Correspondence
ACE Inhibitors and Major Congenital Malformations
N Engl J Med 2006; 355:1280-1281September 21, 2006
- Article
To the Editor:
Cooper et al. (June 8 issue)1 describe an association between first-trimester exposure to angiotensin-converting–enzyme (ACE) inhibitors and congenital malformations. We question whether the authors excluded maternal diabetes mellitus and maternal obesity as explanatory factors. Given the deficiencies of charting and coding in busy medical practices, diabetes in women may not be detected. Women with diabetes mellitus that is poorly documented may have poor glycemic control.
Maternal obesity may also have been a confounder. Obese women may have hypertension that is difficult to control, requiring the use of multiple medications including an ACE inhibitor. Maternal obesity is an independent risk factor for neural-tube defects and cardiac malformations in infants.2-4
4 ReferencesAnthony R. Scialli, M.D.
Armand Lione, Ph.D.
Reproductive Toxicology Center, Bethesda, MD 20815-3007
ascialli@sciences.com 1
Cooper WO ,Hernandez-Diaz S ,Arbogast PG , et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006;354:2443-2451
Full Text | Web of Science | Medline2
Watkins ML ,Rasmussen SA ,Honein MA ,Botto LD ,Moore CA . Maternal obesity and risk for birth defects. Pediatrics 2003;111:1152-1158
Web of Science | Medline3
Mikhail LN ,Walker CK ,Mittendorf R . Association between maternal obesity and fetal cardiac malformations in African Americans. J Natl Med Assoc 2002;94:695-700
Web of Science | Medline4
Cedergren MI ,Kallen BA . Maternal obesity and infant heart defects. Obes Res 2003;11:1065-1071
CrossRef | Medline
To the Editor:
Cooper and colleagues report major congenital malformations after first-trimester exposure to ACE inhibitors. It is not known whether this effect is specific for ACE inhibitors or whether it applies to all other classes of drugs that block the renin–angiotensin system (beta-blockers, angiotensin-receptor blockers, and renin inhibitors).1 The oocyte, embryo, and developing fetus are bathed almost continuously in prorenin, the precursor of renin, from just before ovulation until parturition.2-4 The average prorenin concentration (Vmax) is 65 ng per milliliter per hour in normal plasma, 350 ng per milliliter per hour in plasma during pregnancy, 2000 ng per milliliter per hour in ovarian follicular fluid, 100,000 ng per milliliter per hour in chorionic fluid from gestational sacs during the first trimester of pregnancy, and 2000 ng per milliliter per hour in amniotic fluid. These observations are consistent with a role for the renin–angiotensin system in human embryonic development, placentation, and other aspects of reproductive function. What that role might be is not yet clear, but the report of congenital malformations after exposure to ACE inhibitors in early pregnancy indicates that it is time to find out.
4 ReferencesJean E. Sealey, D.Sc.
Weill Medical College of Cornell University, New York, NY 10021
jsealey@med.cornell. edu Joseph Itskovitz-Eldor, M.D.
Rambam Medical Center, Haifa 31096, Israel1
Laragh J . Laragh's lessons in pathophysiology and clinical pearls for treating hypertension. Am J Hypertens 2001;14:296-304
CrossRef | Web of Science | Medline2
Itskovitz J ,Rubattu S ,Levron J ,Sealey JE . Highest concentrations of prorenin and human chorionic gonadotropin in gestational sacs during early human pregnancy. J Clin Endocrinol Metab 1992;75:906-910
CrossRef | Web of Science | Medline3
Glorioso N ,Atlas SA ,Laragh JH ,Jewelewicz R ,Sealey JE . Prorenin in high concentrations in human ovarian follicular fluid. Science 1986;233:1422-1424
CrossRef | Web of Science | Medline4
Itskovitz J ,Rubattu S ,Rosenwaks Z ,Liu HC ,Sealey JE . Relationship of follicular fluid prorenin to oocyte maturation, steroid levels, and outcome of in vitro fertilization. J Clin Endocrinol Metab 1991;72:165-171
CrossRef | Web of Science | Medline
Author/Editor Response
We appreciate the comments of Scialli and Lione regarding the detection of diabetes. For the reasons they describe with regard to the possibility of insufficient documentation of chronic illnesses by physicians, our primary definition of diabetes was made on the basis of either a diagnosis of diabetes or a prescription for a hypoglycemic agent. We also performed a secondary analysis with a broader definition of diabetes that excluded women with a prescription for a hypoglycemic agent during pregnancy or a diagnosis of diabetes during the first trimester. The results were essentially unchanged. Undetected diabetes could not have directly influenced the physician's decision to prescribe an ACE inhibitor. Given this scenario, confounding is less plausible, since a confounder must be associated with both the exposure (the ACE inhibitor) and the outcome.1
We were aware that hypertension and obesity (a possible, but not yet established, risk factor for congenital malformations2-4) were potential confounders. We thus included a control group of women who used other antihypertensive medications during the first trimester only and did not have an increased risk of congenital malformations. However, to assess the effects of hypertension that is more difficult to control, we performed two additional analyses.
The first analysis excluded women in both the ACE-inhibitor and other antihypertensive groups who filled prescriptions for drugs in two or more classes (e.g., beta-blockers and diuretics) during the 90 days before the last menstrual period. There was a statistically increased risk of major congenital malformations among study infants born to women in the ACE-inhibitor group (risk ratio, 2.22; 95% confidence interval [CI], 1.11 to 4.44), but not to women in the other antihypertensive group (risk ratio, 0.69; 95% CI, 0.25 to 1.87).
In the second analysis, we expanded the other antihypertensive group to include women who had used antihypertensive agents during the second or third trimester, since we considered it likely that the severity of hypertension would be related to the decision to continue the use of the drug during pregnancy. Among the 951 infants born to women in this group, there was no increased risk of congenital malformations (risk ratio, 1.22; 95% CI, 0.86 to 1.72). Both analyses thus suggest that hypertension that was difficult to control did not account for the study findings.
We concur with Sealey and Itskovitz-Eldor regarding the need for studies of the use of other antihypertensive agents during pregnancy. Given the secular trend of increasing maternal age, more women who become pregnant will have hypertension, making it vital to define how best to treat this chronic illness during pregnancy.
4 ReferencesWilliam O. Cooper, M.D., M.P.H.
Wayne A. Ray, Ph.D.
Vanderbilt University School of Medicine, Nashville, TN 37215
william.cooper@vanderbilt. edu 1
Kelsey JL, Whittemore AS, Evans AS, Thompson WD. Methods in observational epidemiology. 2nd ed. New York: Oxford University Press, 1996.
2
Scialli AR . Teratology Public Affairs Committee position paper: maternal obesity and pregnancy. Birth Defects Res A Clin Mol Teratol 2006;76:73-77
CrossRef | Web of Science | Medline3
Moore LL ,Singer MR ,Bradlee ML ,Rothman KJ ,Milunsky A . A prospective study of the risk of congenital defects associated with maternal obesity and diabetes mellitus. Epidemiology 2000;11:689-694
CrossRef | Web of Science | Medline4
Watkins ML ,Rasmussen SA ,Honein MA ,Botto LD ,Moore CA . Maternal obesity and risk for birth defects. Pediatrics 2003;111:1152-1158
Web of Science | Medline
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Orna Diav-Citrin, Svetlana Shechtman, Yehudit Halberstadt, Victoriya Finkel-Pekarsky, Rebecka Wajnberg, Judy Arnon, Elena Di Gianantonio, Maurizio Clementi, Asher Ornoy. (2011) Pregnancy outcome after in utero exposure to angiotensin converting enzyme inhibitors or angiotensin receptor blockers. Reproductive Toxicology 31:4, 540-545
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Greg L. Plosker. (2009) Eprosartan. Drugs 69:17, 2477-2499
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Roland Lennestål, Petra Otterblad Olausson, Bengt Källén. (2009) Maternal use of antihypertensive drugs in early pregnancy and delivery outcome, notably the presence of congenital heart defects in the infants. European Journal of Clinical Pharmacology 65:6, 615-625
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LA MAGEE, J NEWSTEAD, J NG, AM CÔTÉ, P VON DADELSZEN. (2008) PRE-ECLAMPSIA AS A MARKER OF CARDIOVASCULAR DISEASE. Fetal and Maternal Medicine Review 19:04, 271
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Katherine F Croom, Greg L Plosker. (2008) Irbesartan. Drugs 68:11, 1543-1569
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Greg L Plosker, William B White. (2008) Telmisartan/Hydrochlorothiazide. Drugs 68:13, 1877-1899
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(2007) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 16:4, i-xii
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J Newstead, P von Dadelszen, Laura A Magee. (2007) Preeclampsia and future cardiovascular risk. Expert Review of Cardiovascular Therapy 5:2, 283-294
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