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A Multivariate Analysis of Risk Factorsfor PreeclampsiaBrendaEskenazi,PhD; LauraFenster,MPH, PhD;StephenSidney,MD, MPH

Objective.\p=m-\Todetermine, in a multivariate analysis, risk factors for pre-eclampsia thatcould beobservedearly in pregnancyand to establish whethertheseriskfactors aredifferentfornulliparasandmultiparas.

Design.\p=m-\Acase-controlstudyofpreeclampsia.Setting.\p=m-\Womenwho gavebirth at Northern California Kaiser Permanente

MedicalCenters in 1984and 1985.

Participants.\p=m-\Preeclampticcases (n=139) were determined from dis-

charge diagnosis of severepreeclampsia andby confirmationofbloodpressuresandproteinuria frommedicalrecords.Controls(n = 132) wererandomlyselectedwomen who had no dischargediagnosis ofany hypertensive disorderof preg-nancyand who had no evidence of hypertension or proteinuria from medicalrecord review.

Main Variables Examined.\p=m-\Medicalrecords were abstracted for informa-tion regarding maternal age, race, previous pregnancy history, family medicalhistory, socioeconomic status,employmentduring pregnancy,body mass, andsmokingandalcoholconsumption.Results.\p=m-\Multiple logisticregressionanalysesconfirmed that casepatients

were more likely thancontrolpatients tobenulliparous(adjustedoddsratio[OR],5.4;95% confidenceinterval[CI],2.8 to10.3)andthatpreeclampsia inapreviouspregnancygreatly increased the risk in asubsequent one(adjusted OR, 10.8;95%CI, 1.2 to29.1). However, regardless ofparity, preeclamptic women werealso more likely tobeof high body mass (adjusted OR,2.7;95%CI,1.2 to 6.2), toworkduring pregnancy(adjusted OR,2.1; 95% CI, 1.1 to 4.4), and to have afamilyhistoryofhypertension (adjustedOR,1.7; 95%CI, 0.92to 3.2).Having aprevioushistory ofa spontaneous abortion wasprotectivebutonly in multiparouswomen (adjusted OR formultiparas, 0.09; 95% CI, 0.02 to 0.48). In contrast,beingblack was a significantrisk forpreeclampsiabutonlyinnulliparous women(adjustedORfornulliparas,12.3;95%CI, 1.6to 100.8).Conclusions.\p=m-\Therearea numberofriskfactorsforpreeclampsiathatmay

bedetermined early in a woman's pregnancy. Multiparas and nulliparas sharecertain riskfactorsbut not others. A cohortinvestigation is neededto determinetheabilityoftheseriskfactorstopredictwhodevelopspreeclampsia.

(JAMA. 1991;266:237-241)

PREECLAMPSIA, a hypertensive disorderof pregnancy, is a majorcontributor to maternal mortality, prematurebirth, intrauterinegrowthretardation,

Fromthe Programs of Maternal andChild HealthandEpidemiologyand The NorthernCalifornia Occupation-al HealthCenter, School of Public Health, University ofCalifornia, Berkeley(Dr Eskenazi); Reproductive Epi-demiology Program, California Department of HealthServices, Berkeley (Dr Fenster); and Division of Re-search, Kaiser Permanente Medical Center, Oakland,Calif(DrSidney).

Reprint requests to 312 Earl Warren Hall, School of

Public Health, University of California, Berkeley, CA94720 (DrEskenazi).

andperinatalmortality. Low-doseaspirin has been found to be effective inpreventing its development.1"1 However, the use of aspirinduring pregnancymay not bewithout risk.5 Hence, it is

Seealso 260.

important to identify women who arelikelyto be athigh riskfordevelopingpreeclampsia andto identify themearly

in pregnancy so

that they can

benefitfrom intervention. The causes of and

risk factorsforpreeclampsia remain unclear, however, and thus preeclampsiahasbeen called a"diseaseof theories."6With the exception of nulliparity (approximately 75% of women with preeclampsia arenulliparous)7and a previous historyofpreeclampsiain multparas,8few other risk factors are universally agreed on. Furthermore,althoughit has beensuggestedthatthe riskfactors for and causes ofpreeclampsia innulliparasandmultparas may bedifferent,9"" few have examined thesedifferences.

Some researchers have speculatedthat preeclampsia is a disease of theupperclass,12 others more recently believe it is a disease of the impoverished,613and stillothers thinkall socialclasses are atequal risk.14 It has beendifficult to determine the exact role ofsocioeconomic status, since most stud

ies havenotseparatedoutthe contributions of socioeconomic status-relatedvariablessuch as race,employmentstatus, and nutritional status. Nor havethesestudiescontrolledfor or excludedwomen with preexisting diseases thatmay berelated topreeclampsia, such asessential hypertension, cardiovasculardisease, anddiabetes, and that may bemore prevalent in groups with lowersocioeconomic status.

Black women have been observed tobe atgreater risk for developing preeclampsia. Chesley et al9 caution that

thisincreased riskofpreeclampsiamaybedue tothe higherprevalenceofpreexistinghypertensionin black women.Nevertheless, the Collaborative PerinatalProject15found a higherincidenceof both preeclampsia and eclampsia inblack women compared with whitewomenwhether or nottheyhad preexisting hypertensive disease.

Extremes of age are alsopostulatedas risks for preeclampsia16; however,the effectofage may be confoundedbyother factors. For example, youngerwomen are more likely to beprimigrvi

das, andolderwomen are more

likely tohaveessentialhypertension.'

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Therelationshipof body habitus andpreeclampsia has been debated for almost 200years. Someauthorshave concluded that frail women are more susceptible,17 whereas others claimedheavyset women are more vulnerable.1819 Again, Chesley7 suggests thattheassociation with heavier weight is anartifact of including womenwith essential hypertension in studies of preeclampsia. Nevertheless, the WHOStudyGroup20 concludes thathighpre-pregnancybody

mass

increases a wom

an'srisk for preeclampsia.Some attributes seem to protect

women from developingpreeclampsia.For example, cigarette smoking hasbeenconsistentlydemonstrated to protect women againstpreeclampsia.21,22 Itseffect isdoserelatedandindependentofbody mass.22Also, a previously terminated pregnancy, especially if it endslater in gestation, may provide someprotection against preeclampsia in asubsequentpregnancy.23

Thepresent case-controlstudy examines the

interrelationship of these

potentialrisk factors aswell as othersin amultivariate statisticalmodel. Wefocuson thosepotential risk factors that canbe determined early in pregnancy before theusualtimeof diagnosis(after 28weeks' gestation). We also determinewhether these risk factors for preeclampsia differ in multiparous and innulliparous women.

METHODS

ParticipantsCasesand controls were drawn from

women who delivered live births andstillbirths in 1984 and 1985 at the 10hospitals that constitute Kaiser Permanenteof Northern California.

CaseSelection.Cases were selectedfrom the 263 womenwho received adischarge diagnosis of severe preeclampsia or eclampsia (InternationalClassificationofDiseases,NinthRevision, codes 642.5 and 642.6). In addition, cases had to meet the criteria forblood pressure, urinary protein, andmedical history shownin Table 1 . Of the263eligible case patients who received

dischargediagnosesof preeclampsia,76didnot meet thebloodpressurecriteria,another 34didnot meet theurinary proteincriteria,and 14othershad a historyofeither diabetes or chronichypertension. Atotal of 139 cases remained (105nulliparas, 34multparas).

Control Selection.Potential controls (n = 260) were randomly selectedfromthedischargedata tapefromthosewomen who had not received a dis

charge diagnosis of any hypertensivedisorder of pregnancy (InternationalClassificationofDiseases, NinthRevi

sion,codes 642.0 to

642.9). Thecontrol

group was frequency matched to the

Table 1.Criteriafor Inclusion Inthe Case and in the ControlGroups

I Case GroupA. Blood pressure (at least 2 readings fulfilling criteria after20 wks' gestation*)

1 With a recorded baseline blood pressure(before 20 wks'gestation): from baseline, a change in MAPt 220mm Hg; or

2. Without baseline blood pressure:M AP >105 mmHgB. Urinaryprotein (after20 wks'gestation)

1. Twourinaryproteindipstickmeasurements}of 1 + or 1 readingof 22 + ; or2. 2300 mg of protein in a24-h urine collection

C No history of diabetes or chronic hypertensionII. Control Group

A. Bloodpressure1. With a baseline blood pressure: a changefrom baselineIn MAP

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RESULTS

Sociodemographic Characteristicsand MedicalHistory

Table2 showsthedemographic characteristics of cases and controls. Casepatients averaged 27 years of age andwere, on average, a year youngerthancontrolpatients(P =.14). Casepatientswere more likely than control patientstobeliving apart from theirpartner, tobe

black,andto be

employed.However,for women who worked, a similar proportionin both groupshadprofessionalor managerial jobs(30%of cases vs27%ofcontrols). Similarly, 29%ofthe partners of both case and control patientshadprofessional or managerial jobs.

Table 3 presents the pregnancy andmedical history ofcasesand controls.Asexpected, case patients were almostfivetimes more likely than control patients to be nulliparous and twice aslikely to be primigravid.Among womenwho had been pregnant before, morethan twice the proportion of case patients in comparison with control patientshad a history of therapeuticabortion, but half the proportion of casepatientsin comparison withcontrol patients had a history of spontaneousabortion. Six of the case pregnanciesended in twin births (two formultparas, four fornulliparas), whereas noneof the controlsgave birth to twins.

A largerproportion of case patientswereof higherbody mass and asmallerpercentage were of lower body mass.Case patients weighed, on average,2.7kg more priortopregnancy(62.7kgvs 60.0kg, P=.09). Smokershad lowerbody masses than nonsmokers andthere were fewer smokers among thecases; however, even among nonsmokers, case patients werelesslikelyto beof low body mass (OR, 0.39; 95% CI,0.11to 1.20)and more likely to beofhighbodymass(OR, 2.1;95%CI, 1.0to4.5).

Althoughthe pregnanciesof case patients ended approximately 4 weeksearlier than those of control patients(mean, 35.1 vs 39.2 weeks), case patients gained more weight on averageduring the course of their pregnancy

(15.8 vs 14.3kg, P=

.09). Thisresult isexpected given the increase in edemaassociated with preeclampsia.

Approximately 10% of the case patients smoked during pregnancy, andcase patients were lesslikely to smokethan control patients. Similarly, casepatients were less likely to drink alcohol, withonlyabout 20%consumingalcoholduring pregnancy. About 65% ofcase patients and 48% of the controlgroup neither drank alcohol norsmoked.

The case and control groups were

comparableintheir history of heartdisease, renal disease, and urinary tract

Table2Sociodemographic Characteristics of PreeclampticCases and Controls

Characteristic

Cases Controls

No. No.Crude Odds

Ratio

95%Confidence

Interval

Age, y

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infection. Casepatients were over fivetimes (albeit nonsignificantly) morelikely than control patients to have ahistory of seizures prior to pregnancy(OR,5.6;95%CI,0.6to 49.1).However,none of the 11 women diagnosed aseclamptichad a previoushistoryofseizures. Preeclampsia in a previouspregnancyproduced a sixfoldincreased risk.Two control patients and one case patient had gestational diabetes duringthe

present pregnancy.For the most part, case patients didnot differfrom controlpatientsin theirfamily medical history; approximatelyequal proportions of cases as controlshad a positivefamilyhistoryfor diabetes, renal disease, heart disease, andseizures. Onenoteworthy exception isthat more case patients than controlpatients hadfamily memberswith a historyof chronichypertension(OR,1.7).

MultivariateAnalysisVariables (ascategorizedin Tables 2

and3)

entered intothe

multiple regressionmodels includedrace,employmentstatus, maternal age, parity, prepregnancy body mass as measured by theQueteletindex (weight/height2),weightgain in the first 20 weeks ofgestation,smokingduringpregnancy, alcohol consumption during pregnancy, history oftoxemiain a previouspregnancy,familyhistory ofhypertension, year of delivery(1984 or 1985), maritalstatus, weekof gestation at first visit,history of therapeuticabortion, andhistoryofspontaneous abortion. Because of missingdata,the multivariate models containeda sample of235 women (115 cases and120controls).

As shown in Table 4, being nullipa-rous (OR,5.4), working(OR,2.1), having a family history of hypertension(OR, 1.7), and having high prepregnancy body mass (OR, 2.7) were morecommon in cases than in controls. Lowbody mass wasforcedintothismodeltoillustrate the dose-response relationshipof case status with increasedbodymass;low body massisassociated with aslightlyreducedrisk, although notsignificantly, for preeclampsia(OR, 0.43).

Smoking tended to have a protectiveeffect (OR, 0.45). The interaction ofbody mass andsmokingprovednonsignificant. Also, among women who hadbeen pregnant before, a diagnosis ofpreeclampsia in a previous pregnancygreatly increased the risk for being acase patient(OR, 10.8).

Only two risk factors were found tooperate differently in nulliparous andmultiparous women (Table 5). Amongnulliparas but not multparas, beingblackposed asubstantial increasedrisk(OR, 12.3), and amongmultparas but

not nulliparas, having had a previousspontaneous abortion was highly pro-

Table4Multivariate LogisticRegression Model for PredictingCase-Control Status(n = 235)*

Adjusted 95%ConfidenceVariable Odds Ratio Intervalf

Nulliparous(1) vs Multiparous(0)_5J4_2.8-10.3Black (1)vsNonblack(0)_2j>_0.97-6.4Body mass

Low body mass (1) vs Medium(0)_043_0.13-1.4Highbody mass (1) vs Medium(0)_2/7_1.2-6.2

Smoked (1)vs Not(0)_045_0.18-1.1Worked during pregnancy(1) vs Unemployed(0) 2.1 1.1-4.4

Familyhistory of hypertension (1 ) vs None (0) 1.7 0.92-3.2

Historyof

spontaneousabortion

(1)vs No

history 0.31 0.13-0.74

History of preeclampsia(1) vs No history (0) 10.8 1.2-29.1

*Twin pregnancies were excluded from model; because all twins occurred in the case group, there was limiteddispersion whentwin pregnancy was included.

fAII variables listedme tthe P

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duringpregnancy. AstudybyMarcouxetal31foundthat increased leisure-timeactivity(ofwhichworking women presumably have less) protected againstpreeclampsia. Women who work maybe morestressedandhavedifferentlevelsof physicalactivity than nonworkingwomen; however, furtherinvestigationisneededtodeterminethe exact parametersof work that mightincreaserisk.

Cigarettesmoking tended toprotect

againstpreeclampsiain this investigation. We also foundthat, on univariateanalyses, alcoholconsumption was protective. The apparentprotective effectof alcoholmaybe associatedwithsmok

ing since it was not found to besignificantinthemultivariatemodels. In studies of nonpregnant adults, cigarettesmokersand light drinkers, particularlywomen, have been found tohave lowerbloodpressures than abstainers.32,38Although tobaccoand alcohol consumptionmaytend to protectagainstpreeclampsia,the well-knownrisk of bothof these

agentstothe fetus

outweighsthe

slightbenefit. Moreover, Duffus and MacGil-livray34 found that the perinatal deathrate due to preeclampsia was higheramong infants of smokers than ofnonsmokers.

Wedid not demonstrate that age, either old or young, is a risk factor forpreeclampsia. Theslight increasedriskof women under 21 years old observedon univariate analyses disappearedwhen parity wascontrolledfor, asChes-ley suggested.The increased risk at older age was not evident in this sample,perhapsbecause women withessential

hypertension were excluded. In addition, Lehmann16 did not show a clearincrease in the incidence ofpreeclampsia untilafter womenreachedthe age of45years. Wedid nothaveanypatientsabove 41yearsof age.

Having a previoushistoryof spontaneous abortion protected against preeclampsiainmultiparous women. However, it does not appear that anyprevious pregnancy provides protection, inthat having a previous therapeuticabortion did not protect against preeclampsia. MacGillivray23 suggestedthatpreviouspregnancy,especially onethat ended later ingestation, providedprotection against preeclampsia. In arecentstudyof Kaiserpatients,clinically recognizedspontaneousabortions oc curred later in gestation, on average,thantherapeuticabortions.36

Except for being black andhaving ahistoryof spontaneousabortion,the regression modelspredicting risk of preeclampsia wereidenticalfornulliparousandmultiparous women. The differential risk of these variables in the twogroups maybe related tothe stringent

criteria w e used todefinepreeclampticcases and controls. Forexample, when

we applied the finalmultivariate modelto the original sample of women whoreceived a dischargediagnosisof severepreeclampsia o r eclampsia(n = 263)andtherandomsampleof controls(n = 260),wefound that being black posed a significantincreased riskin bothnulliparousand multiparous women. Similarly,spontaneousabortion was significantlyprotectiveinbothnulliparous and multiparous women. Thisfindingsuggests

that a

history of spontaneous abortionmay beprotectiveandbeingblack maybe ariskin bothnulliparous and multiparous womenwithless severeforms of

preeclampsia than that used to defineinclusionin thisstudy.

The usefulness of low-dose aspirintherapy and otherpreventive measuresdependson the clinician's ability toidentify women who are at high risk forpreeclampsiaearly in their pregnancy.Therefore, we included in our logisticmodelonly thosepotential riskfactorsthatcouldbeknownbythe 20thweekof

gestation.These risk factors should be

examined in a cohortstudy to determinethemodel'sability topredictwho develops preeclampsia. Risk factors differsomewhat for nulliparas and multparas; therefore, future investigationsshould includemultparas in studies ofpreeclampsia but examine their risksseparatelyfromthoseof primparas.

The research was funded by a grant from theKaiserFoundationResearchInstitute.

We gratefully acknowledge theassistanceof Betty Wong and William Frank in abstracting andcoding the data. We also acknowledge LindaGrand, MPH, Marianne Sadler, MPH, Paul En

glish, MPH, Irene

Tekawa, MPH, and Robert

Sholtz, MPH, forstatistical consultation and analysesand RobertHosang, MD, MPH, Gary Stewart, MD, Irva Hertz-Picciotto, PhD, BarbaraAbrams, DrPH, and JamesRoberts,MD, for theirreview ofand comments on the research. We alsothankDebraPatterson for hereditorial comments.

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