Gestational Therapy with an Angiotensin II Receptor Antagonist and Transient Renal Failure in a Premature Infant

ABSTRACT

The fetotoxic effects of angiotensin converting enzyme inhibitors when used during the second half of pregnancy are well known. The more recently developed angiotensin II receptor antagonists appear to yield similar fetal abnormalities. We report a premature infant born to a 41-year-old mother with a long history of infertility who had received losartan therapy for hypertension throughout an undetected pregnancy. Ultrasound examination 2 days prior to delivery identified a single fetus at 29 weeks gestation, anhydramnios, and an empty fetal bladder. The neonatal course was complicated by oliguria, hyperkalemia, marked renal dysfunction, respiratory failure, joint contractures, and a large anterior fontanelle with widely separated sutures. Hypotension (mean arterial pressure < 25 torr) on day 1 responded to volume expansion, dopamine, and hydrocortisone. Serum creatinine reached a maximum of 2.7 mg/dL on day 6 and decreased to 0.4 by day 56. No formal urinalysis was performed, but the urine was reported to be visually clear throughout the course. Although a renal ultrasound on day 2 was normal, a follow-up study at 7 months revealed bilateral generalized parenchymal echogenicity, consistent with medical renal disease. Since then, weight and length have been at the 5th percentile or less, with apparent renal tubular acidosis necessitating the addition of sodium citrate supplements. This case emphasizes the importance of maintaining a high index of suspicion for potential pregnancy when contemplating the use of a drug of this class, and considering serial testing for pregnancy when using such drugs, even in patients with a longstanding history of infertility.

Angiotensin converting enzyme inhibitor - angiotensin receptor antagonist - fetotoxicity - renal failure - newborn infant - nephrogenesis

REFERENCES

• 1 Barr Jr M. Teratogen update: angiotensin-converting enzyme inhibitors.  Teratology. 1994;  50 399-409
• 2 Bakris G L. Angiotensin-converting enzyme inhibitors and progression of diabetic nephropathy.  Ann Intern Med. 1993;  118 643-644
• 3 Ravid M, Savin H, Jutrin I, Bental T, Katz B, Lishner M. Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type-II diabetic patients.  Ann Intern Med. 1993;  118 577-581
• 4 Viberti G, Mogensen C E, Groop L C et al.. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria.  JAMA. 1994;  271 275-279
• 5 Khedun S M, Maharaj B, Moodley J. Effects of antihypertensive drugs on the unborn child-what is known, and how should this influence prescribing?.  Paediatr Drugs. 2000;  2 419-436
• 6 Pryde P G, Sedman A B, Nugent C E. Angiotensin-converting enzyme inhibitor fetopathy.  J Am Soc Nephrol. 1993;  3 1575-1582
• 7 Hinsberger A, Wingen A-M, Hoyer P F. Angiotensin-II-receptor inhibitors in pregnancy.  Lancet. 2001;  357 1620
• 8 Saji H, Yamanaka M, Hagiwara A, Ijiri R. Losartan and fetal toxic effects.  Lancet. 2001;  357 363
• 9 Martinovic J, Benachi A, Laurent N, Daikha-Dahmane F, Gubler M C. Fetal toxic effects and angiotensin-II-receptor antagonists.  Lancet. 2001;  358 241-242
• 10 Lambot M-A, Vermeylen D, Noel J-C. Angiotensin-II-receptor inhibitors in pregnancy.  Lancet. 2001;  357 1619-1620
• 11 Chung N A, Lip G Y, Beevers M, Beevers D G. Angiotensin-II-receptor inhibitors in pregnancy.  Lancet. 2001;  357 1620-1621
• 12 Serreau R, Luton D, Macher M-A, Delezoide A-L, Garel C, Jacqz-Aigrain E. Developmental toxicity of the angiotensin II type I receptor antagonists during human pregnancy: a report of 10 cases.  BJOG. 2005;  112 710-712
• 13 Pietrement C, Malot L, Santerne B, Roussel B, Motte J, Morville P. Neonatal acute renal failure secondary to maternal exposure to telmisartan, angiotensin II receptor antagonist.  J Perinatol. 2003;  23 254-255
• 14 Schaefer C. Angiotensin II-receptor-antagonists: further evidence of fetotoxicity but not teratogenicity.  Birth Defects Res Part A Clin Mol Teratol. 2003;  67 591-594
• 15 Chow K M, Lam C M. Angiotensin II receptor antagonist in pregnancy.  J Perinatol. 2004;  24 56-57
• 16 Bos-Thompson M A, Hillaire-Buys D, Muller F et al.. Fetal toxic effects of angiotensin II receptor antagonists: case report and follow-up after birth.  Ann Pharmacother. 2005;  39 157-160
• 17 Alwan S, Polifka J E, Friedman J M. Angiotensin II receptor antagonist treatment during pregnancy.  Birth Defects Res Part A Clin Mol Teratol. 2005;  73 123-130
• 18 Nayar B, Singhal A, Aggarwal R, Malhotra N. Losartan induced fetal toxicity.  Indian J Pediatr. 2003;  70 923-924
• 19 Briggs G G, Nageotte M P. Fatal fetal outcome with the combined use of valsartan and atenolol.  Ann Pharmacother. 2001;  35 859-861
• 20 Cox R M, Anderson J M, Cox P. Defective embryogenesis with angiotensin II receptor antagonists in pregnancy.  BJOG. 2003;  110 1038
• 21 Mann R, Mackay F, Pearce G, Freemantle S, Wilton L. Losartan: a study of pharmacovigilance data on 14,522 patients.  J Hum Hypertens. 1999;  13 551-557
• 22 Wolf G. Angiotensin II and tubular development.  Nephrol Dial Transplant. 2002;  17(suppl 9) 48-51
• 23 Prevot A, Mosig D, Guignard J-P. The effects of losartan on renal function in the newborn rabbit.  Pediatr Res. 2002;  51 728-732
• 24 Garcia-Villalba P, Denkers N D, Wittwer C T, Hoff C, Nelson R D, Mauch T J. Real-time PCR quantification of AT1 and AT2 angiotensin receptor mRNA expression in the developing rat kidney.  Nephron Exp Nephrol. 2003;  94 e154-e159
• 25 Chen Y, Lasaitiene D, Friberg P. The renin-angiotensin system in kidney development.  Acta Physiol Scand. 2004;  181 529-535
• 26 Hollenberg N K, Fisher N D, Price D A. Pathways for angiotensin II generation in intact human tissue: evidence from comparative pharmacological interruption of the renin system.  Hypertension. 1998;  32 387-392
• 27 Lip G YH, Churchill D, Beevers M, Auckett A, Beevers D G. Angiotensin-converting-enzyme inhibitors in early pregnancy.  Lancet. 1997;  350 1446-1447
• 28 Centers for Disease Control and Prevention . Postmarketing surveillance for angiotensin-converting enzyme inhibitor use during the first trimester of pregnancy-United States, Canada, and Israel, 1987-1995.  MMWR Morb Mortal Wkly Rep. 1997;  46 240-242
• 29 Spence S G, Allen H L, Cukierski M A, Manson J M, Robertson R T, Eydelloth R S. Defining the susceptible period of developmental toxicity for the AT-1 selective angiotensin II receptor antagonist losartan in rats.  Teratology. 1995;  51 367-382
• 30 Montouris G. Gabapentin exposure in human pregnancy: results from the gabapentin pregnancy registry.  Epilepsy Behav. 2003;  4 310-317
• 31 Ohman I, Vitols S, Tomson T. Pharmacokinetics of gabapentin during delivery, in the neonatal period, and lactation: does a fetal accumulation occur during pregnancy?.  Epilepsia. 2005;  46 1621-1624
• 32 Chambers C D, Kao K K, Felix R J et al.. Pregnancy outcome in infants prenatally exposed to newer anticonvulsants.  Birth Defects Res Part A Clin Mol Teratol. 2005;  73 316
• 33 Iqbal M M, Gundlapalli S P, Ryan W G, Ryals T, Passman T E. Effects of antimanic mood-stabilizing drugs on fetuses, neonates, and nursing infants.  South Med J. 2001;  94 304-322
• 34 Yerby M S. Clinical care of pregnant women with epilepsy: neural tube defects and folic acid supplementation.  Epilepsia. 2003;  44(suppl 3) 33-40