is on the renal microvasculature, resulting in dilatation of the gbomerular efferent arterioles and a decrease in filtration pressure. Excretion of the ACE inhibitors is principally by the kidney. They are also known to cross the human ( , ‘:N.l .. a ? -, ,4 _J a . - - 4 :“ Figure 3. ACE Inhibitor-exposed kidney tubules, dilated tubules, and increased 1578 4 (Patient 3) showing tubular dysplasia: minimal differentiation of proximal mesenchyme. Periodic acid-Schiff stain; original magnification, x20. Volume 3’ Number convoluted 9’ 1993 Pryde TABLE 1. Cases of pregnancy outcome Author, (Ref. No.), Year Guignard 1981 Dummy (9), Boutroy Burger Renovascular pertension (10), 1984 Caraman eta!. (11). 1984 Caraman eta!. (11). 1984 Rothberg and Iorenz (12), 1984 Fiocchi eta!. (14), 1984 eta!. (15), 1985 Schubiger 29 wk; cesarean I 0% 2nd trimester hy- eta!. (16) Broughton-Pipkmn a!. (17), 1989 et Mehta 3-10% 34 wk; cesarean 10-50% 28 wk; cesarean etiology section; No No RDS, PDA, survived section; No No RDS, PDA, survived section; Yes Yes section Yes Yes Hypocalvaria, dialysis, death day 30 Survived section; No No IUGR, survived section; Yes Yes section; Yes Yes Decreased ACE activity, dialysis, survived Placental abruption, severe RDS, death day 6 IUFD, suspected renal tubular dysgenesis Hypoplastic lungs, hypocalvaria, death day 10 RDS, death day 7 N/A Yes Yes Implied Yes Yes Yes Systemic lupus thematosus Systemic lupus thematosus transplant (21), IUFD, intrauterine patent ductus fetal eryery- death: arteriosus; 26 wk; cesarean section; 3% 34 wk; cesarean section; weight not recorded lUG?, intrauterine N/A, not growth of the American Society of Nephrology restriction; RDS. respiratory Hypoplastic lungs, renal tubular dysgenesis distress syndrome; PIH, pregnancy-induced applicable. placenta. In the fetus, it Is presumed that these agents are, at beast in part, also renally excreted into the amniotic fluid and recycled by fetal swallowing. In animal studies, the administration of captopril in doses comparable to those used In human therapy has been associated with significant rates of fetal loss. Chronically cannulated pregnant ewes given 3 mg/kg of captopril demonstrated fetal loss rates in excess of 80% (7). The administration of 2.5 to 5.0 mg/kg of captopril per day to pregnant rabbits yielded pregnancy loss rates ranging from 37 to 92% (5-7). Severe and prolonged fetal hypotension has been demonstrated in the sheep model (7) and has been implicated in the high rate of fetal wastage. Possible impairment of uteroplacental perfusion by ACE inhibitors has also been suggested (6,7). Journal Yes Yes (20), 1989 PDA. Yes section: vaginal delivery 32 wk; cesarean section; 3-10% Scott and Purohit Abbreviations: N/A 29 wk IUFD, spontaneous Renal hypertension; N/A Pulmonary hypoplasia, decreased ACE activity, death day 8 Elective abortion, hypocalvaria, transverse limb defect PDA-surgical repair, Renal transplant (19), Other and Anuria survived 34 wk; cesarean 1989 0 Neonatal Hypotension 3-10% PIH and Modi or in pairs’ Yes termination 34 wk; cesarean 310% 34 wk; cesarean <3% 35 wk; cesarean 10-50% 36 wk; cesarean 1989 Cunniff eta!. 1990 Oligohydramnios individually <3% eta!. (18), reported Yes <3% Renovascular hypertension Essential hypertension Essential hypertension Unclear section; 34 wk; cesarean Nephrotic Syndrome Renovascular hypertension Glomerulonephritis, 1988 Knott exposure Birth Weight hypertension Ducret inhibitor (Percentile) Preeclampsia eta!. ACE Gestation; Mode of Delivery; Maternal Disease eta!. (8), and 1981 after et al The true rates of adverse fetal effects from ACE inhibitor use in human pregnancy cannot be determined from available information. Certainly, a number of exposed pregnancies have resulted in no discernible adverse effect. In the largest published series, there were 3 1 pregnancies exposed either to captoprib (N = 22) or enabapril (N = 9) (23). The reported adverse fetal outcomes included nine cases of intrauterine growth restriction, three intrauterine deaths, and two infants with patent ductus arteriosus. The other cases in this report were presumably unaffected. However, the list of case reports suggesting adverse ACE inhibitor-related fetal outcome continues to grow and a consistent pattern of manifestations has emerged. We have compiled the reported cases of ACE inhibitor use in pregnancy: Table 1579 ACE Inhibitor Fetopathy TABLE 2. Case series .-o;-’-.- ,..... reporting Author (Ref. No.), Year pregnancy No. of Cases in Series Plouin and Tchobroutsky (22), 1985 7 cases not report- ..‘. outcomes IUGR 2/7 <3% after ACE inhibitor exposurea Oh h dramnios Neonatal Hypotension and Anuria - 2/7 Yes None noted ed elsewhere Other 2/7 Spontaneous abortion 1/7 IUFD 4/7 survived 2/7 PDA Kreft-Jais 1988 et a!. (23), 31 cases not reported 9/31 <3% Not recorded Not recorded elsewhere Rose et a!. (24), 4 cases not reported elsewhere 1989 #{176}Abbrevlatlons as in footnote I PDA surgery Weights not 2/4 Yes recorded 2/4 not recorded 1580 4/4 Yes 2 Full recovery 2 renal insufficiency 4 survivors to Table 1. 1 summarizes single case reports (8- 1 2. 1 4-2 1 ). and Table 2 summarizes case series (22-24). Cases that were reported alone (in Table 1 ). but that were also included in a case series, were excluded from Table 2. The most commonly reported adverse effects in ACE inhibitor-exposed pregnancies are middleto late-trimester onset of oligohydramnios and intrauterine growth restriction, followed by delivery of an infant whose course is complicated by prolonged and often severe hypotenslon and anuria. This sequence was observed in our 3 cases as well as in 1 3 prevlously reported cases (Tables 1 and 2). Our first case and three previously reported cases (8, 1 9,2 1 ) had the morphologic findings of the oligohydramnios deformation sequence, including the neonatally lethal component, pulmonary hypoplasia. In each of our cases, the immediate postpartum period was complicated by profound hypotenslon and anuria. As observed in 1 3 previous cases manifesting this complication, the hypotension was recalcitrant to both volume and pressor support therapy. In Patient 1 death of the neonate occurred before normotension could be established. In Patients 2 and 3, the infants remained profoundly hypotensive and anuric until dialysis was initiated several days after birth. However, the combination of severe hypotension and anuria in a premature and/or growth-retarded infant makes both peritoneal dialysis and hemodialysis extremeby difficult, and the mortality rate is exceptionally high. Each of our patients had renal tubular dysplasia. Identical kidney lesions have been reported in one other case of neonatal renal failure (2 1 ) and suspected in another (1 8) in which transplacental ACE inhibitors were implicated. Renal tubular dysplasia is characterized by dilation of Bowman’s spaces and tubules, diminished to absent differentiation of prox, 1/7 PDA/surgery 3 Stillborn 2 PDA imal convoluted tubules and increased cortical and medublary mesenchyme (and later fibrosis). The histologic changes in the kidney are compatible with ischemic injury, having the added component of deficient tubular differentiation. Renal tubular dysplasia is also found in fetuses unexposed to ACE inhibitors but who have presumably been hypotensive tn utero (e.g. . the donor twin in the twin-twin transfusion syndrome) (28). Although a histologically similar renal lesion has been described in a rare autosomab recessive disorder (29,30), the clinical course and histories of our cases and those previously described suggest a related but etiobogically distinct lesion. The kidneys in two of our patients were large. a finding first noted by Cunniff et at. (2 1 ). Nephromegaly has also been noted as one of the features of the hereditary form of renal tubular dysplasia (29,30). Oligohydramnios, intrauterine growth restriction, and fetal distress are not uncommon complications of hypertensive pregnancies. However, the finding of evolving oligohydramnios followed by the delivery of a neonate with prolonged hypotension and anuria has not been included in the well-described list of complications of maternal hypertension and its tradltional therapy. In this setting. the probability that the observed oligohydramnios was in fact due to drug-related fetal hypotension and renal failure that persisted into the neonatal period needs to be serlously considered. Evidence in support of this hypothesis is the reported occurrence of profound hypotension, anuria, and low ACE activity in neonates given low doses of ACE inhibitors for the treatment of hypertension (3 1 -33). Similarly blunted ACE activity was observed in our second patient. Additional evidence Includes reported observations that the onset of oligohydramnios is temporally related to the initiation of ACE inhibitor therapy (8. 1 6). In one case, the amniotic fluid volume was observed to return Volume 3 ‘ Number 9 ‘ 1993 Pryde toward normal after the drug was discontinued; however, that infant died of respiratory insufficiency on day 6 of life (17). It has been emphasized that the renin-angiotensin system becomes crucially Important under conditions of low renal perfusion pressure (34,35). In this setting, angiotensin Il-mediated efferent arteriolar resistance becomes essential to the maintenance of gbomerular filtration and the production of urine. Under normal circumstances, the fetus and early neonate have a low renal perfusion pressure (36,37). Therefore, it makes good biologic sense to postulate that transplacental administration of ACE inhibitors would cause decreased angiotension II levels in the fetus, which would have the dual effect of a further decrement in systemic blood pressure as well as the loss of compensatory efferent arteriolar tone. The result would be a marked decrease in gbomerular filtration pressure with the attendant loss of urine production, manifest as oligohydramnios. Apart from the renal failure and related abnormalities discussed above, our patients and three previously reported patients (1 2, 1 9) had hypoplasia of the membranous bones of the skull, or hypocalvaria. This created symmetrically enlarged sutures and fontanels and, in severe cases, left the brain essentially unprotected by skull and potentially liable to trauma during labor and delivery. Although there are now only a total of six cases In which this skull lesion is described, we believe it may be more common but unrecognized by physicians not alerted to the phenomenon and therefore not looking for it. The possible pathogenesis of hypocalvaria is considered in more detail by Barr and Cohen (38). Occasionally, there is a drug whose record in pregnancy is so frequently associated with adverse outcome of so specific a pattern that it becomes clear that its use must be restricted before proof of harm can be obtained by epidemiologic studies. We believe this to be the case with the drug class of ACE inhibitors. There are two mammalian models suggesting substantial fetotoxicity in a dose-related fashion. There Is a strong and consistent pattern to the reported human cases of ACE Inhibitor-related adverse outcomes: the syndrome of oligohydramnios-anuria. neonatal hypotension, renal tubular dysplasia, and hypocalvarla is too specific In association with the use of these drugs to be ignored. There is a plausible biologic mechanism to explain the relationship: the features of ACE Inhibitor fetopathy suggest that the underlying pathogenetic mechanism Is fetal hypotension, but clearly more research in animal models is warranted to clarify the pathophysiology of the toxic effect. Although all of the features of the fetopathy may not be specific to ACE inhibitors, we suggest that ACE Inhibitors are particularly liable to produce these fetal renal effects (with their sequels anuria- Journal of the American Society of Nephrology et al oligohydramnios. pulmonary hypoplasia, growth restriction) and hypocalvaria. We suggest that this syndrome be labeled “ACE inhibitor fetopathy” and recommend restrictions on the use of these drugs in pregnancy. RECOMMENDATIONS We have deliberately used the word “fetopathy” rather than “teratogenlcity” In this discussion of ACE Inhibitor-rebated adverse outcomes. To date, there is no convincing evidence of a true teratogenic or firsttrimester effect of ACE inhibitors on the human embryo. and exposure during this time is not construed as an indication for abortion. In contrast, secondand third-trimester exposure seems to carry an Important. but as yet unquantified. risk of fetotoxicity, resulting in major morbidity and mortality. Emphasis on this distinction is important because of the indisputable therapeutic usefulness of the drugs of this class and the potentiality that women will conceive while taking one of them. Hanssens et at. (39) suggest that enalapril may be the more toxic of the clinically available ACE inhibitors. Be that as it may, fetotoxiclty has been observed In association with captopril and lisinopril, as well as enalapril. and there is no reason to assume that any ACE Inhibitor will be really safe for the fetus. Women of reproductive age who can clearly benefit from these drugs should be advised of the hazards to the fetus, educated about the Importance of periconceptionab antihypertenslon regimen change. and counseled about the use of safe and reliable contraception. With other safer antihypertensive agents available, we feel there is no justification for ACE inhibitor use once pregnancy has been documented. REFERENCES 1 . Williams GH: Converting enzyme inhibitors in the treatment of hypertension. N Engb J Med 1988:319:1517-1524. 2. Rotmensch ff1, Viasses PH, Ferguson RK: Angiotensin-converting enzyme inhibitors. Med Clin North Am 1988:72:399-425. 3. Gavras H: The place of angiotensmn converting enzyme inhibitors In the treatment of cardlovascular diseases. N Engl J Med 1988:3 19: 1 54 1 -1543. 4. Taguma Y, Kitamoto Y, Futaki G, et at.: Effect of captopril on heavy protelnuria In azotemic diabetics. N Engl J Med 1985;313:1617-1620. 5. Broughton-Pipkin F, Turner SR. Symonds EM: Possible risk with captoprib during pregnancy. Some animal data. Lancet 1 980:2: [256. 6. Ferris TF, Weir EK: Effect of captoprib on uterme blood flow and prostaglandmn E synthesis in the pregnant rabbit. J Clin Invest 1982:71: 809-815. 7. Broughton-Pipkin F, Symonds EM, Turner SR: The effect of captopril (SQ 14,225) upon mother 1581 ACE Inhibitor 8. 9. 1 0. 1 1. 1 2. 1 3. 1 4. 1 5. 1 6. 1 7. 1 8. 1 9. 20. 21. 22. 23. 1582 Fetopathy and fetus in the chronically cannubated ewe and in the pregnant rabbit. J Physiol 1982:323: 415-422. Guignard JP, Burgener F, Calaine A: Persistent anuria in a neonate: a side effect of captopril? Int J Pediatr Nephrol 1981:2:133. Dummy PC, Burger P du T: Fetal abnormality associated with the use of captoprib during pregnancy. S Afr Med J 1981:60:805. Boutroy MJ, Vent P. Hunault de Ligny B, Milton A: Captopril administration in pregnancy impairs fetal angiotensmn converting enzyme activity and neonatal adaptation. Lancet 1984:2: 935-936. Caraman PL, Milton A, Hunault de Ligny B, et at. : Grossesses sous captopril. Therapie 1984: 39:59-62. Rothberg AD. Lorenz R: Can captopril cause fetal and neonatal renal failure? Pediatr Pharmacol 1 984;4: 189-192. Lindheimer MD, Katz A!: Hypertension in pre nancy (current concepts). N Engb J Med 1 98 313:675-680. Fiocchi R, Ligney P. Fagard R, Staessen J. Amery A: Captopril during pregnancy. Lancet 1984:2:1153. Ducret F, Pointet PH, Laurengeon B, Jacoulet C, Gagnaire J: Grossesse sous inhibiteur de l’enzyme de conversion. Presse Med 1 985; 14:897. Schubiger G, Flury G, Nussberger J: Enalapril for pregnancy-induced hypertension : Acute renal failure in the neonate. Ann Intern Med 1988:108:215-216. Broughton-Pipkin F, Baker PN, Symonds EM: Angiotensmn converting enzyme inhibitors in pregnancy. Lancet 1989:2:96-97. Knott PD, Thorpe SS, Lamont CAR: Congenital renal dysgenesis possibly due to captoprib. Lancet 1989:1:451. Mehta N, Modi N: ACE inhibitors in pregnancy. Lancet 1989:2:96. Scott AA, Purohit DM: Neonatal renal failure: A complication of maternal antihypertensive therapy. Am J Obstet Gynecol 1989:160: 12231224. Cunniff C, Jones KL, Phillipson K, Short S. Wujek J: Oligohydramnios and renal tubular malformation associated with maternal enalapril use. Am J Obstet Gynecol 1990:162: 187-189. Plouin PF, Tchobroutsky C: Inhibition de b’enzyme de conversion de 1 angiotensine au cours de la grossesse humaine. Qumnze cas. Presse Med 1985:14:2175-2178. Kreft-Jais C, Plouin C, Tchobroutsky C, Boutroy MJ: Angiotensmn-converting enzyme inhib- - 24. 25. 26. 27. 28. 29. 30. 3 1. 32. 33. 34. 35. 36. 37. 38. 39. itors during pregnancy: A survey of 22 patients given captopril and nine given enabaprib. Br J Obstet Gynaecol 1988:95:420-422. Rosa FW, Bosco LA, Fossum-Graham C, Mustien JB, Dreis M, Creamer J: Neonatal anuria with maternal angiotensin-converting enzyme inhibition. Obstet Gynecob 1989:74:371-374. Vidt DG, Bravo EL, Fouad FM: Captopril. N Engb J Med 1982:306:214-2 19. Todd PA, Heel RC: Enalapril: A review of its pharmacodynamic properties. and therapeutic use in hypertension and congestive heart failure. Drugs l986;3l:198-248. Gomez HJ, Cirillo VJ, Moncloa F: The clinical pharmacology of bisinoprib. J Cardiovasc Pharmacol 1987:9(Suppb 3):S27-S34. Martin PA, Jones KL, Mendoza A, Barr M, Benirschke K: The effect of ACE inhibition on the fetal kidney: Decreased renal blood flow. Teratology 1993:46:317-321. Ailanson JE, Pantzar JT, MacLeod PM: Possible new autosomab recessive syndrome with unusual renal histopathobogicab changes. Am J Med Genet 1 983; 16:57-60. Bernstein J: Renal tubular dysgenesis. Pediatr Pathol 1988:8:453-456. Tack ED, Perlman JM: Renal failure in sick hypertensive premature infants receiving captopril therapy. J Pediatr 1988:1 12:805-8 10. Penman JM, Volpe JJ: Neurobogic complications of captoprib treatment of neonatal hypertension. Pediatrics 1989:83:47-52. Wells TG, Bunclunan TE, Kearns GL: Treatment of neonatal hypertension with enabapril. J Pediatr 1990:117:664-667. Hall JE, Guyton AC, Jackson TE, Coleman TG, Lohmeier TE, Tnppodo NC: Control of gbomerular filtration rate by renmn-angiotensin system. Am J Physiol 1977;233:F366-372. Blythe WB: Captoprib and renal autoregubation. N Enl J Med 1983:308:390-391. Rudolph AM, Heyman MA, Teramo KAW, Barrett CT, Raffia NCR: Study on the circulation of the previable human fetus. Pediatr Res 1971:5: 452-465. Guignard JP: Renal function in the newborn infant. Pediatr Clin North Am 1982:9: 777-790. Barr M, Cohen MM: ACE inhibitor fetopathy and hypocalvaria: The kidney-skull connection. Teratology 1991:44:485-495. Hanssens M, Keurse MJNC, Vankelecom F, Van Assch FA: Fetal and neonatal effects of treatment with angiotensin-converting enzyme inhibitors in pregnancy. Obstet Gynecol 1991:78: 128-135. Volume 3’ Number 9 1993