antihypertensive drugs and the risk of congenital anomalies

Antihypertensive Drugs and the Risk of Congenital

Anomalies

Catherine Vasilakis-Scaramozza, Ann Aschengrau, Howard J. Cabral, and Susan S. Jick

Study Objective. To estimate the prevalence of congenital anomalies amongthe offspring of women exposed and unexposed to antihypertensive drugsduring early pregnancy.

Design.Matched cohort study.Database. The United Kingdom’s General Practice Research Database.Subjects.Women exposed to antihypertensive drugs during early pregnancy

and a sample of matched unexposed pregnant women.Measurements and Main Results. The prevalence of any anomaly among

unexposed and exposed women was 23.5 (95% confidence interval [CI]14.4–38.3) and 20.9 (95% CI 10.0–43.8) per 1000 pregnancies, respec-tively (relative risk [RR] 0.9, 95% CI 0.4–2.2). The relative risk of limbanomalies among women exposed to b-blockers was 6.4 (95% CI 0.6–70.1). Exposure to angiotensin-converting enzyme (ACE) inhibitors,b-blockers, and calcium channel blockers increased the risk of genitalanomalies (RR 3.8, 95% CI 0.9–16.0; RR 2.8, 95% CI 0.7–11.9; RR 1.3,95% CI 0.1–12.4, respectively).

Conclusion.ACE inhibitors prescribed in the first trimester of pregnancyappeared to increase the risk of congenital anomalies among the offspringof exposed women (RR 2.5, 95% CI 0.5–13.5). These drugs should beavoided in women planning to become pregnant. A marginally increasedrisk was also found with exposure to b-blockers (RR 1.4, 95% CI 0.6–3.3). These findings are based on small numbers and are not statisticallysignificant.

Key Words: antihypertensive, congenital anomalies, prevalence rates, rela-tive risk.(Pharmacotherapy 2013;**(**):**–**)

Background

Although antihypertensive medications arerarely necessary among women of childbearingage, their use has been associated with adverseevents in pregnancy. In particular, use of angioten-sin-converting enzyme (ACE) inhibitors in thethird trimester of pregnancy has been associatedwith ACE inhibitor–induced fetopathy, character-ized by fetal hypotension, anuria-oligohydramnios,growth restriction, pulmonary hypoplasia, renaltubular dysplasia, and hypocalvaria.1–9 Calcium

channel blocker (CCB) use during gestation hasbeen associated with limb defects in animal stud-ies.10 There are limited data addressing the effectsof other antihypertensive drug exposure duringpregnancy. For this reason it is important to obtainmore information on the effects of ACE inhibitorsand other antihypertensives throughout the gesta-tional period. Women treated with antihyperten-sives before pregnancy are currently advised tocontinue treatment during pregnancy, but they areadvised to discontinue ACE inhibitors and replacethem with an alternative antihypertensive.1

O R I G I N A L R E S E A R C H A R T I C L E

When taken in the second or third trimester ofpregnancy, the teratogenic effects of ACE inhibi-tors are believed to be caused by the blockade ofthe conversion of angiotensin I to angiotensin IIin the fetal kidneys.2 Angiotensin II plays a role inearly fetal development of the heart, kidney, andbrain. The inhibition of angiotensin I to angioten-sin II conversion may also be the mechanismassociated with anomalies resulting from expo-sure to ACE inhibitors in the first trimester.3

Studies of antihypertensive use during preg-nancy have focused on exposure to ACE inhibitorsbecause of the recognized risks to the offspringfrom exposure to these drugs. ACE inhibitor usein the second and third trimester has been associ-ated with several malformations including renaltubular dysplasia in the infant.4 Deformities of theskull and bones have been reported followingexposure throughout pregnancy.5 Because theeffects of ACE inhibitors on the fetus are well doc-umented, their exposure in women of childbear-ing age is limited, but some use does occur. Casereports have suggested that the use of ACE inhibi-tors in the first trimester does not necessarilycause anomalies, and exposure in the first trimes-ter should not necessitate termination of the preg-nancy.4, 6, 7 These recommendations are based onvery small numbers of patient experiences. Onestudy reported that exposure to ACE inhibitors inthe first trimester of pregnancy was associatedwith a 2.7-fold increased risk of a major malfor-mation occurring compared with no exposure toACE inhibitors.3 Another study that compared therisk of anomalies between first trimester only useof enalapril, a widely used ACE inhibitor, and useof enalapril later in pregnancy8 and found a 3-foldincreased risk of congenital malformations whenexposure continued beyond the first trimester.These results imply that exposure beyond the firsttrimester leads to an increased risk of congenitalanomalies. Because the data analysis did notincluded unexposed women, or women who usedother antihypertensives during pregnancy, noinformation was provided on the risk of using

ACE inhibitors during early pregnancy only com-pared with other antihypertensives. The mostrecently available data suggested that exposure toACE inhibitors or angiotensin receptor blockers(ARBs) in early pregnancy was not associated witha statistically significant increased risk of congeni-tal anomalies compared with women exposed toother antihypertensives.9 Thus our ability to makereliable conclusions about the safety of ACEinhibitor use during specific gestational periods islimited due to insufficient and conflicting data.Animal studies have found an increased risk oflimb defects from exposure to CCBs during gesta-tion.10 A small prospective study found noincreased risk of major malformations in infantsof 78 women exposed to CCBs during their firsttrimester,11 but this study only had the power toidentify a 5-fold increased risk. Animal studieshave shown the potential for limb and digit defectsto occur with exposure to CCBs in utero, but themechanism is unknown.12

A recent study examining the effects fromexposure to any antihypertensive during preg-nancy reported an increased risk for occurrenceof several cardiovascular anomalies.13 b-Blockers,particularly atenolol, have been associated withlow birthweight,10 but the studies reporting thiseffect have been too small to estimate accuratelythe risk of developing congenital anomalies.14

Use of diuretics during pregnancy has been asso-ciated with low plasma volume expansion, a statethat may affect the fetus,15 but the risk of associ-ated congenital anomalies is unknown. In addi-tion, diuretics are often taken in conjunction withother antihypertensives. A case series in 2011 sug-gested that exposure to ARBs during pregnancymay lead to fetopathy similar to that occurringwith exposure to ACE inhibitors.16

We present the findings of a matched cohortstudy designed to estimate the prevalence ofcongenital anomalies among the offspring ofwomen exposed to antihypertensive drugs dur-ing early pregnancy, and compare the risk ofcongenital anomalies among users of varioustypes of antihypertensive drugs with that amongwomen without exposure to antihypertensivedrugs during early pregnancy.

Methods

Data Source

This study was conducted using data from theUK General Practice Research Database (GPRD)accessed through the Boston Collaborative Drug

From the Department of Epidemiology, Boston Univer-sity School of Public Health, Boston, Massachusetts (C.Vasilakis-Scaramozza, A. Aschengrau, and H.J. Cabral); andthe Boston Collaborative Drug Surveillance Program, Bos-ton University School of Medicine, Lexington, Massachu-setts (S. S. Jick).

For questions or comments, contact to Susan S. Jick,DSc, Boston Collaborative Drug Surveillance Program, Bos-ton University School of Medicine, 11 Muzzey Street, Lex-ington, MA 02421; email: [email protected].

2 PHARMACOTHERAPY Volume **, Number **, 2013

Surveillance Program.17–20 At the time this studywas conducted, the GPRD contained informationfrom 368 general medical practices fromthroughout the United Kingdom, with patientdata from more than 3 million enrollees, andincluded standardized clinical records for everypatient within a practice. These records describemedical diagnoses, prescribed drugs, and includedetails such as smoking, alcohol use, height, andweight from each clinical visit.Although the data in the GPRD are anony-

mized, a family identification number, the dateof birth in the infant’s record, and the date ofdelivery in the mother’s record were used to linkmothers with their offspring. This made it possi-ble to evaluate pregnancy exposures in motherswith pregnancy outcomes. Previous studies usingdata from the GPRD determined that all congen-ital anomalies noted in the patient’s clinicalrecords were recorded in the computerized med-ical record.21, 22

Study Population

This study compared prevalence of congenitalanomalies in offspring of women exposed toantihypertensive drugs in early pregnancy to theoffspring of women with no exposure to antihy-pertensive drugs during pregnancy. In the popu-lation on which data are collected in the GPRD,our analysis was restricted to the offspring ofsingleton pregnancies among women 15–45 years of age that occurred from January 1991through April 2002. The data were drawn frompregnancies that lasted more than 20 weeks ofgestation and included livebirths, stillbirths, andtherapeutic abortions. All subjects were requiredto have a full year of medical data prior to thedelivery date for entry into the study. Exposedwomen were also required to have had a diagno-sis of hypertension at any time prior to, or dur-ing, the pregnancy. An additional requirementwas one or more prescriptions for an antihyper-tensive drug during the first trimester or within4 weeks of the estimated first day of the lastmenstrual period. Each woman exposed to anti-hypertensive drugs during pregnancy wasmatched on age, year of pregnancy outcome,and general practice with two women having nodocumented exposure to antihypertensive drugsduring pregnancy. Electronic medical recordsfrom all exposed women and a random sampleof unexposed women were reviewed to validatethe exposure status, without knowledge of theoutcome of the pregnancy.

Exposure

Exposure was defined as a prescription forone or more of the study drugs during the per-iod from 180 to 335 days prior to the deliverydate for live births, and from 70 to 225 daysprior to the delivery or termination date for still-births and therapeutic abortions. We presumethat antihypertensive medications were pre-scribed because they were medically necessary.As prescriptions were repeatedly filled, theywere therefore unlikely to be regularly missed.The exposures of interest included ACE inhibi-tors, b-blockers, CCBs, a-blockers, central a-ag-onists, ARBs, vasodilators, and diuretics. Due tosmall numbers of patient exposures, we wereonly able to separately categorize patients whoreceived ACE inhibitors, b-blockers, and CCBs.All other antihypertensives were combined toform a single category called “other antihyper-tensives.” We also collected data on the use ofACE inhibitors taken in the second and third tri-mesters because of evidence that use of ACEinhibitors during this time period is associatedwith anomalies in the offspring.

Case Definition

We reviewed the records of all infants born tomothers in the study population using a com-puter search for all congenital anomaly codes tofind evidence that a congenital anomaly wasdocumented any time before the child’s firstbirthday. International Classification of Disease(ICD) 9th revision codes (740.0–759.9, exclud-ing chromosomal anomalies) and Read codesmapped to the relevant ICD codes were used toidentify congenital anomalies. The computerizedmedical records of all potential cases of a con-genital anomaly were reviewed by hand, withoutknowledge of the mother’s drug exposure, toconfirm the presence of an anomaly. Minoranomalies, as defined according to the Centersfor Disease Control and Prevention guidelines,were excluded.23 Chromosomal anomalies werealso excluded, as were anomalies associated withprematurity (i.e., patent foramen ovale, patentductus arteriosus) among premature deliveries.The cause of death and any details of an anom-aly were noted when the outcome was a still-birth or therapeutic abortion. Although wedefined a case as having a recorded congenitalanomaly at any time within a year followingbirth, 21% of subjects did not have a completeyear of follow-up. We analyzed the data for all

ANTIHYPERTENSIVE DRUGS AND THE RISK OF CONGENITAL ANOMALIES Vasilakis-Scaramozza et al 3

subjects and for those with a complete year offollow-up and found no difference in the anom-aly estimates. Therefore, we have included allsubjects in our analyses, regardless of follow-uptime. Most of the major congenital anomalieswere recorded soon after birth, and we had noreason to believe that inclusion of subjects withless than 1 year of follow-up would bias theresults.

Analyses

All analyses were performed using SAS statisti-cal software (SAS v.9.1, SAS Institute, Cary, NC,USA). The relative risk (RR) and its associated95% confidence interval (CI) of developing anyanomaly and specific organ system anomalies inthe offspring of women exposed to any antihy-pertensive drug, and specific antihypertensivedrugs (e.g., ACE inhibitors, CCBs, etc.), duringthe first trimester of pregnancy was estimatedusing generalized estimating equations with anunstructured working correlation structure viaPROC GENMOD in SAS. The procedureadjusted for the inclusion of women with morethan one pregnancy during the study period.A p<0.05 was considered statistically significant.Because possible associations between exposureto antihypertensive drugs and urinary and otherlimb (limb anomalies, excluding clubfoot)anomalies have been reported, we conductedadditional analyses to evaluate these specificanomalies. Because teratogens may affect multi-ple organ systems during development, we alsoanalyzed the association between antihyperten-sive drug exposure and the occurrence of multi-ple anomalies in the same child. Finally, becauseof evidence that use of ACE inhibitors in thesecond and third trimester is associated withanomalies, we also conducted analyses excludingcases where the mother was exposed to an ACEinhibitor during the second or third trimester toisolate effects due to exposure in earlypregnancy.The following potential confounders were

evaluated: prepregnancy body mass index (BMI)(lower than 25, 25–29, and 30 or higher),maternal age (younger than 35, 35 years orolder), smoking status, history of diabetes, insu-lin use, exposure to a known teratogen (seeTable 2 for a list of substances) during the firsttrimester, history of infertility (including use ofinfertility drugs), and premature delivery.A potential confounder was included in the finalanalysis if its inclusion changed the crude

relative risk estimate by 10% or more. Due tosmall numbers, some potential confounders werenot included in certain analyses.The protocol for this study was approved by

the Independent Scientific Advisory Committeefor Medicines and Healthcare Products Regula-tory Agency database research.

Results

There were 341 women exposed to antihyper-tensives during the exposure period and 682unexposed women. Of the exposed women, sixwere exposed to ACE inhibitors in the second orthird trimester. These six women were excludedfrom further analyses, leaving 335 womenexposed to antihypertensives. Table 1 providesdescriptive characteristics for exposed and unex-posed women. Women exposed to antihyperten-sives were more likely to be diabetic and obese.Six women were exposed to ACE inhibitors in

their second or third trimesters. These womenwere more likely to have a high BMI, diabetesand insulin use, and to be nonsmokers. Two ofthe six subjects were exposed to additional anti-hypertensive drugs during early pregnancy. Onewas also exposed to b-blockers and diuretics,and the other was exposed to other antihyper-tensives. There was only one major anomalyamong the offspring of these six subjects: a still-birth with multicystic kidneys. These six womenwere excluded from further analyses.The prevalence of any anomaly among unex-

posed and women exposed to any antihyperten-sive was 23.5 (95% CI 14.4–38.3) and 20.9 (95%CI 10.0–43.8) per 1000 pregnancies, respectively,resulting in a crude relative risk of 0.9 (95% CI0.4–2.2). Adjustment for covariates did not mate-rially change the strength of the association.When the data were analyzed by class of anti-

hypertensive drug received, we found no womenexposed to vasodilators or peripherovascular an-tihypertensives during early pregnancy. Therewere only two women exposed to a-blockersand one woman exposed to an ARB. The cruderelative risk of any anomaly was increased forACE inhibitors and marginally for b-blockers;RRs were 2.9 (95% CI 0.7–12.7) and 1.4 (95%CI 0.6–3.3), respectively. However, the cruderelative risk was decreased for CCBs and otherantihypertensives; RRs were 0.8 (95% CI 0.1–4.5) and 0.6 (95% CI 0.1–2.6), respectively.Including several potential confounders in themodel did not appreciably change the interpreta-tion of the RR estimates (Table 2).


Although urinary anomalies were of particularinterest, the data were too sparse for a formalanalysis. Only one urinary anomaly occurredwithin the entire cohort to a subject who wasexposed to an ACE inhibitor in early pregnancy.There were three cases of other limb anoma-

lies in the study population: one case affected an

infant born to an unexposed woman, one involv-ing a woman who was exposed to b-blockersalone, and one woman who was exposed tob-blockers and another antihypertensive drug.There were no cases involving infants amongwomen exposed to CCBs. The crude RR of alimb anomaly for exposure to any antihyperten-sive in the first trimester was 4.1 (95% CI 0.4–44.8) (Table 3). Due to small numbers, onlymaternal age was controlled and it did notchange the crude estimate of effect. The preva-lence of other limb anomalies was 1.5 per 1000pregnancies (95% CI 0.2–10.4) among unex-posed subjects compared with 9.3 (95% CI 2.3–37.4) per 1000 pregnancies among women withexposure to b-blockers in early pregnancy. Com-pared with unexposed women, the crude RR riskof other limb anomalies was 6.4 (95% CI 0.6–70.1) among the offspring of b-blocker users.The addition of maternal age to the model didnot change the crude effect estimate.Previous reports of genital anomalies have

been associated with use of antihypertensivedrugs, particularly ACE inhibitors, in early preg-nancy. We found seven cases of genital anoma-lies in the study population. Four involvedunexposed women and three involved womenexposed to antihypertensives. Among theexposed cases of genital anomalies, two occurred

Table 1. Distribution of Characteristics According to Maternal Use of Antihypertensive Medication During the FirstTrimester of Pregnancya

No exposure(%)

Anyexposure

(%)

ACEinhibitors

(%)

ACE inhibitors(without2nd- and

3rd-trimesterexposure) (%)

b-Blockers(%)

CCBs(%)

Otherantihypertensives

(%)

N 682 341 46 40 215 55 128Prepregnancy BMI<25 322 (47.2) 94 (27.6) 12 (26.1) 9 (22.5) 71 (33.0) 12 (21.8) 29 (22.7)25–29 164 (24.0) 147 (43.1) 20 (43.5) 20 (50.0) 83 (38.6) 27 (49.1) 57 (44.5)30+ 2 (0.3) 14 (4.1) 1 (2.2) 1 (2.5) 6 (2.8) 5 (9.1) 7 (5.5)Unknown BMI 194 (28.5) 86 (25.2) 13 (28.2) 10 (25.0) 55 (25.6) 11 (20.0) 35 (27.3)Maternal age (yrs)<35 444 (65.1) 217 (63.6) 21 (45.7) 20 (50.0) 148 (68.8) 38 (69.1) 72 (56.2)35+ 238 (34.9) 124 (36.4) 25 (54.3) 20 (50.0) 67 (31.2) 17 (30.9) 56 (43.8)Smoking statusNonsmoker 392 (57.5) 214 (62.7) 28 (60.9) 25 (62.5) 133 (61.9) 40 (72.7) 77 (60.2)Smoker 139 (20.4) 59 (17.3) 8 (17.4) 6 (15.0) 36 (16.7) 6 (10.9) 25 (19.5)Ex-smoker 28 (4.1) 19 (5.6) 4 (8.7) 4 (10.0) 10 (4.7) 5 (9.1) 8 (6.2)Unknown 123 (18.0) 49 (14.4) 6 (13.0) 5 (12.5) 36 (16.7) 4 (7.3) 18 (14.1)History of diabetes 5 (0.7) 16 (4.7) 5 (10.9) 4 (10.0) 7 (3.3) 5 (9.1) 5 (3.9)Insulin use 1 (0.2) 10 (2.9) 4 (8.7) 3 (7.5) 3 (1.4) 4 (7.3) 3 (2.3)Teratogen exposure 1 (0.2) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)History of infertility 10 (1.5) 1 (0.3) 0 (0) 0 (0) 0 (0) 0 (0) 1 (0.8)Premature delivery 1 (0.2) 2 (0.6) 1 (2.2) 1 (2.5) 1 (0.5) 0 (0) 1 (0.8)

ACE = angiotensin-converting enzyme; CCB = calcium channel blocker; BMI = body mass index.aExposure categories are not mutually exclusive. Teratogens include 13-cis-retinoic acid, aminopterin busulfan, carbamazepine, cyclophospha-mide, diphenylhydantoin, etretinate, isotretinoin, methotrexate, phenytoin, thalidomide, trimethadione, and valproic acid.

Table 2. Risk of Congenital Anomaly in Infants Accordingto Maternal Use of Antihypertensive Medication Duringthe First Trimester of Pregnancy (Excluding Subjects withSecond- and Third-Trimester Exposure to Angiotensin-Converting Enzyme Inhibitors)a

No.

of

cases

No. in

exposure

category

Crude

relative

risk

(95% CI)

Adjusted

relative risk

(95% CI)

No

exposure

16 682 Reference Reference

Any

exposure

7 335 0.9 (0.4–2.2) 0.8 (0.3–2.0)

ACE

inhibitors

2 40 2.9 (0.7–12.7) 2.5 (0.5–13.5)

b-Blockers 6 214 1.4 (0.6–3.3) 1.4 (0.6–3.2)CCBs 1 55 0.8 (0.1–4.5) 0.6 (0.1–4.8)Other

exposure

2 125 0.6 (0.1–2.6) 0.5 (0.1–2.7)

CI = confidence interval; ACE = angiotensin-converting enzyme;CCB = calcium channel blocker.aExposure categories are not mutually exclusive. Adjustment forteratogen exposure, history of infertility and premature deliverywas not possible due to small numbers.


among women who were exposed to b-blockersalone, and one occurred in a woman who wasexposed to ACE inhibitors, b-blockers, andCCBs in early pregnancy. Compared with unex-posed mothers, the crude risk ratio of having achild with a genital anomaly was 1.6 amongmothers who were exposed to any antihyperten-sive drug during the first trimester (95% CI 0.4–7.0) (Table 3). Adjustment for multiple riskfactors was not possible due to small numbers ofinvolved cases. When we restricted the analysisto subjects with either no exposure or exposureto ACE inhibitors, b-blockers, or CCBs, thecrude RRs of genital anomalies were 4.2 (95%CI 1.0–18.0) for ACE inhibitors, 2.7 (95% CI0.6–11.4) for b-blockers, and 2.0 (95% CI 0.5–8.8) for CCBs. When we included both prepre-gnancy BMI and insulin use in the same model,the crude RR estimates for ACE inhibitors (RR3.8, 95% CI 0.9–16.0) and CCBs (RR 1.3, 95%CI 0.1–12.4) were attenuated. Because only onecase was exposed to all three drugs, it was notpossible to estimate the independent effect ofeach particular drug on the risk of genitalanomalies.

Discussion

After excluding subjects with second- orthird-trimester ACE inhibitor exposure from theanalysis, our findings suggest that antihyperten-sive drugs overall were not associated with anincreased risk of congenital anomalies in the off-spring when taken during the first trimester.However, we found that exposure to ACE inhib-itors in early pregnancy was associated with anincreased risk of congenital anomalies that wasnot statistically significant. There was also a sug-gestion that use of b-blockers was associatedwith a small increase in risk, although the num-bers were small and the resulting CI was wide.Additionally, we found some increases in the

risk of specific anomalies associated with specificantihypertensive exposures, although these find-ings were based on small numbers. In particular,we found an increased risk of other limb anomaliesin the offspring of women exposed to b-blockersduring the first trimester that was based on onlythree cases. We also found an increased risk ofgenital anomalies among subjects exposed to anti-hypertensive drugs that was based on seven cases.This study was based on a large population of

pregnant women who were representative of theUnited Kingdom. Among the population understudy, we captured all women exposed to anti-hypertensive drugs with a subsequent pregnancyoutcome. For efficiency, we matched eachexposed woman to two unexposed women onmaternal age, year of delivery, and general prac-tice. Because the database records all drugs asthey are prescribed, our exposure variables werenot subject to recall bias. Additionally, all out-comes of congenital anomaly were reviewed byhand to validate case status. This validation wasperformed without knowledge of exposure. Ear-lier validation studies have shown that all con-genital anomalies have been recorded in thecomputerized medical record, so it is unlikelythat many, if any, cases were missed.21, 22

Analysis of potential confounders was limited bythe data available in the GPRD. Specifically, thedatabase did not include information on diet andsocioeconomic status. Information on race, non-prescription medication, illicit drug use, alcoholuse, and folic acid intake is incomplete. Althoughabsence of information on these covariates is a lim-itation of this study, we did match on general prac-tice that can partially serve as a proxy forsocioeconomic status. Regularly used medications,including over-the-counter drugs, have their costscovered by the National Health Service and would

Table 3. Relative Risks of Various Anomalies Accordingto Maternal Use of Antihypertensive Medication Duringthe First Trimester of Pregnancy (Excluding Subjects withSecond- and Third-Trimester Exposure to Angiotensin-Converting Enzyme Inhibitors)

No. of

cases

No. in

exposure

category

Crude relative

risk (95% CI)

Adjusted

relative risk

(95% CI)

Other limb anomaliesa

No

exposure


Any

exposure

2 341 4.1 (0.4–44.8) 4.1 (0.4–44.5)

b-Blockers 2 215 6.4 (0.6–70.1) 6.4 (0.6–74.2)

Genital anomaliesb

No

exposure


Any

exposure

3 341 1.6 (0.4–7.0) 1.5 (0.3–9.3)

ACE

inhibitors

1 46 4.2 (1.0–18.0) 3.8(0.9–16.0)

b-Blockers 3 215 2.7 (0.6–11.4) 2.8 (0.7–11.9)CCBs 1 55 2.0 (0.5–8.7) 1.3 (0.1–12.4)

CI = confidence interval; ACE = angiotensin-converting enzyme;CCB = calcium channel blocker.aLimb anomalies, excluding clubfoot. Adjustment for prepregnancybody mass index, smoking, history of diabetes, insulin use, terato-gen exposure, history of infertility, and premature delivery was notpossible due to small numbers. Adjustment for maternal age didnot change the crude estimate by more than 10%. Analysis of spe-cific exposures was not possible due to small numbers.bExposure categories are not mutually exclusive. Adjustment forsmoking status, teratogen exposure, history of infertility, and pre-mature delivery was not possible due to small numbers.


likely have been captured in this study. It is unli-kely that very occasional use would have influ-enced the outcomes of our statistical analyses.Finally, most patients in the GPRD were white,and an absence of more thorough information onrace should not have had an impact on the results.In this study, we restricted the analysis to

major anomalies. Because researchers often dis-tinguish between major and minor anomaliesusing differing criteria, our results may not bedirectly comparable with other studies. Addi-tionally, we included anomalies that were diag-nosed up until 1 year after delivery. The resultsof other studies of congenital anomalies, using ashorter or longer time period for detection, maynot be directly comparable with our results.Although the children of women exposed to pre-scription drugs during pregnancy may be exam-ined more carefully than children born tounexposed mothers, we have assumed thatmajor anomalies were detected and diagnosed,regardless of maternal drug exposure. Althoughall cases of an anomaly were reviewed by handto verify the presence of a major anomaly, it ispossible that some cases of minor anomalieswere included by classification error.Studies of congenital anomalies are limited by

the rarity of specific congenital anomalies, mak-ing it difficult to obtain sufficient power for sta-ble anomaly-specific estimates. Studies ofantihypertensive use during pregnancy are par-ticularly difficult to perform because hyperten-sion is uncommon in women of childbearingage. Although we found some indication ofincreased risk for ACE inhibitors, and the riskfor some anomalies was more than 2-fold, therarity of the exposure to various antihyperten-sives resulted in wide CIs. Nonetheless, ouradditional data on these associations add impor-tant support to an overall conclusion alreadyknown that a relatively high risk of anomaliesindicates ACE inhibitors should be avoided inwomen at risk or desiring to become pregnant.In summary, ACE inhibitors prescribed in the

first trimester of pregnancy seem to increase therisk of congenital anomalies among the offspringof exposed women, although our finding was notstatistically significant. Exposure to b-blockersmay also slightly increase the risk of congenitalanomalies, although this finding was based onsmall numbers and was not statistically signifi-cant. Although our findings are based on a smallnumber of exposed women, these findings suggestthat, when possible, ACE inhibitors should beavoided in women at risk of becoming pregnant.

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