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Research www.AJOG.org

OBSTETRICS

Hypertension and antihypertensive drugsin pregnancy and perinatal outcomesHagay Orbach, MD; Ilan Matok, PhD; Rafael Gorodischer, MD; Eyal Sheiner, MD, PhD; Sharon Daniel, MD, MPH;Arnon Wiznitzer, MD; Gideon Koren, MD; Amalia Levy, MPH, PhD

OBJECTIVE: Despite high rates of hypertension in pregnancy, the ef-fects of hypertension have not been separated appropriately from theeffects of the medications that are used. We evaluated the safety of ex-posure to antihypertensive medications during pregnancy, while ac-counting for disease effects.

STUDY DESIGN: A population-based retrospective cohort study was per-ormed that compared all pregnancies of women with hypertension whoere either exposed or unexposed to antihypertensive medications. A com-uterized database of the medications that were dispensed to pregnantomen from 1998-2008 was linked with computerized databases thatontained maternal and infant hospitalization records from the districtospital during the same period.

RESULTS: During the study period, 100,029 deliveries occurred; ofthose, 1964 pregnant women experienced chronic hypertension, and620 neonates (0.6%) were exposed to at least 1 antihypertensive med-

2013;208:301.e1-6.

scat

See Journal Club, page 331

trauterine growth restriction (7.2% vs 2.1%, respectively; adjustedodds ratio [OR], 4.37; 95% confidence interval [CI], 3.00–6.36; P �.001), small for gestational age (3% vs 1.7%, respectively; adjustedOR, 2.23; 95% CI, 1.27–3.92; P � .005), and preterm deliveries (�37weeks, 22.9% vs 8.0%, respectively; adjusted OR, 3.69; 95% CI,2.90–4.69; P � .001) were noted among the pregnancies of womenwho were exposed to antihypertensive medications during the third tri-mester. Importantly, a similar association was detected when we com-pared women with chronic hypertension who were not treated duringpregnancy (n � 1074) to women who had no chronic hypertension andwho were unexposed to antihypertensive medications (n � 97,820).

CONCLUSION: Chronic hypertension with or without treatment duringpregnancy is an independent and significant risk factor for adverse peri-natal outcomes such as intrauterine growth restriction, small for gesta-tional age, and preterm delivery.

ication (methyldopa or atenolol) during pregnancy. A higher rate of in- Key words: atenolol, chronic hypertension, methyldopa, pregnancy

Cite this article as: Orbach H, Matok I, Gorodischer R, et al. Hypertension and antihypertensive drugs in pregnancy and perinatal outcomes. Am J Obstet Gynecol

bpecusbctsg

booc

Chronic hypertension is defined asblood pressure that exceeds 140/90

mm Hg at �20 weeks’ gestation or thatpersists longer than the usual postpartumperiod (12 weeks after delivery).1,2 It is a

From the Departments of Public Health (Drs OGorodischer), and Obstetrics and GynecologySciences, Ben-Gurion University of the NegevSheiner, and Wiznitzer); and Clalit Health ServWiznitzer), Beer-Sheva, Israel; the Center for CInstitute, Jewish General Hospital, and the DeOccupational Health, McGill University, MontrDivision of Clinical Pharmacology-Toxicology,Children, and University of Toronto, Toronto, OGurion Motherisk Obstetric Registry of ExposuDaniel, Koren, and Levy).

Received July 31, 2012; revised Nov. 1, 2012; a

The authors report no conflict of interest.

Presented as a poster at the annual meeting of tTherapeutics, Montreal, QC, Canada, May 25-2

Reprints: Amalia Levy, MPH, PhD, Public HealthGurion University of the Negev, POB 653, Beer S

0002-9378/$36.00 • © 2013 Mosby, Inc. All rights re

erious medical condition that compli-ates 1-5% of all pregnancies and that isssociated with an increased risk for ma-ernal and fetal morbidity and death.1,2

The most common maternal complica-

ch, Daniel, and Levy), Pediatrics (Drrs Sheiner and Wiznitzer), Faculty of Healthroka Medical Center (Drs Gorodischer,(Southern District) (Drs Gorodischer and

ical Epidemiology, Lady Davis Researchtment of Epidemiology, Biostatistics, andQC (Dr Matok), and the Motherisk Program,

partment of Pediatrics, The Hospital for Sick(Dr Koren), Canada; and the BeMORE (Ben-collaboration (Drs Matok, Gorodischer,

pted Nov. 13, 2012.

anadian Society of Pharmacology and011.

partment, Faculty of Health Sciences, Ben-va 84105. Israel.lamalia@bgu.ac.il.

ed. • http://dx.doi.org/10.1016/j.ajog.2012.11.011

m

APRIL 2013 Americ

tion that involves 25% of the cases is su-perimposed preeclampsia.2 Other possi-

le maternal complications includelacental abruption, the need for cesar-an delivery, and even death.3,4 The mostommon fetal complications are intra-terine growth restriction (IUGR),mall-for-gestational-age (SGA) new-orn infants, and prematurity.4-6 The in-idence of these adverse effects is relatedo the degree and duration of hyperten-ion and to the involvement of other or-ans.7 Studies have shown that, even after

adjustment for superimposed preeclamp-sia as a risk factor for fetal and maternalmorbidities, pregnancies that are compli-cated with chronic hypertension havehigher rates of cesarean deliveries, IUGR,perinatal mortality, and postpartum hem-orrhage.8 Several risk factors that have

een reported to aggravate the prevalencef chronic hypertension include maternalbesity, diabetes mellitus, heredity, and ra-ial factors. Another risk factor is advanced

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The common drugs that are used in thetreatment of chronic hypertension duringpregnancy are methyldopa or atenolol.Methyldopa is an �2 adrenergic agonist.

ctivation of these receptors in the centralervous system inhibits sympathetic out-ut that leads to a decrease in blood pres-ure.9,10 Atenolol is a selective �1 adrener-

gic inhibitor with a negative chronotropicand inotropic effect on the myocar-dium.9,10 A number of studies have docu-

ented the efficacy of treatment forhronic hypertension during pregnancy;evertheless, an important question that hasot yet been resolved is the independent ef-

ects of nontreated hypertension.11-17 De-pitehighratesofhypertensioninpregnancy,he effects of hypertension have not beeneparated appropriately from those ofhe medications that have been used. Be-ause of the increasing rates of maternalbesity and the trend to postpone preg-ancies to older ages, there is an increas-

ng incidence of chronic hypertension,hich might contribute to maternal and

etal morbidities. The objective of theresent study was to separate the effectsf hypertension from its treatments ondverse pregnancy outcomes.

METHODSThis was a retrospective cohort studythat involved members of “Clalit Healthservices” in southern Israel. Clalit is thelargest health maintenance organizationin Israel, in which 70% of the districtpopulation (which includes 70% ofwomen 15-49 years old) is insured. Thepopulation of the Southern District of Is-rael is slightly greater than one-half amillion citizens. Soroka Medical Center(SMC) is the district hospital in whichpractically all deliveries of the region takeplace.18,19 All infants are examined by a

oard-certified neonatologist.The clinical, medication, and demo-

raphic data of Clalit members are storedn the Clalit data warehouse and can beueried at the level of an individual mem-er. This database contains informationbout dispensing date, the Anatomicalherapeutically Classification code of therug (including the commercial and ge-eric names), dose schedule of drugs ad-

inistration, and dose dispensed in de- n

301.e2 American Journal of Obstetrics & Gynecolo

ned daily dose (the assumed averageaintenance dose per day).Two computerized SMC databases

hat draw information directly fromriginal sources were used. All patientecords at SMC originate from a singleatabase that includes demographic in-

ormation and hospitalization dates thatre generated at the time of the woman’sdmission to the hospital and of the in-ant’s birth. The database of the Obstet-ics and Gynecology Department in-ludes information on maternal medicalonditions during pregnancy and deliv-ry, maternal age, gestational age at de-ivery (in days since last menstrual pe-iod), perinatal death, parity, ethnicroup, self-reported smoking status dur-ng pregnancy, infant birthweight, andpgar score at 1 and 5 minutes. The di-gnoses are reviewed routinely by arained medical secretary before entrynto the database. The other electronicMC database that was used in the pres-nt study was the Demog-Internationallassification of Diseases, Ninth Revision

ICD9) database, which includes demo-raphic and medical diagnoses duringospitalization; the latter is drawn di-ectly from the medical records. Addi-ional infant diagnoses that were re-orded on discharge are coded andncluded into their Demog-ICD9 record.ll diagnoses are classified according to

he ninth revision of the ICD.Women from 15-49 years old who were

egistered with Clalit and who lived in theouthern district of Israel who gave birth atMC were included. The study period wasanuary 1998 to August 2008, duringhich 100,029 deliveries took place. Ap-roximately one-half of the infants in theistrict were born to Jewish parents andne-half of the infants were born to Bed-uin parents. The southern district of Is-ael is populated by 2 distinct ethnicroups, the Jewish and the Bedouins Ar-bs. Because consanguinity is practicedidely in the Bedouin population, theirabies are at higher risk for congenital mal-ormations. The 3 databases (1 from Clalitnd 2 from SMC) described earlier werencoded and linked by a personal identifi-ation number to create a registry of med-cations that were dispensed during preg-

ancy and the pregnancy outcomes.

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We investigated the relationship be-ween exposure to antihypertensiverugs during pregnancy and perinatalutcomes, specifically IUGR, pretermelivery (PTD; �37 weeks’ gestation),ongenital malformations, and lowirthweight (LBW; �2500 g). The ex-osed group included women to whomntihypertensive (methyldopa or aten-lol) drugs were dispensed during therst trimester of pregnancy (�13 weeks’estation). We also assessed methyldopand atenolol individually. The unex-osed group comprised all women with-ut diagnosis of chronic hypertensionnd who were not exposed to antihyper-ensive drugs through the first or thehird trimester during the study period.he nontreated hypertension group in-luded all women with a diagnosis ofhronic hypertension who were notreated for hypertension during the in-ex pregnancy.Congenital malformations data were

btained from SMC databases. We usedhe definitions of major congenital malfor-

ations that had been developed by theenters for Disease Control and Preven-

ion Metropolitan Atlanta Congenital De-ects Program.20,21 This program has beenonducting surveillance for birth defectsince 1967, and its definitions have beenalidated in several previous studies.21

Chromosomal diseases were excluded.The following pregnancy outcomes wereinvestigated in both live neonates and still-born infants: major malformations, peri-natal death, PTD, LBW (�2500 g), veryLBW (�1500 g), and Apgar score at 1 and5 minutes after birth (categorized as Apgar�7 or �8), and preeclampsia. The follow-ing potential confounders were includedin the statistical analysis: maternal age, par-ity, self-reported smoking in pregnancy,maternal diabetes mellitus, lack of prenatalcare, and ethnicity (ie, Jewish or BedouinMoslem). The study was approved by theinstitutional Helsinki Ethics Committeefor Human Investigations. No written in-formed consent was required.

The statistical analyses were per-formed with the SPSS package (version18; SPSS Inc, Chicago, IL). The exposedgroup was compared with the unex-posed by means of chi-square test or

Fisher’s Exact test for differences in cat-

cy/p

www.AJOG.org Obstetrics Research

egoric variables and the Student t test fordifferences in continuous variables.Multivariate logistic regression modelswere constructed to identify indepen-dent risk factors that were associatedwith adverse pregnancy outcomes. Mul-tivariate logistic regression models wereperformed to investigate whether greaterexposure was associated with increasedrisk of IUGR, PTD, congenital malfor-mations, and SGA. Odd ratios (ORs) andtheir 95% confidence intervals (CIs)were computed.

TABLE 2Comparison of pregnancy and periand fetuses to antihypertensive me

Variable

Exposure to antimedication durintrimester of preg

No(n � 97,820)

Y(n

Preterm delivery 7836 (8.0)...................................................................................................................

Low birthweight 10,001 (10.2) 1...................................................................................................................

Perinatal death 1379 (1.4)...................................................................................................................

Apgar score �7..........................................................................................................

At 1 minb 5790 (6.1)..........................................................................................................

At 5 minc 1026 (1.1)...................................................................................................................

Intrauterine growthrestriction

2096 (2.1)

...................................................................................................................

Small for gestational age 1704 (1.7)...................................................................................................................

Preeclampsia 1093 (1.1)...................................................................................................................a Exposed at least 1 time to atenolol or methyldopa; b 2333 in

TABLE 1Characteristics of women who wermedications in the first and the thi

Characteristic

Exposuthe firs

No (n �

Ethnic group, n (%)..........................................................................................................

Jews 34,475..........................................................................................................

Bedouins 63,345...................................................................................................................

Maternal age, yb 28...................................................................................................................

Maternal diabetes mellitus, n (%) 5691...................................................................................................................

Smoking, n (%) 2302...................................................................................................................

Parity, nb 3...................................................................................................................a Women with nontreated hypertension were not included; b D

Orbach. Hypertension/antihypertensive drugs in pregnan

Orbach. Hypertension/antihypertensive drugs in pregnancy/p

RESULTS

During the study period, 100,029 deliv-eries occurred. Six hundred twentywomen (0.6%) with chronic hyperten-sion were exposed to atenolol or methyl-dopa or both during the index pregna-ncy; 271 women (0.2%) were exposed toatenolol or methyldopa or both duringthe first trimester of pregnancy; 114women (0.11%) were exposed to meth-yldopa, and 188 women (0.18%) wereexposed to atenolol. One thousand sev-

al outcomes of exposed and unexpoations in the third trimester of pregn

ertensivehe thirdcy, n (%)a

Exposure to methyldopa duthe third trimester of pregn(%)

433)Pvalue

No(n � 97,820)

Yes(n � 340)

(22.9) � .001 7836 (8.0) 86 (25.3).........................................................................................................................

(24.0) � .001 10,001 (10.2) 84 (24.7).........................................................................................................................

(2.1) .158 1379 (1.4) 9 (2.6).........................................................................................................................

.........................................................................................................................

(12.9) � .001 5790 (6.1) 43 (12.8).........................................................................................................................

(2.3) .012 1026 (1.1) 10 (3.0).........................................................................................................................

(7.2) � .001 2096 (2.1) 24 (7.1)

.........................................................................................................................

(3.0) .005 1704 (1.7) 8 (2.4).........................................................................................................................

(13.9) � .001 1093 (1.1) 53 (15.6).........................................................................................................................

had no 1-minute Apgar score; c 2232 infants had no 5-minute

nd were not exposed to hypertensivtrimester of pregnancya

to antihypertensive medication duringimester of pregnancy

Exdu

7,820) Yes (n � 271) P value N

� .001.........................................................................................................................

.2) 135 (49.8) 34.........................................................................................................................

.8) 136 (50.3) 63.........................................................................................................................

� 5.8 34.85 � 5.5 � .001.........................................................................................................................

8) 68 (25.1) � .001.........................................................................................................................

4) 5 (1.8) .726.........................................................................................................................

2.6 5.2 � 3.6 � .001.........................................................................................................................

re given as mean � SD.

erinatal outcomes. Am J Obstet Gynecol 2013.

erinatal outcomes. Am J Obstet Gynecol 2013.

APRIL 2013 Americ

enty-four women (1.07%) experiencedchronic hypertension during pregnancybut were not exposed to antihypertensivemedication. Five hundred fifteen infantswho were exposed to antihypertensivedrugs in utero for maternal indicationsother than hypertension were excludedfrom the cohort.

Characteristics of the mother exposedand unexposed to antihypertensive med-ications are presented in Table 1. Of theinfants who were born, 4623 infants wereborn with congenital malformations; of

womency

y, n Exposure to atenolol during thethird trimester of pregnancy, n (%)

ueNo(n � 97,820)

Yes(n � 107)

Pvalue

.001 7836 (8.0) 18 (16.8) � .001

..................................................................................................................

.001 10,001 (10.2) 25 (23.4) � .001

..................................................................................................................

.035 1379 (1.4) 0 (0.0) —

..................................................................................................................

..................................................................................................................

.001 5790 (6.1) 15 (14.2) .001

..................................................................................................................

.001 1026 (1.1) 0 —

..................................................................................................................

.001 2096 (2.1) 9 (8.4) � .001

..................................................................................................................

.06 1704 (1.7) 6 (5.6) � .001

..................................................................................................................

.001 1093 (1.1) 10 (9.3) � .001

..................................................................................................................

r score.

sure to antihypertensive medicationg the third trimester of pregnancy

� 97,820) Yes (n � 433) P value

� .001..................................................................................................................

5 (35.2) 213 (49.2)..................................................................................................................

5 (64.8) 220 (50.8)..................................................................................................................

8.5 � 5.8 33.4 � 5.5 � .001..................................................................................................................

1 (5.8) 121 (27.9) � .001..................................................................................................................

2 (2.4) 6 (1.4) .243..................................................................................................................

3.7 � 2.6 4.7 � 3.3 � .001..................................................................................................................

nat seddic an

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Research Obstetrics www.AJOG.org

which, 18 infants (6.6%) had been ex-posed to either methyldopa or atenololduring the first trimester (adjusted OR,1.30; 95% CI, 0.84 –2.01). Exposure toantihypertensive drugs (atenolol ormethyldopa) during the third trimesterwas associated with PTD, LBW, low Ap-gar score, IUGR, SGA, and preeclampsia(Tables 2 and 3). When the data were as-sessed separately, both atenolol andmethyldopa were associated with theseadverse pregnancy outcomes as well(Tables 2 and 3).

Nontreated hypertension during preg-nancy was associated with increased

TABLE 3Crude and adjusted odds ratios forof fetuses to antihypertensive med

Variable

Exposure to antihypertensiduring the third trimester o

Crude odds ratio(95% CI)

Adju(95%

Preterm delivery 3.40 (2.72–4.27) 3.6...................................................................................................................

Low birthweight 2.78 (2.22–3.46) 3.6...................................................................................................................

Perinatal death 1.48 (0.77–2.88) 1.6...................................................................................................................

Apgar score �7..........................................................................................................

At 1 min 2.29 (1.72–3.04) 2.0..........................................................................................................

At 5 min 2.21 (1.18–4.14) 2.2...................................................................................................................

Intrauterine growthrestriction

3.52 (2.44–5.09) 4.3

...................................................................................................................

Small forgestational age

1.75 (1.00–3.04) 2.2

...................................................................................................................

Preeclampsia 14.24 (10.77–18.82) 12.7...................................................................................................................

The models were controlled for maternal age, ethnicity, smoka Women with nontreated hypertension were not included in th

who were treated with methyldopa during the third trimester

Orbach. Hypertension/antihypertensive drugs in pregnan

TABLE 4Comparison of the risk for pretermamong women without hypertensiohypertension who were treated wit

Variable

Without hypertension...................................................................................................................

Nontreated hypertension...................................................................................................................

Exposure to atenolol or methyldopa duringthe third trimester of pregnancy...................................................................................................................

The models were controlled for maternal age, ethnicity, smok

Orbach. Hypertension/antihypertensive drugs in pregnancy/p

301.e4 American Journal of Obstetrics & Gynecolo

risks of PTD, SGA and IUGR, but therisks for PTD and IUGR were lowerthan among treated women with hyper-tension (Table 4).

Treatment of hypertension in earlypregnancy did not improve the out-comes for preeclampsia (adjusted OR,1.50; 95% CI, 0.90 –2.52), SGA (adjustedOR, 1.34; 95% CI, 0.45– 4.00), and PTD(adjusted OR, 0.85; 95% CI, 0.56 –1.30).

COMMENTIn this large cohort study, we found thatchronic hypertension with or without

egnancy adverse outcomes after exptions in the third trimester of pregna

edicationegnancy

Exposure to methyldopa during thethird trimester of pregnancyb

d odds ratio)

Crude odds ratio(95% CI)

Adjusted od(95% CI)

.90–4.69) 3.89 (3.04–4.97) 4.19 (3.22–.........................................................................................................................

.89–4.67) 2.88 (2.25–3.69) 3.77 (2.89–.........................................................................................................................

.83–3.15) 1.90 (0.98–3.70) 2.05 (1.05–.........................................................................................................................

.........................................................................................................................

.52–2.72) 2.28 (1.65–3.14) 1.95 (1.40–.........................................................................................................................

.20–4.28) 2.83 (1.50–5.32) 2.84 (1.50–.........................................................................................................................

.00–6.36) 3.47 (2.29–5.27) 4.32 (2.82–

.........................................................................................................................

.27–3.92) 1.36 (0.67–2.75) 1.01 (1.00–

.........................................................................................................................

.53–17.03) 16.34 (12.12–22.04) 14.24 (10.43.........................................................................................................................

iabetes mellitus, twin pregnancies, lack of prenatal care and par

alysis; b Women who were treated with atenolol during the third tregnancy were not included in the analysis.

erinatal outcomes. Am J Obstet Gynecol 2013.

livery, small for gestational age, andwomen with hypertension who weretenolol or methyldopa during the thi

ds ratio (95% confidence interval)

eterm delivery Small for gestational age

ference Reference.........................................................................................................................

9 (1.59–2.25) 2.06 (1.44–2.95).........................................................................................................................

3 (2.57–4.05) 2.25 (1.29–3.94)

.........................................................................................................................

iabetes mellitus, twin pregnancies, lack of prenatal care and par

erinatal outcomes. Am J Obstet Gynecol 2013.

gy APRIL 2013

treatment during pregnancy is an inde-pendent and significant risk factor foradverse perinatal outcomes such as SGA,IUGR,andPTDascomparedwithbirthout-comes among women without chronic hy-pertension and without exposure to anti-hypertensive medications.

Although many studies have advocatedthat women with severe chronic hyperten-sion during the pregnancy should betreated medically, it is not clear whetherwomen with mild-to-moderate chronichypertension should be treated medical-ly.11-17 It has been difficult to separate the

utcomes of the chronic hypertension it-

ureya

Exposure to atenolol during thethird trimester of pregnancyc

atio Crude odds ratio(95% CI)

Adjusted odds ratio(95% CI)

) 2.32 (1.40–3.86) 2.68 (1.57–4.56)..................................................................................................................

) 2.68 (1.71–4.19) 3.89 (2.42–6.25)..................................................................................................................

) — —..................................................................................................................

..................................................................................................................

) 2.56 (1.48–4.42) 2.65 (1.52–4.61)..................................................................................................................

) — —..................................................................................................................

) 4.19 (2.12–8.31) 5.19 (2.59–10.39)

..................................................................................................................

) 3.35 (1.47–7.65) 4.80 (2.07–11.10)

..................................................................................................................

.45) 9.12 (4.75–17.54) 9.38 (4.84–18.16)

..................................................................................................................

ster of pregnancy were not included in the analysis; c Women

trauterine growth restrictiont treated, and women withtrimester of pregnancy

Intrauterine growthrestriction Preeclampsia

Reference Reference..................................................................................................................

2.09 (1.51–2.89) 7.02 (5.54–8.89)..................................................................................................................

4.40 (3.02–6.40) 12.82 (9.58–17.14)

..................................................................................................................

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8 (2 4.94......... .........

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......... .........

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www.AJOG.org Obstetrics Research

self from the potential adverse effects ofthe medications that are used. Severalstudies have shown that chronic hyper-tension in pregnancy is associated withfetal complications such as SGA, PTD,IUGR, and fetal death4-6; our findingscorroborate those results. Studies havealso shown that women with chronic hy-pertension that is treated with atenololhad higher rates of IUGR and PTD,which are findings that are also corrobo-rated by results of our study (Table2).22-25 We found that women withchronic hypertension who were treatedwith methyldopa during the third tri-mester of pregnancy exhibited higherrates of SGA and PTD. There were differ-ences in the outcome of PTD and pre-eclampsia between patients who weretreated with methyldopa and thosetreated with atenolol (27% vs 17% and16% vs 9%, respectively), although ex-posure to atenolol during the third tri-mester was associated more with SGAcompared with methyldopa (5.6% vs2.4%). Methyldopa has been used inmany institutions as the drug of choicefor gestational hypertension; therefore,it is unlikely that women with more se-vere hypertension were treated withmethyldopa, as opposed to atenolol.These observations should be furtherinvestigated.

No statistical difference was foundwhen early treatment in early pregnancywas compared with treatment in latepregnancy, which might be because theirhypertension was pregnancy-inducedand started in late pregnancy.

In our population, women with chronichypertension who were treated with ei-ther atenolol or methyldopa or bothhad higher rates of LBW, SGA, PTD,and IUGR, even after adjustment formaternal age, ethnicity, smoking, dia-betes mellitus, twin pregnancy, lack ofprenatal care, and parity. Adjustmentfor confounders can address theireffects on the outcomes but cannotdifferentiate between the effects ofthe antihypertensive drugs and the hy-pertension effects on the outcomes.Confounding by indication (in thiscase, hypertension) cannot be adjustedin the model and should be recognized

as a limitation. However, because we

had a large group of women with hy-pertension who were not treated withmedications, we could show that mostof the adverse outcomes occurred evenwithout the drugs. Our study is uniquein having a large cohort of women withhypertension who were not treatedpharmacologically during the indexpregnancy, which provided a rare op-portunity to separate the effect of themedications from those of the medicalcondition. Because we had no dataabout the severity of the hypertension,we assumed that the groups who weretreated by atenolol or methyldopa orboth had experienced more severe hy-pertension than did the group ofwomen with hypertension who werenot treated. This may explain thehigher rates of complications such asLBW or SGA, PTD and IUGR amongthe treated women and support the ar-gument that adverse pregnancy out-comes such as LBW, SGA, PTD, andIUGR in women with chronic hyper-tension mainly are due to the adverseeffects of the hypertension itself andnot of the medications. Moreover, thefact that the group of women who weretreated with atenolol and the group ofwomen who were treated with methyl-dopa had both shown higher rates ofLBW, SGA, PTD, and IUGR, althoughthe mechanism of action of the 2 drugsare completely different, further sup-ports the argument that adverse preg-nancy outcomes in women withchronic hypertension mainly are dueto the effect of the hypertension itselfand not these medications.

In conclusion, with the use of a popula-tion-based and relatively large cohort thatseparated the role of hypertension fromthat of the medications that were used, ourstudy supports the major adverse effects ofhypertension itself on pregnancy outcome,rather than atenolol and methyldopa. f

REFERENCES1. Haddad B, Sibai BM. Chronic hypertensionin pregnancy. Ann Med 1999;31:246-52.2. Livingston CJ, Sibai BM. Chronic hyperten-sion in pregnancy. Obstet Gynecol Clin NorthAm 2001;28:447-63.3. Chronic hypertension. In: Cunningham F, Lev-

eno K, Bloom S, Hauth J, Rouse D, Spong C, eds.

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Williams obstetrics, 23rd ed. New York: McGraw-Hill; 2005: 986-91.4. Rey E, Couturier A. The prognosis of preg-nancy in women with chronic hypertension.Am J Obstet Gynecol 1994;171:410-6.5. McCowan LM, Buist RG, North RA, GambleG. Perinatal morbidity in chronic hypertension.BJOG 1996;103:123-9.6. Ferrer RL, Sibai BM, Mulrow CD, ChiquetteE, Stevens KR, Cornell J. Management of mildchronic hypertension during pregnancy: a re-view. Obstet Gynecol 2000;96:849-60.7. Sibai BM. Chronic hypertension in preg-nancy. Obstet Gynecol 2002;100:369-77.8. Vanek M, Sheiner E, Levy A, Mazor M.Chronic hypertension and the risk for adversepregnancy outcome after superimposed pre-eclampsia. Int J Obstet Gynecol 2004;86:7-11.9. Widmaier EP, Raff H, Strong KT. The vas-cular system. In: Vander’s human physiology:the mechanisms of body function, eleventhed. New York, NY: McGraw-Hill; 2010:384-409.10. Brunton L, Lazo J, Parker K. Neurotrans-mission: the autonomic and somatic motornervous systems. In: Goodman and Gilman’s:the pharmacological basis of therapeutics,11th ed. New York, NY: McGraw Hill; 2006:143-6.11. Bayliss H, Churchil D, Beevers M, BeeversDG. Anti-hypertensive drugs and fetal growth:evidence for “pharmacological programming” inthe first trimester? Hypertens Pregnancy 2002;21:161-74.12. Abalos E, Duley L, Steyn DW, Henderson-Smart DJ. Antihypertensive drug therapy for mild tomoderate hypertension during pregnancy. Co-chrane Database Syst Rev 2007;1:CD002252.13. Bunhidy F, Acs N, Puho EH, Czeizel AE. Theefficacy of antihypertensive treatment in preg-nant woman with chronic and gestational hy-pertension: a population based study. Hyper-tens Res 2010;33:460-6.14. Ray JG, Vermeulen MJ, Burrows EA, Bur-rows RF. Use of antihypertensive medicationsin pregnancy and the risk for adverse perinataloutcomes: McMaster outcome study of hyper-tension in pregnancy 2. BMC Pregnancy Childbirth2001;1:6.15. Borghi C, Esposti DD, Cassani A, Im-mordino V, Bovicelli L, Ambrosioni E. The treat-ment of hypertension in pregnancy. J Hyper-tens Suppl 2002;20:6-52.16. Leeman M. Arterial hypertension in preg-nancy. Rev Med Brux 2008;29:5-340.17. Magee LA. Drugs in pregnancy: antihyper-tensives. Best Pract Clin Obstet Gynaecol2001;15:827-45.18. Central Bureau of Statistics. Statistical ab-stract of Israel 2008: No. 59: Population bydistrict, subdistrict and religion; Table 2.6.Available at: http://www.cbs.gov.il/reader.

Accessed June 26, 2012.

an Journal of Obstetrics & Gynecology 301.e5

2

Research Obstetrics www.AJOG.org

19. Idem. State of Israel: Hoda’a laitonut.Available at: http://www.cbs.gov.il/hodaot

007n/01_07_215b.pdf. Accessed June 26,2012.20. Centers for Disease Control and Preven-tion. Metropolitan Atlanta Congenital DefectsProgram coding manual. Available at: http://www.cdc.gov/ncbddd/bd/macdp.htm. Acc-essed June 26, 2012.

21. Rasmussen SA, Olney RS, Holmes LB, Lin

301.e6 American Journal of Obstetrics & Gynecolo

AE, Keppler-Noreuil KM, Moore CA. Guidelinesfor case classification for the national birth de-fects prevention study. Birth Defects Res A ClinMol Teratol 2003;67:193-201.22. Khalil A, Harrington K, Muttukrishna S,Jauniaux E. Effect of antihypertensive therapywith alpha-methyldopa on uterine arteryDoppler in pregnancies with hypertensive dis-orders. Ultrasound Obstet Gynecol 2010;35:

688-94.

gy APRIL 2013

23. Montán S. Drugs used in hypertensive dis-eases in pregnancy. Curr Opin Obstet Gynecol2004:16:111-5.24. Lydakis C, Lip GY, Beevers M, Beevers DG.Atenolol and fetal growth in pregnancies compli-cated by hypertension. Am J Hypertens 1999;12:541-7.25. Czeizel AE, Banhidy F. Chronic hyperten-sion in pregnancy. Curr Opin Obstet Gynecol

2011:23:76-81.