Expectant management of mild preeclampsia versus superimposed preeclampsia up to 37 weeks

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OBSTETRICS

Expectant management of mild preeclampsiaversus superimposed preeclampsia up to37 weeksAmy M. Valent, DO; Emily A. DeFranco, DO, MS; Allessa Allison, MD; Ahmed Salem, MD;Lori Klarquist, DO; Kyle Gonzales, DO; Mounira Habli, MD; C. David Adair, MD;Casey Armistead, RN; Yuping Wang, MD, PhD; David Lewis, MD, MBA; Baha Sibai, MD

OBJECTIVE: We sought to compare maternal and neonatal outcomes RESULTS: We found no significant differences in rates of neonatal
of expectantly managed pregnancies complicated by chronic hyper-tension with superimposed preeclampsia vs mild preeclampsia up to37 weeks of gestation.
STUDY DESIGN: This was a multicenter retrospective cohort studyof all pregnancies complicated by chronic hypertension withsuperimposed preeclampsia or mild preeclampsia expectantlymanaged in the hospital from January 2008 through December2011. The primary outcomes, adverse maternal and neonatalcomposite morbidities, were compared between these 2 groups.Frequency differences of maternal adverse outcomes were strati-fied by gestational age at delivery of <34 and 34-366/7 weeks ofgestation.

From the Division of Maternal-Fetal Medicine, Department of Obstetrics andDeFranco); Center for Prevention of PretermBirth, Perinatal Institute, Cincinnaof Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, GooDivision of Maternal-Fetal Medicine, Department of Obstetrics and GynecologAL (Drs Allison and Lewis and Ms Armistead); Division of Maternal-Fetal MedCollege of Medicine, Chattanooga, TN (Drs Gonzales and Adair); DepartmentCenter, Shreveport, LA (Dr Wang); and Division of Maternal-Fetal Medicine, DUniversity of Texas, Houston, TX (Dr Sibai).

Received June 3, 2014; revised Sept. 13, 2014; accepted Oct. 28, 2014.

The authors report no conflict of interest.

Presented in poster format at the 79th annual meeting of the Central Associ

Corresponding author: Amy M. Valent, DO. [email protected]

0002-9378/$36.00 � ª 2014 Elsevier Inc. All rights reserved. � http://dx.doi.org/10.1

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composite morbidity or latency periods between women with super-imposed preeclampsia and mild preeclampsia. Adverse neonataloutcomes were significantly higher at <34 compared to 34-366/7

weeks of gestation (97-98% vs 48-50%) in both cohorts. Maternaladverse composite outcome occurred more frequently in women withsuperimposed preeclampsia compared to mild preeclampsia (15% vs5%, P¼ .003; relative risk, 3.0; 95% confidence interval, 1.45e6.29).

CONCLUSION:Women with superimposed preeclampsia have similarneonatal outcomes but more maternal complications than womenwith preeclampsia without severe features who are expectantlymanaged <37 weeks.

Key words: expectant management, hypertension, preeclampsia

Cite this article as: Valent AM, DeFranco EA, Allison A, et al. Expectant management of mild preeclampsia versus superimposed preeclampsia up to 37 weeks. Am JObstet Gynecol 2014;212:x.ex-x.ex.

ypertensive disorders are among
H the most common pregnancycomplications. Preeclampsia compli-cates 3-7% of all pregnancies with a 4-5times higher incidence in the presence ofchronic hypertension.1-4 These condi-tions markedly increase the risk of bothmaternal and neonatal morbidity andmortality.1,5
Expectant management with closematernal and fetal surveillance and

planned delivery at 37 weeks of gestationis recommended for patients with mildpreeclampsia in the absence of otherdelivery indications.6-8 The recentAmerican Congress of Obstetriciansand Gynecologists (ACOG) Task Forceon Hypertension in Pregnancy statesthat preterm preeclampsia without se-vere features may be followed expec-tantly with inpatient or outpatientmanagement.7 However, many expert

Gynecology, University ofti Children’s Hospital Medid Samaritan Hospital (Drsy, University of South Alaicine, Department of Obsof Obstetrics and Gynecoepartment of Obstetrics

ation of Obstetricians and

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authorities recommend hospitalizationwith a diagnosis of preeclampsia as sig-nificant morbidity and mortality areincreased even without progression tosevere disease.

The broad disease spectrum, espe-cially in the setting of concomitant organinsult, and the challenge of diagnosingpreeclampsia in the presence of chronichypertension has led to a paucity ofquality studies regarding optimal

Cincinnati School of Medicine (Drs Valent andcal Center (Drs DeFranco andHabli); andDivisionSalem, Klarquist, and Habli), Cincinnati, OH;bama Children’s and Women’s Hospital, Mobile,tetrics and Gynecology, University of Tennesseelogy, Louisiana State University Health Sciencesand Gynecology, University of Texas Health,

Gynecologists, Chicago, IL, Oct. 17-20, 2012.

erican Journal of Obstetrics & Gynecology 1.e1:15 pm � ce

mailto:[email protected]

http://dx.doi.org/10.1016/j.ajog.2014.10.1090

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management. The ACOG PracticeBulletin, addressing chronic hyperten-sion in pregnancy, recommends deliveryat 34 weeks of gestation for patients withsuperimposed preeclampsia.9 Manage-ment and delivery timing in this patientpopulation is based on indirect con-clusions from severe preeclampsiastudies.10-12 Patient surveillance andexpectant management of severe pre-eclampsia and chronic hypertensionwith superimposed preeclampsia attertiary care institutions are similarlyassociated with prolonged pregnancy,decreased neonatal intensive care unitstays, and respiratory distress syndrome(RDS) without significant maternalcompromise<34 weeks.10,11,13 Evidencesupporting that delivery at 34 weeks ofgestation is superior to expectant man-agement until 37 weeks of gestationfor superimposed preeclampsia withoutsevere disease is lacking.7

Despite the inconsistent recommen-dations regarding the optimal deliverytiming for superimposed preeclampsiadiagnosed in the preterm periodcompared to mild preeclampsia, sur-prisingly few studies have compared thematernal and fetal outcomes of these 2conditions.13,14 Women with chronichypertension even without subsequentsuperimposed preeclampsia have in-creased adverse perinatal outcomesincluding but not limited to gestationaldiabetes, fetal growth restriction, cesar-ean delivery, and worsening hyperten-sion.1,3,15 Preeclampsia is a risk factor forlong-term cardiovascular conditions andit is biologically plausible that super-imposed preeclampsia represents furthercardiovascular disease and endothelialdysfunction progression, which placeswomen at higher risk of adverse out-comes.16 Although there are promisingstudies using imaging and biomarkers topredict preeclampsia and potential dis-ease progression, we still do not fullyunderstand the natural disease processor etiology of preeclampsia, especiallysuperimposed preeclampsia.17,18

The purpose of this study is tocompare the rates of adverse maternaland neonatal outcomes in patientswith mild preeclampsia and superim-posed preeclampsia who are managed

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expectantly in the hospital<37 weeks ofgestation. Secondary goal of this study isto analyze outcomes of pregnancies thatare stratified between 34-366/7 vs <34weeks of gestation to gain a betterunderstanding of the natural history ofthese 2 disease processes. We hypothe-size that in the hospital setting with closemonitoring, patients with superimposedpreeclampsia can bemanaged safely withsimilar perinatal risks as patients withmild preeclampsia without a hyperten-sive history.

MATERIALS AND METHODS

This was a multicenter retrospectivecohort study including 4 tertiary careteaching hospitals. All patients admittedto the University of Cincinnati MedicalCenter; University of South AlabamaChildren’s and Women’s Hospital; GoodSamaritan Hospital, Cincinnati; andUniversity of Tennessee College ofMedicine, Chattanooga, from January2008 through December 2011 with adiagnosis of mild preeclampsia orchronic hypertension with super-imposed preeclampsia were evaluatedfor inclusion in this study. The studyperiod was prior to the ACOG TaskForce on Hypertension in Pregnancyrecommendations for the change interminology from “mild preeclampsia”to “preeclampsia” and to distinguishsuperimposed preeclampsia with andwithout severe features.7

This study was approved by the insti-tutional review board at the Universityof Cincinnati, Cincinnati, OH (#12-03-02-01) and individual institutionalreview board approval was obtained atall participating centers. InternationalClassification of Diseases, Ninth Revisioncodes and/or antepartum and unitrecording systems were used to identifyall maternal and associated neonatalcharts with the diagnosis of preeclamp-sia, chronic hypertension, superimposedpreeclampsia, and/or preterm birth.Coinvestigators at the individual in-stitutions reviewed all potentially eligiblecharts, and collected data regardingmaternal demographic characteristics,gestational age at diagnosis and delivery,latency period, mode of delivery, in-dications for delivery, and maternal and

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neonatal outcomes. Inclusion criteriacomprised all singleton pregnancies be-tween 240/7 and 366/7 weeks of gestationwith the diagnosis of mild preeclampsiaand chronic hypertension with super-imposed preeclampsia that weremanaged expectantly in the hospital.Exclusion criteria were the diagnosis ofsevere preeclampsia >340/7 weeks ofgestation at the time of admission, pre-eclampsia requiring delivery immedi-ately after corticosteroids or maternalstabilization, preterm labor or prelaborrupture of membranes on admission,major medical comorbidities not in-cluding chronic hypertension, multifetalgestation, congenital anomalies, or othermaternal or fetal contraindications toexpectant management.

The primary outcomes of the studywere composites of maternal andneonatal adverse morbidities. Thematernal composite was defined as�1 ofthe following: pulmonary edema,placental abruption, oliguria, andeclampsia. The composite of neonatalmorbidities included �1 of thefollowing: RDS, intraventricular hem-orrhage, necrotizing enterocolitis,bronchopulmonary dysplasia, 5-minuteApgar score of <7, and neonatal death.Secondary outcome was the latencyduration from day of admission todelivery. Other maternal morbidities ofinterest included progression to severepreeclampsia, HELLP (hemolysis, ele-vated liver enzymes, and low plateletcount) syndrome, abnormal liver en-zymes, thrombocytopenia, and maternaldeath. Additional neonatal complica-tions studied comprised admission tothe neonatal intensive care unit andsuspected neonatal sepsis. Suspectedneonatal sepsis was defined as a neonatereceiving antibiotics during a sepsisevaluation regardless of the cultureresult. All neonatal complications werediagnosed by a board-certified neona-tologist. The collected cohort consistedof minimal missing information forprimary outcomes of interest, exposurevariables, and covariates (<5%).

Patients included in this study werecategorized into 2 groups based on thepresence or absence of chronic hyper-tension. Hypertension was defined as

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systolic blood pressure �140 mm Hg ordiastolic blood pressure �90 mm Hg on2 different occasions >4-6 hours apartor persistent, elevated pressures re-quiring antihypertensive therapy.Chronic hypertension was defined as theuse of antihypertensive medicationsprior to conception, diagnosis of hyper-tension <20 weeks’ gestation, or thepresence of hypertension for >12 weekspostpartum in a previous pregnancy.Superimposed preeclampsia was definedas women with chronic hypertensionwho subsequently developed preec-lampsia with an acute exacerbation ofpreexisting hypertension in additionto either new-onset proteinuria definedby �0.3 g of total urinary proteinexcretion over a 24-hour period or asubstantial increase in baseline protein-uria if present early in pregnancy. Mildpreeclampsia was defined as hyper-tension >20 weeks’ gestation with thepresence of proteinuria.

Upon admission, the patient wasevaluated to ensure she did not meetcriteria for severe preeclampsia. Fetalviability was confirmed, baseline labo-ratory values (including but not limitedto liver enzyme tests, renal panel, uri-nalysis for protein evaluation, andcomplete blood cell count) and a 24-hour urine collection for total proteinexcretion were subsequently completedin the hospital. Serial ultrasound biom-etry every 3-4 weeks was performed toassess fetal growth. Antenatal surveil-lance with nonstress test, biophysicalprofile, Doppler studies, fetal kickcounts, or a combination of these mo-dalities was used to determine fetal well-being. Laboratory assessments andcareful maternal clinical evaluations ofvital signs, urine output, symptoms, orsigns of disease progression wereroutinely performed. Patients admittedat <34 weeks of gestation receivedantenatal corticosteroids for fetal lungmaturity. Women without evidence ofadvancing, severe disease received oralantihypertensive medications for man-agement of severe range blood pressures(systolic �160 mm Hg and/or diastolic�110 mm Hg).

For womenwith mild preeclampsia orsuperimposed preeclampsia, expectant

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management was continued unless fetalor maternal indications required imme-diate intervention. Isolated fetal growthrestriction and isolated proteinuria >5g/d without the presence of other severesigns or symptoms were not indicationsfor delivery at the study institutions. Theprogression of severe disease �34 weeksof gestation was an indication fordelivery for all patients. Fetal reasons fordelivery included nonreassuring fetalheart tracing or abnormal fetal testing,which involved fetal growth restrictionwith persistent oligohydramnios, um-bilical artery Doppler velocimetry withreversed end-diastolic flow, or non-reassuring biophysical profile score.Maternal indications for deliveryincluded the development of renalinsufficiency, eclampsia, placental ab-ruption, pulmonary edema, persistentgastrointestinal or neurologic symp-toms, uncontrollable hypertension withintravenous and/or orally titrated anti-hypertensive therapy, or laboratoryvalues suggesting thrombocytopenia(<100,000/mL) or HELLP syndrome(hemolysis, elevated liver enzymes [2times the normal transaminase concen-trations], and low platelet).The criteria for severe preeclampsia

included the presence of �1 of thefollowing: 2 systolic blood pressures�160 mm Hg or diastolic blood pres-sures �110 mm Hg >4-6 hours apartafter administration of intravenousantihypertensive therapy, oliguria (<500mL or <0.5 mL/kg/h over 24 hours),cyanosis, thrombocytopenia, elevatedliver enzymes, pulmonary edema,eclampsia, or worsening/persistent gas-trointestinal or neurologic symptoms(ie, headache, epigastric pain, visualdisturbances, altered mental status). Thedevelopment of HELLP syndrome wasdefined by evidence of hemolysis on aperipheral blood smear, elevated lactatedehydrogenase per institutional labora-tory standards, decreased platelets, andelevated liver enzyme tests.The frequency of maternal and

neonatal adverse composite outcomeswere compared between pregnanciescomplicated by mild preeclampsia andsuperimposed preeclampsia. Both com-posite outcomes and integrated variables

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were compared after stratification bygestational age into pregnancies thatdelivered <34 and between 34-366/7

weeks of gestation. Estimated gestationalage was determined with a combinationof last menstrual period, ultrasoundimaging, and clinical assessment, whichis commonly accepted in general prac-tice. Gestational weeks >366/7 were notincluded in the data analysis becauseexpectant management of preeclampsiais not the advocated approach due to theprogressive risk for adverse perinataloutcomes.7,8

Statistical analysis was performed us-ing StatView (SAS Institute Inc, Cary,NC) and GraphPad Prism, version 5.00for Windows (GraphPad Software, SanDiego, CA). Demographic characteris-tics were compared using Student t testfor continuous variables and c2 or Fisherexact test for categorical variables.Comparisons with a P value < .05 or95% confidence interval (CI) withoutinclusion of the null were consideredstatistically significant.

RESULTS

Over the 3-year study period, 357 pa-tients met inclusion criteria for thisstudy; 171 pregnancies complicated bychronic hypertension with super-imposed preeclampsia and 186 womenwith mild preeclampsia. University ofSouth Alabama Children’s and Women’sHospital contributed 109 mother-infantpairs; the University of CincinnatiMedical Center contributed 100 pairs;Good Samaritan Hospital contributed95 pairs; and University of TennesseeCollege of Medicine, Chattanooga, pro-vided 53 mother-infant outcome data.The demographic characteristics of the2 groups are presented in Table 1. Pa-tients with chronic hypertension withsuperimposed preeclampsia were older,more commonly multiparous, andblack. Higher rates of oral antihyper-tensive therapy during pregnancy andpostpartum period were observedamong women with superimposed pre-eclampsia compared to women withouta history of chronic hypertension.Although patients with superimposedpreeclampsia were diagnosed and deliv-ered at an earlier gestational age than


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TABLE 1Maternal characteristics

CharacteristicSuperimposepreeclampsia, n [ 171

Preeclampsia,n [ 186 P value

Age, y 30 � 6 26 � 6 < .001

Race and ethnicity

Caucasian 83 (49) 114 (61) .02

Black 85 (50) 68 (39) .01

Other 3 (2) 4 (2) 1.0

Primigravida 64 (32) 115 (62) < .001

Mode of delivery

Vaginal 35 (21) 72 (38) < .001

Repeat cesarean 51 (30) 26 (14) < .001

Primary cesarean 85 (50) 88 (47) .73

Oral antenatal antihypertensivemedications

128 (75) 15 (1) < .001

Regimen with �1 medication 43 (25) 0 (0) < .001

Continuous variable are presented as mean � SD. Dichotomous variables are presented as number (percent).

Valent. Expectant management of preeclampsia. Am J Obstet Gynecol 2014.


women diagnosed with mild pre-eclampsia, primary cesarean deliveryrates were not significantly differentbetween the 2 groups.

The Figure demonstrates the mostcommon indications for delivery amongthis cohort. Women with superimposedpreeclampsia were more likely to bedelivered for uncontrollable, elevatedblood pressures (57% vs 39%, P< .001),and pregnancies complicated by mildpreeclampsia were delivered more com-monly for the development of persistentneurologic or gastrointestinal symptoms(20% vs 6%, P < .001).

Although patients with mild pre-eclampsia had significantly shorter hos-pitalization stays compared to womenwith superimposed preeclampsia, nodifference in the latency periods betweendiagnosis and delivery among the 2groups were appreciated, even afterstratification at<34 or 34-366/7 weeks ofgestation (Tables 1 and 2). Pulmonaryedema was more frequently observed inpregnancies with superimposed pre-eclampsia, particularly deliveries <34weeks of gestation. Maternal adversecomposite outcome occurred morefrequently in womenwith superimposedpreeclampsia (15%) compared to those


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with preeclampsia (5%) (relative risk[RR], 3.0; 95% CI, 1.45e6.29). The rateof adverse maternal outcome wassignificantly higher in women withsuperimposed preeclampsia delivered atlater preterm gestational ages between34-366/7 weeks (RR, 4.0; 95% CI,1.13e14.39), as compared to<34 weeksof gestation (RR, 2.3; 95% CI,0.95e5.64; Table 3).Prior to stratification into 2 preterm

gestational age categories, small forgestational age (26% vs 16%, P ¼ .02)and low birthweight (1941� 790 vs 2161� 834 g, P < .001) were more frequentamong neonates born to mothers withsuperimposed preeclampsia, but nosignificant difference in the frequencyof critical neonatal complications suchas necrotizing enterocolitis, RDS,neonatal mortality, or intraventricularhemorrhage was appreciated betweenthe 2 groups. Table 4 presents differencesin neonatal outcomes between the 2groups stratified by gestational age atdelivery. Aside from a 5-minute Apgarscore <7, no significant differences inestimated gestational age at deliveryor neonatal outcomes were detectedbetween women with preeclampsiaand superimposed preeclampsia when

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stratified between<34 or 34-366/7 weeksof gestation. However, compared to34-366/7 weeks, both cohorts delivering<34 weeks of gestation had higher ratesof adverse neonatal compositemorbidityand mortality.

A total of 8 perinatal losses occurred inthe study cohort with all deliveries <34weeks of gestation. There were 2 cases ofstillbirth in the 24th week of pregnancy,both complicated by intrauterine growthrestriction with estimated fetal weightsof <300 g in the superimposed pre-eclampsia cohort. Five neonatal deathswere among extremely preterm births at<26 weeks of gestation in both studygroups.

COMMENT

This study is one of the first and largestto compare the maternal and neonataloutcomes following expectant man-agement of pregnancies with mildpreeclampsia and superimposed pre-eclampsia up to 37 weeks of gestation.Our multicenter, observational studydemonstrates that expectant, inpatientmanagement of these 2 diseases result insimilar neonatal outcomes. Without thepresence of severe disease at the time ofadmission, they have comparable meanlatency periods from diagnosis to de-livery irrespective of the gestational ageat diagnosis.

We found that women with super-imposed preeclampsia were morecommonly black, older, multiparous,and required oral antihypertensivetherapy, which is consistent with previ-ous studies.19 This higher frequency ofantihypertensive treatment may beindicative of ongoing chronic treatmentof their underlying disorder rather thana marker of progressive, severe diseaseduring pregnancy. Antihypertensivetherapy has not been shown to improverates of preterm birth or progression tosuperimposed preeclampsia but is rec-ommended to reduce the risk of severehypertension, worsening end-organdamage, and maternal complicationsincluding cerebral hemorrhage andinfarction.12,20,21 Physicians are aware ofthe increased perinatal risks amongchronic hypertensive women, likelyresulting in a lower threshold for

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web4C=FPO

FIGUREIndications for delivery

Bar graph representing common indications for delivery in pregnancies complicated by super-

imposed preeclampsia (blue) and preeclampsia (green) expectantly managed in hospital setting. The

frequencies do not add up to the 100% due to missing or other indications for delivery.

LFT, liver function testing; HELLP, hemolysis, elevated liver enzymes, and low platelet count; NR-ANFS, nonreassuring antenatal fetalsurveillance.

*Persistent neurological or gastrointestinal symptoms.



conservative inpatient supervision,aggressive blood pressure management,and longer hospitalizations. Hyperten-sive exacerbations and undiagnosed

TABLE 2Maternal outcomes

Outcome variableSuperimposedpreeclampsia, n

EGA at diagnosis, wk 314/7 � 33/7

Latency, d 10 � 135 [2e11]

Days in hospital 13 � 129 [6e16]

Severe preeclampsia 149 (87)

Pulmonary edema 7 (4)

Placental abruption 11 (6)

Thrombocytopenia 8 (5)

Elevated liver enzymes 24 (14)

Oliguria 7 (4)

HELLP 2 (1)

Eclampsia 1 (1)

Maternal compositea 25 (15)

Continuous variable are presented as mean � SD or median [innumber (percent).

EGA, estimated gestational age; HELLP, hemolysis, elevated live

a Morbidity defined as �1 of the following: pulmonary edema, p

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microvascular disease can complicate theclinical picture, diagnosis, and manage-ment strategies. However, our studyshows that with careful inpatient

[ 171Preeclampsia,n [ 186 P value

324/7 � 31/7 .004

8 � 85 [3e10]

.12

10 � 78 [6e11]

< .001

157 (84) .56

0 (0) .01

5 (3) .18

12 (6) .62

29 (16) .79

5 (3) .66

7 (4) .22

1 (1) 1.0

9 (5) .003

terquartile range]. Dichotomous variables are presented as

r enzymes, and low platelet count.

lacental abruption, eclampsia, oliguria.

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management, women with super-imposed preeclampsia can continuepregnancy >34 weeks of gestation withtitrating doses of antihypertensives aslong as the blood pressure responds tothese increases.

Women in both groups were foundto have high rates of neonatal mor-tality and respiratory morbidities,especially deliveries <34 weeks ofgestation. Hypertensive disorders maycontribute to impaired fetal growthand increase the risk for birth ofsmall-for-gestational-age infants.22,23

Consistent with previously publishedstudies, we found that women withsuperimposed preeclampsia had higherrates of small for gestational age andoverall lower average birthweights thanpatients with mild preeclampsia, butno difference was observed whenstratified by gestational age at de-livery.3,9,24 This could be explained inpart by the increased use of oral anti-hypertensive maintenance therapy insuperimposed preeclamptic patients,which is known to reduce mean arte-rial pressure and is associated withsmall for gestational age independentof duration of therapy.25

Given the minimal observed differ-ence in frequency of these adverseneonatal outcomes with a probabilityvalue >5%, we conclude that no signif-icant difference in neonatal outcomesoccurs following births to superimposedpreeclampsia and mild preeclampsiapregnancies managed expectantly in thelate preterm period. Similarly, the like-lihood of an adverse neonatal outcomefor births<34 weeks of gestation did notdiffer between the 2 cohorts but thefrequency of adverse neonatal morbiditywas significantly higher (94-97%) thanthose managed and delivered between34-366/7 weeks of gestation. We didobserve a higher frequency of RDS inlate preterm infants than is commonlyreported in prospectively performedstudies.26 This may be related tomisclassification of some cases of oxygenrequirement or respiratory complica-tions as RDS that may not have not havemet strict criteria for RDS if defined assuch prospectively. Despite this, it isunlikely that RDS cases were


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TABLE 3Maternal outcomes stratified by preterm gestational age groups

Outcome variable

<340/7 wks of gestation 34-366/7 wks of gestation

Superimposedpreeclampsia, n [ 92




EGA at diagnosis, wk 292/7 � 25/7 301/7 � 25/7 .08 336/7 � 24/7 344/7 � 16/7 .22

Latency, d 8.6 � 11.1 6.2 � 4.1 .06 11.7 � 15.6 8.5 � 9.6 .09

Days in hospital 12.2 � 9.1 9.6 � 3.7 .02 14.6 � 14.2 9.1 � 7.7 < .001

Severe preeclampsia 80 (87) 67 (77) .70 69 (87) 90 (85) .80

Pulmonary edema 6 (7) 0 (0) .02 1 (1) 0 (0) .85

Placental abruption 6 (7) 4 (5) .93 5 (6) 1 (1) .10

Thrombocytopenia 6 (7) 6 (7) 1.0 2(3) 6 (6) .51

Elevated liver enzymes 12 (13) 10 (12) 1.0 12 (15) 19 (18) .77

Oliguria 4 (4) 2 (2) .82 3 (4) 3 (3) 1.0

HELLP 1 (1) 5 (6) .15 1 (1) 2 (2) 1.0

Eclampsia 1 (1) 1 (1) 1.0 0 (0) 0 (0) 1.0

Maternal compositea 16 (17) 6 (8) .08 9 (11) 3 (2) .04


EGA, estimated gestational age; HELLP, hemolysis, elevated liver enzymes, and low platelet count.

a Morbidity defined as �1 of the following: pulmonary edema, placental abruption, eclampsia, oliguria.



differentially misclassified between thesuperimposed preeclampsia and mildpreeclampsia groups.

The majority of pregnancies in thisstudy complicated by superimposedpreeclampsia and mild preeclampsiadeveloped severe preeclampsia. Com-pared to previous severe preeclampsiastudies and acknowledging variancein sample sizes, similar rates of HELLPand placental abruption were observedin this study.11,13 Tuuli et al19 retrospec-tively studied the same pregnancy pop-ulations but observed lower rates ofplacental abruption. However, theirstudy included patients over an 18 yearperiod and disease management haschanged progressively during this time.

Although a higher frequency of overallcomposite maternal morbidity wasobserved in women with superimposedpreeclampsia, the statistical differencesin the overall composite morbidity be-tween 34-366/7 weeks of gestation weredriven by increased rates of placentalabruption without a significant differ-ence in neonatal outcome compared topregnancies with mild preeclampsia.Expectant management >34 weeks of


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gestation did not increase the risk ofserious maternal complications such asHELLP, eclampsia, or pulmonaryedema.Higher rates of pulmonary edema

were observed among women withsuperimposed preeclampsia but all ofthe events occurred <34 weeks and notin later gestational ages. Severe hyper-tension was a more frequent deliveryindication for women with super-imposed preeclampsia compared toworsening neurologic or gastrointes-tinal symptoms in those women withmild preeclampsia. An acute hyperten-sive crisis commonly precipitates pul-monary edema causing significantvasoconstriction, increased afterload,and redistribution of fluid centrally intopulmonary circulation, placing allwomen with preeclampsia at increasedrisk.27,28 Alternatively, these womenmay represent advanced endothelialdysfunction predisposing them todisease progression or insufficientmaternal immunologic response ortolerance at an early gestation.The latency duration found in this

study is consistent with previously

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published studies reporting an averageduration between 8.4-9.7 days inpregnancies complicated by super-imposed preeclampsia.13,14 However,prior studies followed managementrecommendations suggested for severepreeclampsia in women diagnosed withsuperimposed preeclampsia, deliveringat 34 weeks of gestation even in theabsence of signs or symptoms of severedisease. The practice of planned earlydelivery at 34 weeks for women withsuperimposed preeclampsia in the pre-viously reported studies may haveinfluenced the reported outcomes,possibly demonstrating shorter latencyperiods and more adverse neonatal out-comes related to prematurity.

Expectant management in the pre-term period and delivery at 37 weeks,unless earlier delivery was indicated dueto the development of signs or symp-toms of severe disease, is consistent withthe most recent recommendations fromthe ACOG Task Force on Hypertensionin Pregnancy.7 This study was performedprior to the institution of the task forceguidelines for management. However,removal of 5 g of proteinuria and fetal

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TABLE 4Neonatal outcomes

Outcome variable

<340/7 wks of gestation 34-366/7 wks of gestation





EGA at delivery 304/7 � 24/7 310/7 � 24/7 .18 355/7 � 10/7 356/7 � 10/7 .17

Days in hospital 34.4 � 28.2 39.8 � 32.3 .25 6.0 � 4.6 7.3 � 9.0 .24

NICU admission 86 (93) 71 (89) .41 35 (44) 49 (46) .91

5-min Apgar �7 15 (16) 16 (20) .67 16 (20) 7 (7) .01

Birthweight, g 1450 � 628 1446 � 628 .96 2576 � 579 2621 � 596 .61

SGA 28 (30) 15 (19) .11 17 (22) 14 (13) .20

RDS 33 (36) 21 (26) .23 14 (18) 19 (18) 1.0

BPD 7 (8) 6 (8) 1.0 1 (1) 2 (2) 1.0

NEC 7 (8) 4 (5) .71 0 (0) 1 (1) 1.0

Suspected sepsisa 13 (14) 13 (16) .86 14 (18) 20 (19) 1.0

IVH 9 (10) 7 (9) 1.0 1 (1) 3 (3) .87

Death 6 (7) 2 (3) .38 0 (0) 0 (0) 1.0

Neonatal compositeb 89 (97) 75 (94) .57 38 (48) 53 (50) .92


BPD, bronchopulmonary dysplasia; EGA, estimated gestational age; IVH, intraventricular hemorrhage of any grade; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; RDS, respiratorydistress syndrome; SGA, small for gestational age.

a Neonate received antibiotics; b Morbidity defined as �1 of the following: NICU admission, Apgar score �7 at 5 min, RDS, BPD, NEC, IVH, and death (fetal or neonatal).



growth restriction as indications for de-livery in the new recommendationswould not have changed the outcomes ofthis study as they were not direct in-dications for delivery at any participatingcenter. Although the old criteria hadoliguria as a sign of severe disease, thefrequencies of oliguria were not statisti-cally significant between the 2 groupsand would not have changed the rate ofadverse maternal outcome in our study.

A major strength of this study is thelarge number of patients managed at 4tertiary level centers, representing widenational demographic regions and pop-ulations; therefore, we believe our find-ings are widely generalizable. This studyaddresses an issue that is not well studiedand important in perinatal management.We specifically excluded patients fromthis study with other serious diseasecomorbidities such as renal disease, sys-temic lupus erythematosus, and otherend-organ dysfunction. Likely throughdifferent disease processes, womenwith these disease states have risks for

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worse perinatal outcomes regardless ofinclusion in either group and would notrepresent the risks and outcomes spe-cifically of these hypertensive diseasesfocused in this study.This study faces the inherent weak-

nesses of any observational study.Relying on International Classification ofDiseases, Ninth Revision codes for hy-pertensive diseases and preterm birth,not all patients who meet inclusioncriteria may have been identified at allparticipating centers. The maternal-fetalmedicine specialists at each institutionmay have variations in management andpracticing styles despite all centersconsistently managing both patient co-horts expectantly until 37 weeks ofgestation during the study period.Exclusion of other comorbidities, espe-cially pregestational diabetes, maysomewhat limit the generalizability ofour findings to all patient populationspresenting with chronic hypertensionand preeclampsia; however, we believethese patients represent a unique

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high-risk population who warrant indi-vidualized management regardless ofadditional pregnancy complications.Selection bias could influence the studyfindings as physicians may have chosento deliver women with superimposedpreeclampsia who were perceived to beat higher risk immediately, leaving alower risk study population that may notrepresent the risks and outcomes of thisentire cohort. When the 2 groups werefurther stratified by gestational age atdelivery (<34 and 34-366/7 weeks), ourstudy groups were further restricted innumbers and limited the sample size todetect a true difference for more rareadverse outcomes. However, the statis-tically significant findings represent truerisk differences.

We found considerable perinatalmorbidity and mortality risks associatedwith preeclampsia and chronic hyper-tension with superimposed preeclamp-sia. However, compared to each other,neonatal complication rates do not differirrespective of gestational age. Although


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at later gestational ages maternal ad-verse outcomes are increased predomi-nantly in women with superimposedpreeclampsia, overall adverse neonatalmorbidity is much lower without an in-crease in serious maternal morbidities.This study further supports both cohortsand especially superimposed pre-eclampsia should be managed at centerswhere appropriate maternal and ne-onatal resources are available. Ascurrently practiced among women withmild preeclampsia, it is reasonable andsafe to manage superimposed preec-lampsia similarly with close inpatientobservation and delivery at 37 weeks ofgestation, unless an earlier indicationarises based on worsening disease, todecrease neonatal morbidity. This retro-spective study creates the basic platformto study both populations prospectivelywith larger cohorts to clearly determine ifthese are 2 different disease processes andtruly require different delivery manage-ment and timing. -

ACKNOWLEDGMENT

The authors thank Suneet Chauhan, MD, for hiscontribution to the study design and support forthe development of this study.

REFERENCES

1. Sibai BM, Lindheimer M, Hauth J, et al. Riskfactors for preeclampsia, abruptio placentae,and adverse neonatal outcomes among womenwith chronic hypertension; National Institute ofChild Health and Human Development Networkof Maternal-Fetal Medicine Units. N Engl J Med1998;339:667-71.2. Sibai BM, Caritis SN, Thom E, et al. Preven-tion of preeclampsia with low-dose aspirin inhealthy, nulliparous pregnant women; the Na-tional Institute of Child Health and HumanDevelopment Network of Maternal-Fetal Medi-cine Units. N Engl J Med 1993;329:1213-8.3. Vanek M, Sheiner E, Levy A, Mazor M.Chronic hypertension and the risk for adversepregnancy outcome after superimposed pre-eclampsia. Int J Gynaecol Obstet 2004;86:7-11.4. Ananth CV, Keyes KM, Wapner RJ. Pre-eclampsia rates in the United States, 1980-2010: age-period-cohort analysis. BMJ2013;347:f6564.


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5. Kuklina EV, Ayala C, Callaghan WM. Hyper-tensive disorders and severe obstetric morbidityin the United States. Obstet Gynecol 2009;113:1299-306.6. Sibai BM. Management of late preterm andearly-term pregnancies complicated by mildgestational hypertension/pre-eclampsia. SeminPerinatol 2011;35:292-6.7. American College of Obstetricians andGynecologists; Task Force on Hypertensionin Pregnancy. Hypertension in pregnancy:report of the American College of Obstetriciansand Gynecologists’ Task Force on Hypertensionin Pregnancy. Obstet Gynecol 2013;122:1122-31.8. Koopmans CM, Bijlenga D, Groen H, et al.Induction of labor versus expectant monitoringfor gestational hypertension or mild pre-eclampsia after 36 weeks’ gestation (HYPI-TAT): a multicenter, open-label randomizedcontrolled trial. Lancet 2009;374:979-88.9. American College of Obstetricians andGynecologists. Chronic hypertension in preg-nancy. ACOG Practice bulletin no. 125. ObstetGynecol 2012;119:396-407.10. Odendaal HJ, Pattinson RC, Bam R,Grove D, Kotze TJ. Aggressive or expectantmanagement for patients with severe pre-eclampsia between 28-34 weeks’ gestation: arandomized controlled trial. Obstet Gynecol1990;76:1070-5.11. Sibai BM, Mercer BM, Schiff E,Friedman SA. Aggressive versus expectantmanagement of severe preeclampsia at 28 to 32weeks’ gestation: a randomized controlled trial.Am J Obstet Gynecol 1994;171:818-22.12. Sibai BM, Koch MA, Freire S, et al. Theimpact of prior preeclampsia on the risk ofsuperimposed preeclampsia and other adversepregnancy outcomes in patients with chronichypertension. Am J Obstet Gynecol 2011;204:345.e1-6.13. Vigil-De Gracia P, Montufar-Rueda C,Ruiz J. Expectant management of severe pre-eclampsia and preeclampsia superimposed onchronic hypertension between 24 and 34weeks’ gestation. Eur J Obstet Gynecol ReprodBiol 2003;107:24-7.14. Samuel A, Lin C, Parviainen K, Jeyabalan A.Expectant management of preeclampsiasuperimposed on chronic hypertension.J Matern Fetal Neonatal Med 2011;24:907-11.15. Ferrer RL, Sibai BM, Mulrow CD,Chiquette E, Stevens KR, Cornell J. Manage-ment of mild chronic hypertension during preg-nancy: a review. Obstet Gynecol 2000;96:849-60.16. Mosca L, Aggarwal B, Mochari-Greenberger H, et al. Association betweenhaving a caregiver and clinical outcomes 1 year

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after hospitalization for cardiovascular disease.Am J Cardiol 2012;109:135-9.17. Cnossen JS, Morris RK, ter Riet G, et al.Use of uterine artery Doppler ultrasonographyto predict pre-eclampsia and intrauterine growthrestriction: a systematic review and bivariablemeta-analysis. CMAJ 2008;178:701-11.18. Powers RW, Jeyabalan A, Clifton RG, et al.Soluble fms-like tyrosine kinase 1 (sFlt1), endo-glin and placental growth factor (PlGF) in pre-eclampsia among high risk pregnancies. PLoSOne 2010;5:e13263.19. Tuuli MG, Rampersad R, Stamilio D,Macones G, Odibo AO. Perinatal outcomes inwomen with preeclampsia and superimposedpreeclampsia: do they differ? Am J ObstetGynecol 2011;204:508.e1-7.20. Committee on Obstetric Practice. Emergenttherapy for acute-onset, severe hypertensionwith preeclampsia or eclampsia. Committeeopinion no. 514. Obstet Gynecol 2011;118:1465-8.21. Martin JN Jr, Thigpen BD, Moore RC,Rose CH, Cushman J, May W. Stroke and se-vere preeclampsia and eclampsia: a paradigmshift focusing on systolic blood pressure. ObstetGynecol 2005;105:246-54.22. Allen VM, Joseph K, Murphy KE, Magee LA,Ohlsson A. The effect of hypertensive disordersin pregnancy on small for gestational age andstillbirth: a population based study. BMC Preg-nancy Childbirth 2004;4:17.23. Zetterstrom K, Lindeberg SN, Haglund B,Hanson U. Chronic hypertension as a riskfactor for offspring to be born small for gesta-tional age. ActaObstet Gynecol Scand 2006;85:1046-50.24. Chappell LC, Enye S, Seed P, Briley AL,Poston L, Shennan AH. Adverse perinataloutcomes and risk factors for preeclampsiain women with chronic hypertension: aprospective study. Hypertension 2008;51:1002-9.25. von Dadelszen P, Ornstein MP, Bull SB,Logan AG, Koren G, Magee LA. Fall in meanarterial pressure and fetal growth restriction inpregnancy hypertension: a meta-analysis. Lan-cet 2000;355:87-92.26. Lubow JM, How HY, Habli M, Maxwell R,Sibai BM. Indications for delivery and short-termneonatal outcomes in late preterm as comparedwith term births. Am J Obstet Gynecol2009;200:e30-3.27. Dennis AT, Solnordal CB. Acute pulmonaryedema in pregnant women. Anaesthesia2012;67:646-59.28. Schobel HP, Fischer T, Heuszer K,Geiger H, Schmieder RE. Preeclampsiaea stateof sympathetic overactivity. N Engl J Med1996;335:1480-5.

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Expectant management of mild preeclampsia versus superimposed preeclampsia up to 37 weeks

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