- Email: [email protected]
Fetopathy associated with exposure to angiotensin converting enzyme inhibitors and angiotensin receptor antagonists
Early Human Development (2006) 82, 23 — 28
available at www.sciencedirect.com
www.elsevier.com/locate/earlhumdev
Fetopathy associated with exposure to angiotensin converting enzyme inhibitors and angiotensin receptor antagonists Albert Quan * Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9063, USA
KEYWORDS Renin—angiotensin; Angiotensin receptor; AT1 antagonist; Hypocalvaria
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.
D 2005 Published by Elsevier Ireland Ltd.
Contents 1. 2. 3. 4.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . Angiotensin converting enzyme inhibitors . . . . . . . . . . . Adverse effects of angiotensin converting enzyme inhibitors Adverse effects of angiotensin converting enzyme inhibitors 4.1. Hemodynamic and renal effects . . . . . . . . . . . . 4.2. Hypocalvaria . . . . . . . . . . . . . . . . . . . . . . . 4.3. Patent ductus arteriosus . . . . . . . . . . . . . . . . .
* Tel.: +1 214 648 3528; fax: +1 214 648 2034. E-mail address: [email protected]. 0378-3782/$ - see front matter D 2005 Published by Elsevier Ireland Ltd. doi:10.1016/j.earlhumdev.2005.11.001
. . . . . . . . during during . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . pregnancy: animal pregnancy: human . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . data . . studies. . . . . . . . . . . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
24 25 25 25 26 26 26
24
A. Quan
5. Angiotensin II receptor antagonist . . . . . . . . . . . 6. Adverse effects of angiotensin II receptor antagonist 7. Summary and current recommendations . . . . . . . 8. Key guidelines . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . during . . . . . . . . . . . .
. . . . . . . pregnancy . . . . . . . . . . . . . . . . . . . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
26 26 27 27 27
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
1. 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
RENIN-ANGIOTENSIN SYSTEM Angiotensinogen
Renin
Angiotensin I Bradykinin Angiotensin converting enzyme Angiotensin converting enzyme inhibitor Inactive peptide Angiotensin II Angiotensin receptor antagonist
Angiotensin II Receptor Type I
Aldosterone
Extracellular volume
Figure 1
. . . . .
Renin—angiotensin system.
Vasoconstriction
Blood pressure
Fetopathy associated with exposure to angiotensin converting enzyme inhibitors and angiotensin receptor antagonists 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.
2. 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, fosinopril, and quinapril. In general, the adverse effects associated with use of ACE inhibitors have been few and include hypotension, hyperkalemia, acute renal failure, skin rash, angioneurotic edema, or an irritating non-productive cough [1]. The hyperkalemia is a consequence of inhibition of aldosterone secretion, while acute renal failure results from the loss of glomerular efferent arteriolar resistance with a fall in filtration fraction. The skin rash and angioneurotic edema are allergic symptoms and the cough is likely related to alterations in the bradykinin metabolism.
3. 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
25
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 of 8 ewes were stillborn [4]. The effect of ACE inhibitors has also been examined in the pregnant rabbit. Administration of captopril to late gestational age rabbits (24—28 days—term is 31 days) had a 37% stillbirth rate compared to the 6% in saline control rabbits [4]. In addition, captopril significantly prolonged the gestational length compared to the control rabbits. Orally administered captopril in the pregnant rabbit from midgestation until term (15 to 30th day) resulted in fetal death in 86% of newborn rabbits versus 1% in control animals [5]. Captopril administration in pregnant rabbits was also found to reduce uterine blood flow and was associated with an 86% to 92% fetal mortality, depending upon the dosage of captopril used. These investigators concluded that inhibition of angiotensin II synthesis reduced uterine blood flow and increased fetal mortality [6]. ACE inhibitors have also been examined in the primate baboon. In a prospective placebo controlled trial, use of enalapril during pregnancy resulted in a significant rise in the incidence of fetal death or fetal growth retardation [7]. The observation that the fetal deaths were associated with only a very modest fall in maternal blood pressure suggested that fetal mortality was likely secondary to a direct effect of enalapril on the fetal renin—angiotensin system, rather than to the effects of placental ischemia [7]. Post-mortem examination of the dead fetuses revealed no fetal anomalies. Taken together, these animal data would suggest that use of ACE inhibitors during pregnancy lead to decreased uteroplacental blood flow, low birth weight, fetal hypotension, preterm delivery, and fetal death.
4. 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 trimester of pregnancy and congenital fetal defects [8]. The absence of firm evidence for a teratogenic effect of ACE inhibitors has prompted some investigators to state that it would not be appropriate to terminate a pregnancy because of drug exposure early in pregnancy [9]. The adverse fetal effects may be a consequence of the pharmacologic effect of ACE inhibitors and not a result of any dysmorphogenic or genetic effect. However, there are several reports of malformed fetuses in mothers who have used ACE inhibitors during the first trimester. The fetal effects noted include phocomelia, fetal death, omphalocele, congenital heart defect, hypertrichosis, growth retardation, respiratory failure, renal failure, and intraventricular hemorrhage [10,11,12]. Interpretation of these observations and the role of early first trimester
26 ACE inhibitor administration is confounded by the fact that use of such drugs often occurred throughout the entire pregnancy and not just limited to the first trimester. In addition, virtually all of the mothers were taking other various medications in addition to the ACE inhibitors. The use of ACE inhibitors during the second or third trimesters of pregnancy is believed to clearly have adverse fetal effects [13]. The most commonly reported adverse effects of ACE inhibitors taken during this stage of pregnancy include intrauterine growth retardation, neonatal hypotension, renal failure, oligohydramnios, and patent ductus arteriosus [10—13].
4.1. Hemodynamic and renal effects Neonatal hypotension was noted in approximately 10% of reported pregnancies where ACE inhibitors were used [14— 19]. The neonatal hypotension is unique in that it is refractory to treatment with volume expansion or pressor support 1[20—22]. In many of the earliest cases of maternal captopril use in mid to late gestation, the neonates had hypotension accompanied by oligo/anuria with renal failure, some of whom required peritoneal dialysis [4,14,18,19,23— 25]. A review of the cases of maternal ACE inhibitor exposure found that 9 of 14 of reported cases involved anuric renal failure [26]. In addition to the treatment of uremia, peritoneal dialysis is also believed to help by decreasing the high levels of ACE inhibitor in the neonate accumulated from maternal use [27]. In many of these reported cases, oligohydramnios was noted and presumably due to reduced renal function and urine output by the fetus. The oligohydramnios was often accompanied by limb contractures, hypoplastic lungs, respiratory failure and death in the neonatal period [26,27]. The mechanism by which pulmonary hypoplasia develops is unknown, but may be related to compression of the fetal chest wall in the oligohydramniotic milieu with a restriction of fetal breathing movements [28]. Overall, respiratory complications were found in 14% of newborns who were exposed to maternal ACE inhibitors [29]. Although the kidneys often appeared grossly normal, closer examination revealed similar histopathologic findings in such patients. These findings include juxtaglomerular hyperplasia and renal tubular dilatation which is characterized by dilatation of Bowman’s space and tubules with diminished or absent differentiation of proximal convoluted tubules, and increased cortical and medullary fibrosis [20,30—32]. These microscopic findings are comparable to the histologic findings in infants suffering ischemic insults. In a renal morphologic study, 20 controls were compared with 13 fetuses with multiple malformations, 6 fetuses with twin—twin transfusions, and one with ACE inhibitor exposure [33]. The results demonstrate renal tubular dilatation in two cases of twin—twin transfusion, the ACE inhibitor case and a methyldopa exposed case [33]. These results lend support to the thesis that renal tubular dilatation of ACE inhibitors results from renal hypoperfusion and ischemia [33]. In addition, angiotensin II maintains adequate glomerular filtration in the low perfusion pressure system of the fetal kidney [34]. It is also plausible that inhibition of the fetal glomerular filtration rate via inhibition of fetal
A. Quan angiotensin II production may also impair normal renal tubular development [20].
4.2. Hypocalvaria A uniquely observed adverse effect of maternal ACE inhibitor use is the finding of greatly reduced size of the calvarial bones [20,26,30]. Brain development is left undisturbed. The cranial sutures and fontanels are significantly enlarged and can leave the brain inadequately protected from trauma during labor and delivery. More often, however, milder cases may be classified as enlarged fontanels or widely split sutures. The cause of hypocalvaria resulting from maternal ACE inhibitor use is unknown. It has been hypothesized that fetal hypotension induced by maternal ACE inhibitor use may result in calvarial hypoxia and lead to hypoplastic growth [35]. The calvarium is membranous bone and requires high oxygen levels to develop normally. Alternatively, it is also possible that inhibition of angiotensin II formation via an ACE inhibitor use could inhibit an unknown growth factor of calvarial development [1].
4.3. Patent ductus arteriosus There are four known cases of fetal patent ductus arteriosus (PDA) associated with maternal ACE inhibitor use. Three of the four patients were born prematurely at 34—35 weeks gestation and required surgical correction of the PDA [15,36,37]. Medical management with indomethacin was only successful in one child [37]. It is possible that the PDA in these patients were the result of premature birth. However, the relationship between the action of ACE inhibitors to raise bradykinin and prostaglandin levels and the persistence of a PDA raises the possibility that ACE inhibitors use might contribute to the failure of PDAs to close.
5. 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 hypertension, but often have fewer side effects common to the ACE inhibitors, such as the dry non-productive cough. ACE inhibition may also prevent the breakdown of bradykinin via angiotensin converting enzyme in a parallel pathway. The buildup of bradykinin may be related to some of the side effects of ACE inhibitors [28].
6. 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
Fetopathy associated with exposure to angiotensin converting enzyme inhibitors and angiotensin receptor antagonists 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 were reported where valsartan was taken in the first trimester [39]. One pregnancy was terminated via a therapeutic abortion because of hypertension, but no fetal abnormalities were noted. Two other pregnancies ended because of miscarriages, but, again, no fetal abnormalities were noted. The fourth pregnancy resulted in a healthy newborn. Another recent study reported three normal infants whose mothers received treatment with valsartan during their first trimester [40]. Thus, there is no clear deleterious effect of AT1 antagonists when used by the mother during the first trimester of pregnancy. In contrast, use of AT1 antagonists during the second and third trimesters of pregnancies have yielded similar deleterious effects to that seen with the ACE inhibitors. High rates of mortality were observed, where 2 of 15 cases of fetal exposure to maternal AT 1 antagonists were stillborn and 4 of the 15 cases died within 3 to 4 days after birth [28,38,41— 48]. Oligohydramnios was reported in 14 of 15 cases of use of AT1 antagonist late in pregnancy. Neonatal anuria was also common and observed in 8 of 11 live births. As expected, fetal anuria was often accompanied by oligohydramnios. Presumably, maternal use of AT1 antagonist suppressed fetal renal function, reduced urine output and lead to oligohydramnios with fetal/neonatal anuria. Microscopic examination of renal histology in the 5 neonates who were either stillborn or died shortly after birth revealed similar findings as that of ACE inhibitor use. These findings include tubular dilatation, absent or poor proximal tubular differentiation, and high renin expression in the juxtaglomerular apparatus. It has been assumed that the histologic findings result from AT1 antagonist related hypoperfusion of the fetal kidney [49,50]. In addition, the reduction in the fetal glomerular filtration rate owing to blockade of the angiotensin II receptor may also lead to abnormal renal tubular development. Neonatal hypoplastic lungs were also reported in 3 of 15 cases of maternal use of AT1 antagonists [28]. All three cases were fatal. Pulmonary hypoplasia likely results from oligohydramnios in a similar manner as described above for ACE inhibition. Hypoplastic calvaria were similarly reported in infants of mothers who used AT1 antagonists during pregnancy. In a recent review, 9 of the 15 infants born to women treated with AT1 receptor antagonists had hypoplastic skull development [28]. The mechanism by which hypocalvaria develops is unknown, but may be related to hypoperfusion of the membranous bone of the calvaria secondary to the AT1 antagonists.
7. 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
27
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 failure with oligo/anuria, renal tubular abnormalities, and calvarial hypoplasia. The timing of the disruption of the fetal renin—angiotensin system may also play an important role in fetal outcome. Fetal exposure to ACE inhibitors or AT1 antagonists during the first trimester is likely to be of minimal risk and should not be an indication for termination of the pregnancy. Fetal exposure of ACE inhibitors or AT1 antagonists during the second or third trimesters is associated with the above reported deleterious findings. The Food and Drug Administration has officially warned against use of ACE inhibitors during the second and third trimesters of pregnancy. Hypertensive non-pregnant women using ACE inhibitors or AT1 antagonists are advised to seek early prenatal care and switch to another antihypertensive agent if possible. The fetus already exposed to maternal use of these drugs should be monitored closely with serial sonograms for assessment of fetal growth, amniotic fluid volume, and organ malformations. Whenever possible, the neonate exposed to ACE inhibitors or AT1 antagonists should be delivered at a tertiary care medical center, where support services are available to treat hypotension, respiratory distress, and renal failure.
8. 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.
References [1] Buttar HS. An overview of the influence of ACE inhibitors on fetal—placental circulation and perinatal development. Mol Cell Biochem 1997;176:61 – 71. [2] Quan A, Baum M. Endogenous production of angiotensin II modulates rat proximal tubule transport. J Clin Invest 1996;97: 2878 – 82. [3] Hilgers KF, Norwood VF, Gomez RA. Angiotensin’s role in renal development. Semin Nephrol 1997;17:492 – 501. [4] Broughton-Pipkin F, Symonds EM, Turner SR. The effect of captopril (SQ14225) upon mother and fetus in the chronically cannulated ewe and in the pregnant rabbit. J Physiol 1982;323: 415 – 22. [5] Keith IM, Will JA, Weir EK. Captopril: association with fetal death and pulmonary vascular changes in the rabbit (41446). Proc Soc Exp Biol Med 1982;170:378 – 83. [6] Ferris TF, Weir EK. Effect of captopril on uterine blood flow and prostaglandin E synthesis in the pregnant rabbit. J Clin Invest 1983;71:809 – 15.
28 [7] Harewood WJ, Phippard AF, Duggin GG. Fetotoxicity of angiotensin-converting enzyme inhibition in primate pregnancy: a prospective, placebo-controlled study in baboons (Papio hamadryas). Am J Obstet Gynecol 1994;171:633 – 42. [8] GG Briggs, RK Freeman, SJ Yaffe. Drugs in pregnancy and lactation. Baltimore, MD, Williams and Wilkins; 1994; p. 120—126. 317—324, 495—497. [9] Brent RL, Beckman DA. Angiotensin-converting enzyme inhibitors, an embryopathic class of drugs with unique properties: information for clinical teratology counselors. Teratology 1991;43:543 – 6. [10] Duminy PC, Burger PT. Fetal abnormality associated with the use of captopril during pregnancy. S Afr Med J 1981;60:805. [11] Kaler SG, Patrinos ME, Lambert GH. Hypertrichosis and congenital anomalies associated with maternal use of minoxidil. Pediatrics 1987;79:434 – 6. [12] Rothberg AD, Lorenz R. Can captopril cause fetal and neonatal renal failure? Pediatr Pharmacol 1984;4:189 – 92. [13] Nightingale SL. Warnings on the use of ACE inhibitors in second and third trimester of pregnancy. JAMA 1992;267:2445. [14] Broughton-Pipkin F, Baker PN, Symonds EM. ACE inhibitors in pregnancy. Lancet 1989;2:96 – 7. [15] Boutroy MJ, Vert P, Hurault de Ligny B, Miton A. Captopril administration in pregnancy impairs fetal angiotensin converting enzyme activity and neonatal adaptation. Lancet 1984;2:935 – 6. [16] Guignard JP, Burgener F, Calame A. Persistent anuria in neonate: a side effect of captopril. Int J Pediatr Nephrol 1981;2:133. [17] Mehta N, Modi N. ACE inhibitors in pregnancy. Lancet 1989;2:96. [18] Rosa FW, Bosco LA, Graham CF. Neonatal anuria with maternal angiotensin converting enzyme inhibition. Obstet Gynecol 1989;74:371 – 4. [19] Cunniff C, Jones KL, Phillipson J. Oligohydramnios sequence and renal tubular malformation associated with maternal enalapril use. Am J Obstet Gynecol 1990;162:187 – 9. [20] Mastrobattista J. Angiotensin converting enzyme inhibitors in pregnancy. Semin Perinatol 1997;21:124 – 34. [21] Biocchi R, Lijnen P, Fagard R. Captopril during pregnancy. Lancet 1984;2:1153. [22] Pryde PG, Nugent CE, Sedman AB. ACE inhibitor fetopathy. Am J Obstet Gynecol 1992;166:348. [23] Lubbe WF. The use of captopril in pregnancy. N Z Med J 1983;96:1029 – 30. [24] Schubiger G, Flury G, Nussberger J. Enalapril for pregnancy induced hypertension: acute renal failure in a neonate. Ann Intern Med 1988;108:215 – 6. [25] Plouin PF, Tchoboutsky C. Inhibition of angiotensin converting enzyme in human pregnancy: 15 cases. Presse Med 1985;14: 2175 – 8. [26] Pryde PG, Sedman AB, Nugent CE, Barr M. Angiotensin converting enzyme inhibitor fetopathy. J Am Soc Nephrol 1993;3:1575 – 82. [27] Lindheimer MD, Barron WM. Enalapril and pregnancy induced hypertension. Ann Intern Med 1988;108:911. [28] Alwan S, Polifka JE, Friedman JM. Angiotensin II receptor antagonist treatment during pregnancy. Birth Defects Res (Part A) 2005;73:123 – 30.
A. Quan [29] Hanssens M, Keirse MJNC, Vankelecom F, Van Assche FA. Fetal and neonatal effects of treatment with angiotensin converting enzyme inhibitors in pregnancy. Obstet Gynecol 1991;78: 128 – 35. [30] Barr M. Teratogen update: angiotensin converting enzyme inhibitors. Teratology 1994;50:399 – 409. [31] Knott PD, Thorp SS, Lamont CAR. Congenital renal dysgenesis possibly due to captopril. Lancet 1989;1:451. [32] Martin RA, Jones KL, Mendoza A, Barr M, Benirschke K. Effect of ACE inhibition on the fetal kidney: decreased renal blood flow. Teratology 1992;46:317 – 21. [33] Landing GH, Ang SM, Herta N, Larson EF, Turner M. Labeled lectin studies of renal tubular dysgenesis and renal tubular atrophy of postnatal renal ischemia and end stage kidney disease. Pediatr Pathol 1994;14:87 – 99. [34] Piper JM, Ray WA, Rosa FW. Pregnancy outcome following exposure to angiotensin converting enzyme inhibitors. Obstet Gynecol 1992;80:429 – 32. [35] Barr M, Cohen MM. ACE inhibitor fetopathy and hypocalvaria: the kidney—skull connection. Teratology 1991;44:485 – 95. [36] Hurault de Ligny B, Ryckelynck JP, Mintz P. Captopril therapy in preeclampsia. Nephron 1987;46:329 – 30. [37] Kreft-Jais C, Plouin PF, Tchoboutsky C, Boutroy MJ. Angiotensin converting enzyme inhibitors during pregnancy: a survey of 22 patients given captopril and nine given enalapril. Br J Obstet Gynaecol 1988;95:420 – 2. [38] Schaefer C. Angiotensin II receptor antagonists: further evidence of fetotoxicity but not teratogenicity. Birth Defects Res Part A Clin Mol Teratol 2003;67:591 – 4. [39] Biswas PN, Wilton LV, Shakir SW. The safety of valsartan: results of a postmarketing surveillance study on 12,881 patients in England. J Hum Hypertens 2002;16:795 – 803. [40] Chung NA, Lip GYH, Beevers M, Beevers DG. Angiotensin II receptor inhibitors in pregnancy. Lancet 2001;357:1620. [41] Saji H, Yamanaka M, Hagiwara A, Ijiri R. Losartan and fetal toxic effects. Lancet 2001;357:363. [42] Lambot MA, Vermeylen D, Noel JC. Angiotensin II receptor inhibitors in pregnancy. Lancet 2001;357:1619 – 20. [43] Hinsberger A, Wingen AM, Hoyer PF. Angiotensin II receptor inhibitors in pregnancy. Lancet 2001;357:1620. [44] Martinovic J, Benachi A, Laurent N. Fetal toxic effects and angiotensin II receptor antagonists. Lancet 2001;358:241 – 2. [45] Briggs GG, Nagoette MP. Fatal fetal outcome with the combined use of valsartan and atenolol. Ann Pharmacother 2001;35:859 – 61. [46] Cox RM, Anderson JM, Cox P. Defective embryogenesis with angiotensin II receptor antagonists in pregnancy. Br J Obstet Gynaecol 2003;110:1038 – 40. [47] Pietrement C, Malot L, Santerne B. Neonatal acute renal failure secondary to maternal exposure to telmisartan, angiotensin II receptor antagonist. J Perinatol 2003;23:254 – 5. [48] Nayar B, Singhal A, Aggarwal R, Malhotra N. Losartan induced fetal toxicity. Indian J Pediatr 2003;70:138 – 42. [49] Hulton SA, Thomson PD, Cooper PA, Rothberg AD. Angiotensin converting enzyme inhibitors in pregnancy may result in neonatal renal failure. S Afr Med J 1990;78:673 – 6. [50] Lavoratti G, Seracini D, Fiorini P. Neonatal anuria by ACE inhibitors during pregnancy. Nephron 1997;76:235 – 6.
available at www.sciencedirect.com
www.elsevier.com/locate/earlhumdev
Fetopathy associated with exposure to angiotensin converting enzyme inhibitors and angiotensin receptor antagonists Albert Quan * Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9063, USA
KEYWORDS Renin—angiotensin; Angiotensin receptor; AT1 antagonist; Hypocalvaria
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.
D 2005 Published by Elsevier Ireland Ltd.
Contents 1. 2. 3. 4.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . Angiotensin converting enzyme inhibitors . . . . . . . . . . . Adverse effects of angiotensin converting enzyme inhibitors Adverse effects of angiotensin converting enzyme inhibitors 4.1. Hemodynamic and renal effects . . . . . . . . . . . . 4.2. Hypocalvaria . . . . . . . . . . . . . . . . . . . . . . . 4.3. Patent ductus arteriosus . . . . . . . . . . . . . . . . .
* Tel.: +1 214 648 3528; fax: +1 214 648 2034. E-mail address: [email protected]. 0378-3782/$ - see front matter D 2005 Published by Elsevier Ireland Ltd. doi:10.1016/j.earlhumdev.2005.11.001
. . . . . . . . during during . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . pregnancy: animal pregnancy: human . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . data . . studies. . . . . . . . . . . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
24 25 25 25 26 26 26
24
A. Quan
5. Angiotensin II receptor antagonist . . . . . . . . . . . 6. Adverse effects of angiotensin II receptor antagonist 7. Summary and current recommendations . . . . . . . 8. Key guidelines . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . during . . . . . . . . . . . .
. . . . . . . pregnancy . . . . . . . . . . . . . . . . . . . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
. . . . .
26 26 27 27 27
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
1. 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
RENIN-ANGIOTENSIN SYSTEM Angiotensinogen
Renin
Angiotensin I Bradykinin Angiotensin converting enzyme Angiotensin converting enzyme inhibitor Inactive peptide Angiotensin II Angiotensin receptor antagonist
Angiotensin II Receptor Type I
Aldosterone
Extracellular volume
Figure 1
. . . . .
Renin—angiotensin system.
Vasoconstriction
Blood pressure
Fetopathy associated with exposure to angiotensin converting enzyme inhibitors and angiotensin receptor antagonists 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.
2. 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, fosinopril, and quinapril. In general, the adverse effects associated with use of ACE inhibitors have been few and include hypotension, hyperkalemia, acute renal failure, skin rash, angioneurotic edema, or an irritating non-productive cough [1]. The hyperkalemia is a consequence of inhibition of aldosterone secretion, while acute renal failure results from the loss of glomerular efferent arteriolar resistance with a fall in filtration fraction. The skin rash and angioneurotic edema are allergic symptoms and the cough is likely related to alterations in the bradykinin metabolism.
3. 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
25
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 of 8 ewes were stillborn [4]. The effect of ACE inhibitors has also been examined in the pregnant rabbit. Administration of captopril to late gestational age rabbits (24—28 days—term is 31 days) had a 37% stillbirth rate compared to the 6% in saline control rabbits [4]. In addition, captopril significantly prolonged the gestational length compared to the control rabbits. Orally administered captopril in the pregnant rabbit from midgestation until term (15 to 30th day) resulted in fetal death in 86% of newborn rabbits versus 1% in control animals [5]. Captopril administration in pregnant rabbits was also found to reduce uterine blood flow and was associated with an 86% to 92% fetal mortality, depending upon the dosage of captopril used. These investigators concluded that inhibition of angiotensin II synthesis reduced uterine blood flow and increased fetal mortality [6]. ACE inhibitors have also been examined in the primate baboon. In a prospective placebo controlled trial, use of enalapril during pregnancy resulted in a significant rise in the incidence of fetal death or fetal growth retardation [7]. The observation that the fetal deaths were associated with only a very modest fall in maternal blood pressure suggested that fetal mortality was likely secondary to a direct effect of enalapril on the fetal renin—angiotensin system, rather than to the effects of placental ischemia [7]. Post-mortem examination of the dead fetuses revealed no fetal anomalies. Taken together, these animal data would suggest that use of ACE inhibitors during pregnancy lead to decreased uteroplacental blood flow, low birth weight, fetal hypotension, preterm delivery, and fetal death.
4. 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 trimester of pregnancy and congenital fetal defects [8]. The absence of firm evidence for a teratogenic effect of ACE inhibitors has prompted some investigators to state that it would not be appropriate to terminate a pregnancy because of drug exposure early in pregnancy [9]. The adverse fetal effects may be a consequence of the pharmacologic effect of ACE inhibitors and not a result of any dysmorphogenic or genetic effect. However, there are several reports of malformed fetuses in mothers who have used ACE inhibitors during the first trimester. The fetal effects noted include phocomelia, fetal death, omphalocele, congenital heart defect, hypertrichosis, growth retardation, respiratory failure, renal failure, and intraventricular hemorrhage [10,11,12]. Interpretation of these observations and the role of early first trimester
26 ACE inhibitor administration is confounded by the fact that use of such drugs often occurred throughout the entire pregnancy and not just limited to the first trimester. In addition, virtually all of the mothers were taking other various medications in addition to the ACE inhibitors. The use of ACE inhibitors during the second or third trimesters of pregnancy is believed to clearly have adverse fetal effects [13]. The most commonly reported adverse effects of ACE inhibitors taken during this stage of pregnancy include intrauterine growth retardation, neonatal hypotension, renal failure, oligohydramnios, and patent ductus arteriosus [10—13].
4.1. Hemodynamic and renal effects Neonatal hypotension was noted in approximately 10% of reported pregnancies where ACE inhibitors were used [14— 19]. The neonatal hypotension is unique in that it is refractory to treatment with volume expansion or pressor support 1[20—22]. In many of the earliest cases of maternal captopril use in mid to late gestation, the neonates had hypotension accompanied by oligo/anuria with renal failure, some of whom required peritoneal dialysis [4,14,18,19,23— 25]. A review of the cases of maternal ACE inhibitor exposure found that 9 of 14 of reported cases involved anuric renal failure [26]. In addition to the treatment of uremia, peritoneal dialysis is also believed to help by decreasing the high levels of ACE inhibitor in the neonate accumulated from maternal use [27]. In many of these reported cases, oligohydramnios was noted and presumably due to reduced renal function and urine output by the fetus. The oligohydramnios was often accompanied by limb contractures, hypoplastic lungs, respiratory failure and death in the neonatal period [26,27]. The mechanism by which pulmonary hypoplasia develops is unknown, but may be related to compression of the fetal chest wall in the oligohydramniotic milieu with a restriction of fetal breathing movements [28]. Overall, respiratory complications were found in 14% of newborns who were exposed to maternal ACE inhibitors [29]. Although the kidneys often appeared grossly normal, closer examination revealed similar histopathologic findings in such patients. These findings include juxtaglomerular hyperplasia and renal tubular dilatation which is characterized by dilatation of Bowman’s space and tubules with diminished or absent differentiation of proximal convoluted tubules, and increased cortical and medullary fibrosis [20,30—32]. These microscopic findings are comparable to the histologic findings in infants suffering ischemic insults. In a renal morphologic study, 20 controls were compared with 13 fetuses with multiple malformations, 6 fetuses with twin—twin transfusions, and one with ACE inhibitor exposure [33]. The results demonstrate renal tubular dilatation in two cases of twin—twin transfusion, the ACE inhibitor case and a methyldopa exposed case [33]. These results lend support to the thesis that renal tubular dilatation of ACE inhibitors results from renal hypoperfusion and ischemia [33]. In addition, angiotensin II maintains adequate glomerular filtration in the low perfusion pressure system of the fetal kidney [34]. It is also plausible that inhibition of the fetal glomerular filtration rate via inhibition of fetal
A. Quan angiotensin II production may also impair normal renal tubular development [20].
4.2. Hypocalvaria A uniquely observed adverse effect of maternal ACE inhibitor use is the finding of greatly reduced size of the calvarial bones [20,26,30]. Brain development is left undisturbed. The cranial sutures and fontanels are significantly enlarged and can leave the brain inadequately protected from trauma during labor and delivery. More often, however, milder cases may be classified as enlarged fontanels or widely split sutures. The cause of hypocalvaria resulting from maternal ACE inhibitor use is unknown. It has been hypothesized that fetal hypotension induced by maternal ACE inhibitor use may result in calvarial hypoxia and lead to hypoplastic growth [35]. The calvarium is membranous bone and requires high oxygen levels to develop normally. Alternatively, it is also possible that inhibition of angiotensin II formation via an ACE inhibitor use could inhibit an unknown growth factor of calvarial development [1].
4.3. Patent ductus arteriosus There are four known cases of fetal patent ductus arteriosus (PDA) associated with maternal ACE inhibitor use. Three of the four patients were born prematurely at 34—35 weeks gestation and required surgical correction of the PDA [15,36,37]. Medical management with indomethacin was only successful in one child [37]. It is possible that the PDA in these patients were the result of premature birth. However, the relationship between the action of ACE inhibitors to raise bradykinin and prostaglandin levels and the persistence of a PDA raises the possibility that ACE inhibitors use might contribute to the failure of PDAs to close.
5. 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 hypertension, but often have fewer side effects common to the ACE inhibitors, such as the dry non-productive cough. ACE inhibition may also prevent the breakdown of bradykinin via angiotensin converting enzyme in a parallel pathway. The buildup of bradykinin may be related to some of the side effects of ACE inhibitors [28].
6. 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
Fetopathy associated with exposure to angiotensin converting enzyme inhibitors and angiotensin receptor antagonists 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 were reported where valsartan was taken in the first trimester [39]. One pregnancy was terminated via a therapeutic abortion because of hypertension, but no fetal abnormalities were noted. Two other pregnancies ended because of miscarriages, but, again, no fetal abnormalities were noted. The fourth pregnancy resulted in a healthy newborn. Another recent study reported three normal infants whose mothers received treatment with valsartan during their first trimester [40]. Thus, there is no clear deleterious effect of AT1 antagonists when used by the mother during the first trimester of pregnancy. In contrast, use of AT1 antagonists during the second and third trimesters of pregnancies have yielded similar deleterious effects to that seen with the ACE inhibitors. High rates of mortality were observed, where 2 of 15 cases of fetal exposure to maternal AT 1 antagonists were stillborn and 4 of the 15 cases died within 3 to 4 days after birth [28,38,41— 48]. Oligohydramnios was reported in 14 of 15 cases of use of AT1 antagonist late in pregnancy. Neonatal anuria was also common and observed in 8 of 11 live births. As expected, fetal anuria was often accompanied by oligohydramnios. Presumably, maternal use of AT1 antagonist suppressed fetal renal function, reduced urine output and lead to oligohydramnios with fetal/neonatal anuria. Microscopic examination of renal histology in the 5 neonates who were either stillborn or died shortly after birth revealed similar findings as that of ACE inhibitor use. These findings include tubular dilatation, absent or poor proximal tubular differentiation, and high renin expression in the juxtaglomerular apparatus. It has been assumed that the histologic findings result from AT1 antagonist related hypoperfusion of the fetal kidney [49,50]. In addition, the reduction in the fetal glomerular filtration rate owing to blockade of the angiotensin II receptor may also lead to abnormal renal tubular development. Neonatal hypoplastic lungs were also reported in 3 of 15 cases of maternal use of AT1 antagonists [28]. All three cases were fatal. Pulmonary hypoplasia likely results from oligohydramnios in a similar manner as described above for ACE inhibition. Hypoplastic calvaria were similarly reported in infants of mothers who used AT1 antagonists during pregnancy. In a recent review, 9 of the 15 infants born to women treated with AT1 receptor antagonists had hypoplastic skull development [28]. The mechanism by which hypocalvaria develops is unknown, but may be related to hypoperfusion of the membranous bone of the calvaria secondary to the AT1 antagonists.
7. 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
27
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 failure with oligo/anuria, renal tubular abnormalities, and calvarial hypoplasia. The timing of the disruption of the fetal renin—angiotensin system may also play an important role in fetal outcome. Fetal exposure to ACE inhibitors or AT1 antagonists during the first trimester is likely to be of minimal risk and should not be an indication for termination of the pregnancy. Fetal exposure of ACE inhibitors or AT1 antagonists during the second or third trimesters is associated with the above reported deleterious findings. The Food and Drug Administration has officially warned against use of ACE inhibitors during the second and third trimesters of pregnancy. Hypertensive non-pregnant women using ACE inhibitors or AT1 antagonists are advised to seek early prenatal care and switch to another antihypertensive agent if possible. The fetus already exposed to maternal use of these drugs should be monitored closely with serial sonograms for assessment of fetal growth, amniotic fluid volume, and organ malformations. Whenever possible, the neonate exposed to ACE inhibitors or AT1 antagonists should be delivered at a tertiary care medical center, where support services are available to treat hypotension, respiratory distress, and renal failure.
8. 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.
References [1] Buttar HS. An overview of the influence of ACE inhibitors on fetal—placental circulation and perinatal development. Mol Cell Biochem 1997;176:61 – 71. [2] Quan A, Baum M. Endogenous production of angiotensin II modulates rat proximal tubule transport. J Clin Invest 1996;97: 2878 – 82. [3] Hilgers KF, Norwood VF, Gomez RA. Angiotensin’s role in renal development. Semin Nephrol 1997;17:492 – 501. [4] Broughton-Pipkin F, Symonds EM, Turner SR. The effect of captopril (SQ14225) upon mother and fetus in the chronically cannulated ewe and in the pregnant rabbit. J Physiol 1982;323: 415 – 22. [5] Keith IM, Will JA, Weir EK. Captopril: association with fetal death and pulmonary vascular changes in the rabbit (41446). Proc Soc Exp Biol Med 1982;170:378 – 83. [6] Ferris TF, Weir EK. Effect of captopril on uterine blood flow and prostaglandin E synthesis in the pregnant rabbit. J Clin Invest 1983;71:809 – 15.
28 [7] Harewood WJ, Phippard AF, Duggin GG. Fetotoxicity of angiotensin-converting enzyme inhibition in primate pregnancy: a prospective, placebo-controlled study in baboons (Papio hamadryas). Am J Obstet Gynecol 1994;171:633 – 42. [8] GG Briggs, RK Freeman, SJ Yaffe. Drugs in pregnancy and lactation. Baltimore, MD, Williams and Wilkins; 1994; p. 120—126. 317—324, 495—497. [9] Brent RL, Beckman DA. Angiotensin-converting enzyme inhibitors, an embryopathic class of drugs with unique properties: information for clinical teratology counselors. Teratology 1991;43:543 – 6. [10] Duminy PC, Burger PT. Fetal abnormality associated with the use of captopril during pregnancy. S Afr Med J 1981;60:805. [11] Kaler SG, Patrinos ME, Lambert GH. Hypertrichosis and congenital anomalies associated with maternal use of minoxidil. Pediatrics 1987;79:434 – 6. [12] Rothberg AD, Lorenz R. Can captopril cause fetal and neonatal renal failure? Pediatr Pharmacol 1984;4:189 – 92. [13] Nightingale SL. Warnings on the use of ACE inhibitors in second and third trimester of pregnancy. JAMA 1992;267:2445. [14] Broughton-Pipkin F, Baker PN, Symonds EM. ACE inhibitors in pregnancy. Lancet 1989;2:96 – 7. [15] Boutroy MJ, Vert P, Hurault de Ligny B, Miton A. Captopril administration in pregnancy impairs fetal angiotensin converting enzyme activity and neonatal adaptation. Lancet 1984;2:935 – 6. [16] Guignard JP, Burgener F, Calame A. Persistent anuria in neonate: a side effect of captopril. Int J Pediatr Nephrol 1981;2:133. [17] Mehta N, Modi N. ACE inhibitors in pregnancy. Lancet 1989;2:96. [18] Rosa FW, Bosco LA, Graham CF. Neonatal anuria with maternal angiotensin converting enzyme inhibition. Obstet Gynecol 1989;74:371 – 4. [19] Cunniff C, Jones KL, Phillipson J. Oligohydramnios sequence and renal tubular malformation associated with maternal enalapril use. Am J Obstet Gynecol 1990;162:187 – 9. [20] Mastrobattista J. Angiotensin converting enzyme inhibitors in pregnancy. Semin Perinatol 1997;21:124 – 34. [21] Biocchi R, Lijnen P, Fagard R. Captopril during pregnancy. Lancet 1984;2:1153. [22] Pryde PG, Nugent CE, Sedman AB. ACE inhibitor fetopathy. Am J Obstet Gynecol 1992;166:348. [23] Lubbe WF. The use of captopril in pregnancy. N Z Med J 1983;96:1029 – 30. [24] Schubiger G, Flury G, Nussberger J. Enalapril for pregnancy induced hypertension: acute renal failure in a neonate. Ann Intern Med 1988;108:215 – 6. [25] Plouin PF, Tchoboutsky C. Inhibition of angiotensin converting enzyme in human pregnancy: 15 cases. Presse Med 1985;14: 2175 – 8. [26] Pryde PG, Sedman AB, Nugent CE, Barr M. Angiotensin converting enzyme inhibitor fetopathy. J Am Soc Nephrol 1993;3:1575 – 82. [27] Lindheimer MD, Barron WM. Enalapril and pregnancy induced hypertension. Ann Intern Med 1988;108:911. [28] Alwan S, Polifka JE, Friedman JM. Angiotensin II receptor antagonist treatment during pregnancy. Birth Defects Res (Part A) 2005;73:123 – 30.
A. Quan [29] Hanssens M, Keirse MJNC, Vankelecom F, Van Assche FA. Fetal and neonatal effects of treatment with angiotensin converting enzyme inhibitors in pregnancy. Obstet Gynecol 1991;78: 128 – 35. [30] Barr M. Teratogen update: angiotensin converting enzyme inhibitors. Teratology 1994;50:399 – 409. [31] Knott PD, Thorp SS, Lamont CAR. Congenital renal dysgenesis possibly due to captopril. Lancet 1989;1:451. [32] Martin RA, Jones KL, Mendoza A, Barr M, Benirschke K. Effect of ACE inhibition on the fetal kidney: decreased renal blood flow. Teratology 1992;46:317 – 21. [33] Landing GH, Ang SM, Herta N, Larson EF, Turner M. Labeled lectin studies of renal tubular dysgenesis and renal tubular atrophy of postnatal renal ischemia and end stage kidney disease. Pediatr Pathol 1994;14:87 – 99. [34] Piper JM, Ray WA, Rosa FW. Pregnancy outcome following exposure to angiotensin converting enzyme inhibitors. Obstet Gynecol 1992;80:429 – 32. [35] Barr M, Cohen MM. ACE inhibitor fetopathy and hypocalvaria: the kidney—skull connection. Teratology 1991;44:485 – 95. [36] Hurault de Ligny B, Ryckelynck JP, Mintz P. Captopril therapy in preeclampsia. Nephron 1987;46:329 – 30. [37] Kreft-Jais C, Plouin PF, Tchoboutsky C, Boutroy MJ. Angiotensin converting enzyme inhibitors during pregnancy: a survey of 22 patients given captopril and nine given enalapril. Br J Obstet Gynaecol 1988;95:420 – 2. [38] Schaefer C. Angiotensin II receptor antagonists: further evidence of fetotoxicity but not teratogenicity. Birth Defects Res Part A Clin Mol Teratol 2003;67:591 – 4. [39] Biswas PN, Wilton LV, Shakir SW. The safety of valsartan: results of a postmarketing surveillance study on 12,881 patients in England. J Hum Hypertens 2002;16:795 – 803. [40] Chung NA, Lip GYH, Beevers M, Beevers DG. Angiotensin II receptor inhibitors in pregnancy. Lancet 2001;357:1620. [41] Saji H, Yamanaka M, Hagiwara A, Ijiri R. Losartan and fetal toxic effects. Lancet 2001;357:363. [42] Lambot MA, Vermeylen D, Noel JC. Angiotensin II receptor inhibitors in pregnancy. Lancet 2001;357:1619 – 20. [43] Hinsberger A, Wingen AM, Hoyer PF. Angiotensin II receptor inhibitors in pregnancy. Lancet 2001;357:1620. [44] Martinovic J, Benachi A, Laurent N. Fetal toxic effects and angiotensin II receptor antagonists. Lancet 2001;358:241 – 2. [45] Briggs GG, Nagoette MP. Fatal fetal outcome with the combined use of valsartan and atenolol. Ann Pharmacother 2001;35:859 – 61. [46] Cox RM, Anderson JM, Cox P. Defective embryogenesis with angiotensin II receptor antagonists in pregnancy. Br J Obstet Gynaecol 2003;110:1038 – 40. [47] Pietrement C, Malot L, Santerne B. Neonatal acute renal failure secondary to maternal exposure to telmisartan, angiotensin II receptor antagonist. J Perinatol 2003;23:254 – 5. [48] Nayar B, Singhal A, Aggarwal R, Malhotra N. Losartan induced fetal toxicity. Indian J Pediatr 2003;70:138 – 42. [49] Hulton SA, Thomson PD, Cooper PA, Rothberg AD. Angiotensin converting enzyme inhibitors in pregnancy may result in neonatal renal failure. S Afr Med J 1990;78:673 – 6. [50] Lavoratti G, Seracini D, Fiorini P. Neonatal anuria by ACE inhibitors during pregnancy. Nephron 1997;76:235 – 6.