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Expectant management of mild preeclampsia versus superimposed preeclampsia up to 37 weeks
Research
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OBSTETRICS
Expectant management of mild preeclampsia versus superimposed preeclampsia up to 37 weeks Amy 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 hypertension with superimposed preeclampsia vs mild preeclampsia up to 37 weeks of gestation.
composite morbidity or latency periods between women with superimposed preeclampsia and mild preeclampsia. Adverse neonatal outcomes were significantly higher at <34 compared to 34-366/7 weeks of gestation (97-98% vs 48-50%) in both cohorts. Maternal adverse composite outcome occurred more frequently in women with superimposed preeclampsia compared to mild preeclampsia (15% vs 5%, P ¼ .003; relative risk, 3.0; 95% confidence interval, 1.45e6.29).
STUDY DESIGN: This was a multicenter retrospective cohort study of all pregnancies complicated by chronic hypertension with superimposed preeclampsia or mild preeclampsia expectantly managed in the hospital from January 2008 through December 2011. The primary outcomes, adverse maternal and neonatal composite morbidities, were compared between these 2 groups. Frequency differences of maternal adverse outcomes were stratified by gestational age at delivery of <34 and 34-366/7 weeks of gestation.
CONCLUSION: Women with superimposed preeclampsia have similar neonatal outcomes but more maternal complications than women with preeclampsia without severe features who are expectantly managed <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 J Obstet Gynecol 2014;212:x.ex-x.ex.
H
ypertensive disorders are among the most common pregnancy complications. Preeclampsia complicates 3-7% of all pregnancies with a 4-5 times higher incidence in the presence of chronic hypertension.1-4 These conditions markedly increase the risk of both maternal and neonatal morbidity and mortality.1,5 Expectant management with close maternal and fetal surveillance and
planned delivery at 37 weeks of gestation is recommended for patients with mild preeclampsia in the absence of other delivery indications.6-8 The recent American Congress of Obstetricians and Gynecologists (ACOG) Task Force on Hypertension in Pregnancy states that preterm preeclampsia without severe features may be followed expectantly with inpatient or outpatient management.7 However, many expert
authorities recommend hospitalization with a diagnosis of preeclampsia as significant morbidity and mortality are increased even without progression to severe disease. The broad disease spectrum, especially in the setting of concomitant organ insult, and the challenge of diagnosing preeclampsia in the presence of chronic hypertension has led to a paucity of quality studies regarding optimal
From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Cincinnati School of Medicine (Drs Valent and DeFranco); Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical Center (Drs DeFranco and Habli); and Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Good Samaritan Hospital (Drs Salem, Klarquist, and Habli), Cincinnati, OH; Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of South Alabama Children’s and Women’s Hospital, Mobile, AL (Drs Allison and Lewis and Ms Armistead); Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Tennessee College of Medicine, Chattanooga, TN (Drs Gonzales and Adair); Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center, Shreveport, LA (Dr Wang); and Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Health, University 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 Association of Obstetricians and Gynecologists, Chicago, IL, Oct. 17-20, 2012. Corresponding author: Amy M. Valent, DO. [email protected] 0002-9378/$36.00 ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2014.10.1090
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management. The ACOG Practice Bulletin, addressing chronic hypertension in pregnancy, recommends delivery at 34 weeks of gestation for patients with superimposed preeclampsia.9 Management and delivery timing in this patient population is based on indirect conclusions from severe preeclampsia studies.10-12 Patient surveillance and expectant management of severe preeclampsia and chronic hypertension with superimposed preeclampsia at tertiary care institutions are similarly associated with prolonged pregnancy, decreased neonatal intensive care unit stays, and respiratory distress syndrome (RDS) without significant maternal compromise <34 weeks.10,11,13 Evidence supporting that delivery at 34 weeks of gestation is superior to expectant management until 37 weeks of gestation for superimposed preeclampsia without severe disease is lacking.7 Despite the inconsistent recommendations regarding the optimal delivery timing for superimposed preeclampsia diagnosed in the preterm period compared to mild preeclampsia, surprisingly few studies have compared the maternal and fetal outcomes of these 2 conditions.13,14 Women with chronic hypertension even without subsequent superimposed preeclampsia have increased adverse perinatal outcomes including but not limited to gestational diabetes, fetal growth restriction, cesarean delivery, and worsening hypertension.1,3,15 Preeclampsia is a risk factor for long-term cardiovascular conditions and it is biologically plausible that superimposed preeclampsia represents further cardiovascular disease and endothelial dysfunction progression, which places women at higher risk of adverse outcomes.16 Although there are promising studies using imaging and biomarkers to predict preeclampsia and potential disease progression, we still do not fully understand the natural disease process or etiology of preeclampsia, especially superimposed preeclampsia.17,18 The purpose of this study is to compare the rates of adverse maternal and neonatal outcomes in patients with mild preeclampsia and superimposed preeclampsia who are managed
ajog.org expectantly in the hospital <37 weeks of gestation. Secondary goal of this study is to analyze outcomes of pregnancies that are stratified between 34-366/7 vs <34 weeks of gestation to gain a better understanding of the natural history of these 2 disease processes. We hypothesize that in the hospital setting with close monitoring, patients with superimposed preeclampsia can be managed safely with similar perinatal risks as patients with mild preeclampsia without a hypertensive history.
M ATERIALS
AND
M ETHODS
This was a multicenter retrospective cohort study including 4 tertiary care teaching hospitals. All patients admitted to the University of Cincinnati Medical Center; University of South Alabama Children’s and Women’s Hospital; Good Samaritan Hospital, Cincinnati; and University of Tennessee College of Medicine, Chattanooga, from January 2008 through December 2011 with a diagnosis of mild preeclampsia or chronic hypertension with superimposed preeclampsia were evaluated for inclusion in this study. The study period was prior to the ACOG Task Force on Hypertension in Pregnancy recommendations for the change in terminology from “mild preeclampsia” to “preeclampsia” and to distinguish superimposed preeclampsia with and without severe features.7 This study was approved by the institutional review board at the University of Cincinnati, Cincinnati, OH (#1203-02-01) and individual institutional review board approval was obtained at all participating centers. International Classification of Diseases, Ninth Revision codes and/or antepartum and unit recording systems were used to identify all maternal and associated neonatal charts with the diagnosis of preeclampsia, chronic hypertension, superimposed preeclampsia, and/or preterm birth. Coinvestigators at the individual institutions reviewed all potentially eligible charts, and collected data regarding maternal demographic characteristics, gestational age at diagnosis and delivery, latency period, mode of delivery, indications for delivery, and maternal and
neonatal outcomes. Inclusion criteria comprised all singleton pregnancies between 240/7 and 366/7 weeks of gestation with the diagnosis of mild preeclampsia and chronic hypertension with superimposed preeclampsia that were managed expectantly in the hospital. Exclusion criteria were the diagnosis of severe preeclampsia >340/7 weeks of gestation at the time of admission, preeclampsia requiring delivery immediately after corticosteroids or maternal stabilization, preterm labor or prelabor rupture of membranes on admission, major medical comorbidities not including chronic hypertension, multifetal gestation, congenital anomalies, or other maternal or fetal contraindications to expectant management. The primary outcomes of the study were composites of maternal and neonatal adverse morbidities. The maternal composite was defined as 1 of the following: pulmonary edema, placental abruption, oliguria, and eclampsia. The composite of neonatal morbidities included 1 of the following: RDS, intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, 5-minute Apgar score of <7, and neonatal death. Secondary outcome was the latency duration from day of admission to delivery. Other maternal morbidities of interest included progression to severe preeclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, abnormal liver enzymes, thrombocytopenia, and maternal death. Additional neonatal complications studied comprised admission to the neonatal intensive care unit and suspected neonatal sepsis. Suspected neonatal sepsis was defined as a neonate receiving antibiotics during a sepsis evaluation regardless of the culture result. All neonatal complications were diagnosed by a board-certified neonatologist. The collected cohort consisted of minimal missing information for primary outcomes of interest, exposure variables, and covariates (<5%). Patients included in this study were categorized into 2 groups based on the presence or absence of chronic hypertension. Hypertension was defined as
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ajog.org systolic blood pressure 140 mm Hg or diastolic blood pressure 90 mm Hg on 2 different occasions >4-6 hours apart or persistent, elevated pressures requiring antihypertensive therapy. Chronic hypertension was defined as the use of antihypertensive medications prior to conception, diagnosis of hypertension <20 weeks’ gestation, or the presence of hypertension for >12 weeks postpartum in a previous pregnancy. Superimposed preeclampsia was defined as women with chronic hypertension who subsequently developed preeclampsia with an acute exacerbation of preexisting hypertension in addition to either new-onset proteinuria defined by 0.3 g of total urinary protein excretion over a 24-hour period or a substantial increase in baseline proteinuria if present early in pregnancy. Mild preeclampsia was defined as hypertension >20 weeks’ gestation with the presence of proteinuria. Upon admission, the patient was evaluated to ensure she did not meet criteria for severe preeclampsia. Fetal viability was confirmed, baseline laboratory values (including but not limited to liver enzyme tests, renal panel, urinalysis for protein evaluation, and complete blood cell count) and a 24hour urine collection for total protein excretion were subsequently completed in the hospital. Serial ultrasound biometry every 3-4 weeks was performed to assess fetal growth. Antenatal surveillance with nonstress test, biophysical profile, Doppler studies, fetal kick counts, or a combination of these modalities was used to determine fetal wellbeing. Laboratory assessments and careful maternal clinical evaluations of vital signs, urine output, symptoms, or signs of disease progression were routinely performed. Patients admitted at <34 weeks of gestation received antenatal corticosteroids for fetal lung maturity. Women without evidence of advancing, severe disease received oral antihypertensive medications for management of severe range blood pressures (systolic 160 mm Hg and/or diastolic 110 mm Hg). For women with mild preeclampsia or superimposed preeclampsia, expectant
management was continued unless fetal or maternal indications required immediate intervention. Isolated fetal growth restriction and isolated proteinuria >5 g/d without the presence of other severe signs or symptoms were not indications for delivery at the study institutions. The progression of severe disease 34 weeks of gestation was an indication for delivery for all patients. Fetal reasons for delivery included nonreassuring fetal heart tracing or abnormal fetal testing, which involved fetal growth restriction with persistent oligohydramnios, umbilical artery Doppler velocimetry with reversed end-diastolic flow, or nonreassuring biophysical profile score. Maternal indications for delivery included the development of renal insufficiency, eclampsia, placental abruption, pulmonary edema, persistent gastrointestinal or neurologic symptoms, uncontrollable hypertension with intravenous and/or orally titrated antihypertensive therapy, or laboratory values suggesting thrombocytopenia (<100,000/mL) or HELLP syndrome (hemolysis, elevated liver enzymes [2 times the normal transaminase concentrations], and low platelet). The criteria for severe preeclampsia included the presence of 1 of the following: 2 systolic blood pressures 160 mm Hg or diastolic blood pressures 110 mm Hg >4-6 hours apart after administration of intravenous antihypertensive therapy, oliguria (<500 mL or <0.5 mL/kg/h over 24 hours), cyanosis, thrombocytopenia, elevated liver enzymes, pulmonary edema, eclampsia, or worsening/persistent gastrointestinal or neurologic symptoms (ie, headache, epigastric pain, visual disturbances, altered mental status). The development of HELLP syndrome was defined by evidence of hemolysis on a peripheral blood smear, elevated lactate dehydrogenase per institutional laboratory standards, decreased platelets, and elevated liver enzyme tests. The frequency of maternal and neonatal adverse composite outcomes were compared between pregnancies complicated by mild preeclampsia and superimposed preeclampsia. Both composite outcomes and integrated variables
Research
were compared after stratification by gestational age into pregnancies that delivered <34 and between 34-366/7 weeks of gestation. Estimated gestational age was determined with a combination of last menstrual period, ultrasound imaging, and clinical assessment, which is commonly accepted in general practice. Gestational weeks >366/7 were not included in the data analysis because expectant management of preeclampsia is not the advocated approach due to the progressive risk for adverse perinatal outcomes.7,8 Statistical analysis was performed using StatView (SAS Institute Inc, Cary, NC) and GraphPad Prism, version 5.00 for Windows (GraphPad Software, San Diego, CA). Demographic characteristics were compared using Student t test for continuous variables and c2 or Fisher exact test for categorical variables. Comparisons with a P value < .05 or 95% confidence interval (CI) without inclusion of the null were considered statistically significant.
R ESULTS Over the 3-year study period, 357 patients met inclusion criteria for this study; 171 pregnancies complicated by chronic hypertension with superimposed preeclampsia and 186 women with mild preeclampsia. University of South Alabama Children’s and Women’s Hospital contributed 109 mother-infant pairs; the University of Cincinnati Medical Center contributed 100 pairs; Good Samaritan Hospital contributed 95 pairs; and University of Tennessee College of Medicine, Chattanooga, provided 53 mother-infant outcome data. The demographic characteristics of the 2 groups are presented in Table 1. Patients with chronic hypertension with superimposed preeclampsia were older, more commonly multiparous, and black. Higher rates of oral antihypertensive therapy during pregnancy and postpartum period were observed among women with superimposed preeclampsia compared to women without a history of chronic hypertension. Although patients with superimposed preeclampsia were diagnosed and delivered at an earlier gestational age than
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TABLE 1
Maternal characteristics Superimpose preeclampsia, n [ 171
Characteristic
Preeclampsia, n [ 186
P value
30 6
26 6
< .001
Caucasian
83 (49)
114 (61)
.02
Black
85 (50)
68 (39)
.01
Other
3 (2)
4 (2)
1.0
64 (32)
115 (62)
< .001
Vaginal
35 (21)
72 (38)
< .001
Repeat cesarean
51 (30)
26 (14)
< .001
Primary cesarean
85 (50)
88 (47)
.73
Oral antenatal antihypertensive medications
128 (75)
15 (1)
< .001
Regimen with 1 medication
43 (25)
0 (0)
< .001
Age, y Race and ethnicity
Primigravida Mode of delivery
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 preeclampsia, primary cesarean delivery rates were not significantly different between the 2 groups. The Figure demonstrates the most common indications for delivery among this cohort. Women with superimposed preeclampsia were more likely to be delivered for uncontrollable, elevated blood pressures (57% vs 39%, P <.001), and pregnancies complicated by mild preeclampsia were delivered more commonly for the development of persistent neurologic or gastrointestinal symptoms (20% vs 6%, P < .001). Although patients with mild preeclampsia had significantly shorter hospitalization stays compared to women with superimposed preeclampsia, no difference in the latency periods between diagnosis and delivery among the 2 groups were appreciated, even after stratification at <34 or 34-366/7 weeks of gestation (Tables 1 and 2). Pulmonary edema was more frequently observed in pregnancies with superimposed preeclampsia, particularly deliveries <34 weeks of gestation. Maternal adverse composite outcome occurred more frequently in women with superimposed preeclampsia (15%) compared to those
with preeclampsia (5%) (relative risk [RR], 3.0; 95% CI, 1.45e6.29). The rate of adverse maternal outcome was significantly higher in women with superimposed preeclampsia delivered at later preterm gestational ages between 34-366/7 weeks (RR, 4.0; 95% CI, 1.13e14.39), as compared to <34 weeks of gestation (RR, 2.3; 95% CI, 0.95e5.64; Table 3). Prior to stratification into 2 preterm gestational age categories, small for gestational age (26% vs 16%, P ¼ .02) and low birthweight (1941 790 vs 2161 834 g, P < .001) were more frequent among neonates born to mothers with superimposed preeclampsia, but no significant difference in the frequency of critical neonatal complications such as necrotizing enterocolitis, RDS, neonatal mortality, or intraventricular hemorrhage was appreciated between the 2 groups. Table 4 presents differences in neonatal outcomes between the 2 groups stratified by gestational age at delivery. Aside from a 5-minute Apgar score <7, no significant differences in estimated gestational age at delivery or neonatal outcomes were detected between women with preeclampsia and superimposed preeclampsia when
stratified between <34 or 34-366/7 weeks of gestation. However, compared to 34-366/7 weeks, both cohorts delivering <34 weeks of gestation had higher rates of adverse neonatal composite morbidity and mortality. A total of 8 perinatal losses occurred in the study cohort with all deliveries <34 weeks of gestation. There were 2 cases of stillbirth in the 24th week of pregnancy, both complicated by intrauterine growth restriction with estimated fetal weights of <300 g in the superimposed preeclampsia cohort. Five neonatal deaths were among extremely preterm births at <26 weeks of gestation in both study groups.
C OMMENT This study is one of the first and largest to compare the maternal and neonatal outcomes following expectant management of pregnancies with mild preeclampsia and superimposed preeclampsia up to 37 weeks of gestation. Our multicenter, observational study demonstrates that expectant, inpatient management of these 2 diseases result in similar neonatal outcomes. Without the presence of severe disease at the time of admission, they have comparable mean latency periods from diagnosis to delivery irrespective of the gestational age at diagnosis. We found that women with superimposed preeclampsia were more commonly black, older, multiparous, and required oral antihypertensive therapy, which is consistent with previous studies.19 This higher frequency of antihypertensive treatment may be indicative of ongoing chronic treatment of their underlying disorder rather than a marker of progressive, severe disease during pregnancy. Antihypertensive therapy has not been shown to improve rates of preterm birth or progression to superimposed preeclampsia but is recommended to reduce the risk of severe hypertension, worsening end-organ damage, and maternal complications including cerebral hemorrhage and infarction.12,20,21 Physicians are aware of the increased perinatal risks among chronic hypertensive women, likely resulting in a lower threshold for
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FIGURE web 4C=FPO
Indications for delivery
Bar graph representing common indications for delivery in pregnancies complicated by superimposed 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 fetal surveillance. *Persistent neurological or gastrointestinal symptoms. Valent. Expectant management of preeclampsia. Am J Obstet Gynecol 2014.
conservative inpatient supervision, aggressive blood pressure management, and longer hospitalizations. Hypertensive exacerbations and undiagnosed
microvascular disease can complicate the clinical picture, diagnosis, and management strategies. However, our study shows that with careful inpatient
TABLE 2
Maternal outcomes Superimposed preeclampsia, n [ 171
Outcome variable EGA at diagnosis, wk
314/7 33/7
Latency, d Days in hospital Severe preeclampsia
Preeclampsia, n [ 186
P value
324/7 31/7
.004
10 13 5 [2e11]
88 5 [3e10]
.12
13 12 9 [6e16]
10 7 8 [6e11]
< .001
149 (87)
157 (84)
.56
Pulmonary edema
7 (4)
0 (0)
.01
Placental abruption
11 (6)
5 (3)
.18
Thrombocytopenia
8 (5)
12 (6)
.62
24 (14)
29 (16)
.79
Oliguria
7 (4)
5 (3)
.66
HELLP
2 (1)
7 (4)
.22
1 (1)
1 (1)
25 (15)
9 (5)
Elevated liver enzymes
Eclampsia Maternal composite
a
1.0 .003
Continuous variable are presented as mean SD or median [interquartile range]. Dichotomous variables are presented as number (percent). 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.
Valent. Expectant management of preeclampsia. Am J Obstet Gynecol 2014.
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management, women with superimposed preeclampsia can continue pregnancy >34 weeks of gestation with titrating doses of antihypertensives as long as the blood pressure responds to these increases. Women in both groups were found to have high rates of neonatal mortality and respiratory morbidities, especially deliveries <34 weeks of gestation. Hypertensive disorders may contribute to impaired fetal growth and increase the risk for birth of small-for-gestational-age infants.22,23 Consistent with previously published studies, we found that women with superimposed preeclampsia had higher rates of small for gestational age and overall lower average birthweights than patients with mild preeclampsia, but no difference was observed when stratified by gestational age at delivery.3,9,24 This could be explained in part by the increased use of oral antihypertensive maintenance therapy in superimposed preeclamptic patients, which is known to reduce mean arterial pressure and is associated with small for gestational age independent of duration of therapy.25 Given the minimal observed difference in frequency of these adverse neonatal outcomes with a probability value >5%, we conclude that no significant difference in neonatal outcomes occurs following births to superimposed preeclampsia and mild preeclampsia pregnancies managed expectantly in the late preterm period. Similarly, the likelihood of an adverse neonatal outcome for births <34 weeks of gestation did not differ between the 2 cohorts but the frequency of adverse neonatal morbidity was significantly higher (94-97%) than those managed and delivered between 34-366/7 weeks of gestation. We did observe a higher frequency of RDS in late preterm infants than is commonly reported in prospectively performed studies.26 This may be related to misclassification of some cases of oxygen requirement or respiratory complications as RDS that may not have not have met strict criteria for RDS if defined as such prospectively. Despite this, it is unlikely that RDS cases were
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TABLE 3
Maternal outcomes stratified by preterm gestational age groups <340/7 wks of gestation Superimposed preeclampsia, n [ 92
Outcome variable EGA at diagnosis, wk
29
2/7
2
5/7
8.6 11.1
Latency, d Days in hospital
12.2 9.1
Severe preeclampsia
34-366/7 wks of gestation Preeclampsia, n [ 80 30
1/7
2
5/7
P value
Superimposed preeclampsia, n [ 79 6/7
2
4/7
Preeclampsia, n [ 106
P value
1
.22
34
4/7
6/7
.08
33
6.2 4.1
.06
11.7 15.6
8.5 9.6
.09
9.6 3.7
.02
14.6 14.2
9.1 7.7
< .001
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
1.0
Elevated liver enzymes
12 (13)
10 (12)
12 (15)
19 (18)
Oliguria
4 (4)
2 (2)
.82
3 (4)
3 (3)
1.0
HELLP
1 (1)
5 (6)
.15
1 (1)
2 (2)
1.0
1 (1)
1 (1)
0 (0)
0 (0)
1.0
16 (17)
6 (8)
9 (11)
3 (2)
Eclampsia Maternal composite
a
1.0 .08
.77
.04
Continuous variable are presented as mean SD. Dichotomous variables are presented as number (percent). 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.
Valent. Expectant management of preeclampsia. Am J Obstet Gynecol 2014.
differentially misclassified between the superimposed preeclampsia and mild preeclampsia groups. The majority of pregnancies in this study complicated by superimposed preeclampsia and mild preeclampsia developed severe preeclampsia. Compared to previous severe preeclampsia studies and acknowledging variance in sample sizes, similar rates of HELLP and placental abruption were observed in this study.11,13 Tuuli et al19 retrospectively studied the same pregnancy populations but observed lower rates of placental abruption. However, their study included patients over an 18 year period and disease management has changed progressively during this time. Although a higher frequency of overall composite maternal morbidity was observed in women with superimposed preeclampsia, the statistical differences in the overall composite morbidity between 34-366/7 weeks of gestation were driven by increased rates of placental abruption without a significant difference in neonatal outcome compared to pregnancies with mild preeclampsia. Expectant management >34 weeks of
gestation did not increase the risk of serious maternal complications such as HELLP, eclampsia, or pulmonary edema. Higher rates of pulmonary edema were observed among women with superimposed preeclampsia but all of the events occurred <34 weeks and not in later gestational ages. Severe hypertension was a more frequent delivery indication for women with superimposed preeclampsia compared to worsening neurologic or gastrointestinal symptoms in those women with mild preeclampsia. An acute hypertensive crisis commonly precipitates pulmonary edema causing significant vasoconstriction, increased afterload, and redistribution of fluid centrally into pulmonary circulation, placing all women with preeclampsia at increased risk.27,28 Alternatively, these women may represent advanced endothelial dysfunction predisposing them to disease progression or insufficient maternal immunologic response or tolerance at an early gestation. The latency duration found in this study is consistent with previously
published studies reporting an average duration between 8.4-9.7 days in pregnancies complicated by superimposed preeclampsia.13,14 However, prior studies followed management recommendations suggested for severe preeclampsia in women diagnosed with superimposed preeclampsia, delivering at 34 weeks of gestation even in the absence of signs or symptoms of severe disease. The practice of planned early delivery at 34 weeks for women with superimposed preeclampsia in the previously reported studies may have influenced the reported outcomes, possibly demonstrating shorter latency periods and more adverse neonatal outcomes related to prematurity. Expectant management in the preterm period and delivery at 37 weeks, unless earlier delivery was indicated due to the development of signs or symptoms of severe disease, is consistent with the most recent recommendations from the ACOG Task Force on Hypertension in Pregnancy.7 This study was performed prior to the institution of the task force guidelines for management. However, removal of 5 g of proteinuria and fetal
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TABLE 4
Neonatal outcomes <340/7 wks of gestation Superimposed preeclampsia, n [ 92
Outcome variable
4/7
2
4/7
34-366/7 wks of gestation Preeclampsia, n [ 80 0/7
2
P value
Superimposed preeclampsia, n [ 79
4/7
.18
35
5/7
1
0/7
EGA at delivery
30
Days in hospital
34.4 28.2
39.8 32.3
.25
6.0 4.6
NICU admission
86 (93)
71 (89)
.41
35 (44)
5-min Apgar 7
31
Preeclampsia, n [ 106 35
6/7
1
0/7
7.3 9.0
P value .17 .24
49 (46)
.91
15 (16)
16 (20)
.67
16 (20)
7 (7)
.01
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 (1)
2 (2)
1.0
NEC
7 (8)
4 (5)
.71
0 (0)
1 (1)
1.0
13 (14)
13 (16)
.86
14 (18)
20 (19)
1.0
9 (10)
7 (9)
1 (1)
3 (3)
6 (7)
2 (3)
.38
0 (0)
0 (0)
89 (97)
75 (94)
.57
38 (48)
53 (50)
Birthweight, g
a
Suspected sepsis IVH Death
Neonatal composite
b
1.0
1.0
.87 1.0 .92
Continuous variable are presented as mean SD. Dichotomous variables are presented as number (percent). BPD, bronchopulmonary dysplasia; EGA, estimated gestational age; IVH, intraventricular hemorrhage of any grade; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; RDS, respiratory distress 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).
Valent. Expectant management of preeclampsia. Am J Obstet Gynecol 2014.
growth restriction as indications for delivery in the new recommendations would not have changed the outcomes of this study as they were not direct indications for delivery at any participating center. Although the old criteria had oliguria as a sign of severe disease, the frequencies of oliguria were not statistically significant between the 2 groups and would not have changed the rate of adverse maternal outcome in our study. A major strength of this study is the large number of patients managed at 4 tertiary level centers, representing wide national demographic regions and populations; therefore, we believe our findings are widely generalizable. This study addresses an issue that is not well studied and important in perinatal management. We specifically excluded patients from this study with other serious disease comorbidities such as renal disease, systemic lupus erythematosus, and other end-organ dysfunction. Likely through different disease processes, women with these disease states have risks for
worse perinatal outcomes regardless of inclusion in either group and would not represent the risks and outcomes specifically of these hypertensive diseases focused in this study. This study faces the inherent weaknesses of any observational study. Relying on International Classification of Diseases, Ninth Revision codes for hypertensive diseases and preterm birth, not all patients who meet inclusion criteria may have been identified at all participating centers. The maternal-fetal medicine specialists at each institution may have variations in management and practicing styles despite all centers consistently managing both patient cohorts expectantly until 37 weeks of gestation during the study period. Exclusion of other comorbidities, especially pregestational diabetes, may somewhat limit the generalizability of our findings to all patient populations presenting with chronic hypertension and preeclampsia; however, we believe these patients represent a unique
high-risk population who warrant individualized management regardless of additional pregnancy complications. Selection bias could influence the study findings as physicians may have chosen to deliver women with superimposed preeclampsia who were perceived to be at higher risk immediately, leaving a lower risk study population that may not represent the risks and outcomes of this entire cohort. When the 2 groups were further stratified by gestational age at delivery (<34 and 34-366/7 weeks), our study groups were further restricted in numbers and limited the sample size to detect a true difference for more rare adverse outcomes. However, the statistically significant findings represent true risk differences. We found considerable perinatal morbidity and mortality risks associated with preeclampsia and chronic hypertension with superimposed preeclampsia. However, compared to each other, neonatal complication rates do not differ irrespective of gestational age. Although
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at later gestational ages maternal adverse outcomes are increased predominantly in women with superimposed preeclampsia, overall adverse neonatal morbidity is much lower without an increase in serious maternal morbidities. This study further supports both cohorts and especially superimposed preeclampsia should be managed at centers where appropriate maternal and neonatal resources are available. As currently practiced among women with mild preeclampsia, it is reasonable and safe to manage superimposed preeclampsia similarly with close inpatient observation and delivery at 37 weeks of gestation, unless an earlier indication arises based on worsening disease, to decrease neonatal morbidity. This retrospective study creates the basic platform to study both populations prospectively with larger cohorts to clearly determine if these are 2 different disease processes and truly require different delivery management and timing. ACKNOWLEDGMENT The authors thank Suneet Chauhan, MD, for his contribution to the study design and support for the development of this study.
REFERENCES 1. Sibai BM, Lindheimer M, Hauth J, et al. Risk factors for preeclampsia, abruptio placentae, and adverse neonatal outcomes among women with chronic hypertension; National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1998;339:667-71. 2. Sibai BM, Caritis SN, Thom E, et al. Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women; the National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1993;329:1213-8. 3. Vanek M, Sheiner E, Levy A, Mazor M. Chronic hypertension and the risk for adverse pregnancy outcome after superimposed preeclampsia. Int J Gynaecol Obstet 2004;86:7-11. 4. Ananth CV, Keyes KM, Wapner RJ. Preeclampsia rates in the United States, 19802010: age-period-cohort analysis. BMJ 2013;347:f6564.
ajog.org 5. Kuklina EV, Ayala C, Callaghan WM. Hypertensive disorders and severe obstetric morbidity in the United States. Obstet Gynecol 2009;113: 1299-306. 6. Sibai BM. Management of late preterm and early-term pregnancies complicated by mild gestational hypertension/pre-eclampsia. Semin Perinatol 2011;35:292-6. 7. American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy: report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013;122: 1122-31. 8. Koopmans CM, Bijlenga D, Groen H, et al. Induction of labor versus expectant monitoring for gestational hypertension or mild preeclampsia after 36 weeks’ gestation (HYPITAT): a multicenter, open-label randomized controlled trial. Lancet 2009;374:979-88. 9. American College of Obstetricians and Gynecologists. Chronic hypertension in pregnancy. ACOG Practice bulletin no. 125. Obstet Gynecol 2012;119:396-407. 10. Odendaal HJ, Pattinson RC, Bam R, Grove D, Kotze TJ. Aggressive or expectant management for patients with severe preeclampsia between 28-34 weeks’ gestation: a randomized controlled trial. Obstet Gynecol 1990;76:1070-5. 11. Sibai BM, Mercer BM, Schiff E, Friedman SA. Aggressive versus expectant management of severe preeclampsia at 28 to 32 weeks’ gestation: a randomized controlled trial. Am J Obstet Gynecol 1994;171:818-22. 12. Sibai BM, Koch MA, Freire S, et al. The impact of prior preeclampsia on the risk of superimposed preeclampsia and other adverse pregnancy outcomes in patients with chronic hypertension. Am J Obstet Gynecol 2011;204: 345.e1-6. 13. Vigil-De Gracia P, Montufar-Rueda C, Ruiz J. Expectant management of severe preeclampsia and preeclampsia superimposed on chronic hypertension between 24 and 34 weeks’ gestation. Eur J Obstet Gynecol Reprod Biol 2003;107:24-7. 14. Samuel A, Lin C, Parviainen K, Jeyabalan A. Expectant management of preeclampsia superimposed 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. Management of mild chronic hypertension during pregnancy: a review. Obstet Gynecol 2000;96: 849-60. 16. Mosca L, Aggarwal B, MochariGreenberger H, et al. Association between having a caregiver and clinical outcomes 1 year
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 ultrasonography to predict pre-eclampsia and intrauterine growth restriction: a systematic review and bivariable meta-analysis. CMAJ 2008;178:701-11. 18. Powers RW, Jeyabalan A, Clifton RG, et al. Soluble fms-like tyrosine kinase 1 (sFlt1), endoglin and placental growth factor (PlGF) in preeclampsia among high risk pregnancies. PLoS One 2010;5:e13263. 19. Tuuli MG, Rampersad R, Stamilio D, Macones G, Odibo AO. Perinatal outcomes in women with preeclampsia and superimposed preeclampsia: do they differ? Am J Obstet Gynecol 2011;204:508.e1-7. 20. Committee on Obstetric Practice. Emergent therapy for acute-onset, severe hypertension with preeclampsia or eclampsia. Committee opinion no. 514. Obstet Gynecol 2011;118: 1465-8. 21. Martin JN Jr, Thigpen BD, Moore RC, Rose CH, Cushman J, May W. Stroke and severe preeclampsia and eclampsia: a paradigm shift focusing on systolic blood pressure. Obstet Gynecol 2005;105:246-54. 22. Allen VM, Joseph K, Murphy KE, Magee LA, Ohlsson A. The effect of hypertensive disorders in pregnancy on small for gestational age and stillbirth: a population based study. BMC Pregnancy Childbirth 2004;4:17. 23. Zetterstrom K, Lindeberg SN, Haglund B, Hanson U. Chronic hypertension as a risk factor for offspring to be born small for gestational age. Acta Obstet Gynecol Scand 2006;85: 1046-50. 24. Chappell LC, Enye S, Seed P, Briley AL, Poston L, Shennan AH. Adverse perinatal outcomes and risk factors for preeclampsia in women with chronic hypertension: a prospective study. Hypertension 2008;51: 1002-9. 25. von Dadelszen P, Ornstein MP, Bull SB, Logan AG, Koren G, Magee LA. Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: a meta-analysis. Lancet 2000;355:87-92. 26. Lubow JM, How HY, Habli M, Maxwell R, Sibai BM. Indications for delivery and short-term neonatal outcomes in late preterm as compared with term births. Am J Obstet Gynecol 2009;200:e30-3. 27. Dennis AT, Solnordal CB. Acute pulmonary edema in pregnant women. Anaesthesia 2012;67:646-59. 28. Schobel HP, Fischer T, Heuszer K, Geiger H, Schmieder RE. Preeclampsiaea state of sympathetic overactivity. N Engl J Med 1996;335:1480-5.
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OBSTETRICS
Expectant management of mild preeclampsia versus superimposed preeclampsia up to 37 weeks Amy 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 hypertension with superimposed preeclampsia vs mild preeclampsia up to 37 weeks of gestation.
composite morbidity or latency periods between women with superimposed preeclampsia and mild preeclampsia. Adverse neonatal outcomes were significantly higher at <34 compared to 34-366/7 weeks of gestation (97-98% vs 48-50%) in both cohorts. Maternal adverse composite outcome occurred more frequently in women with superimposed preeclampsia compared to mild preeclampsia (15% vs 5%, P ¼ .003; relative risk, 3.0; 95% confidence interval, 1.45e6.29).
STUDY DESIGN: This was a multicenter retrospective cohort study of all pregnancies complicated by chronic hypertension with superimposed preeclampsia or mild preeclampsia expectantly managed in the hospital from January 2008 through December 2011. The primary outcomes, adverse maternal and neonatal composite morbidities, were compared between these 2 groups. Frequency differences of maternal adverse outcomes were stratified by gestational age at delivery of <34 and 34-366/7 weeks of gestation.
CONCLUSION: Women with superimposed preeclampsia have similar neonatal outcomes but more maternal complications than women with preeclampsia without severe features who are expectantly managed <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 J Obstet Gynecol 2014;212:x.ex-x.ex.
H
ypertensive disorders are among the most common pregnancy complications. Preeclampsia complicates 3-7% of all pregnancies with a 4-5 times higher incidence in the presence of chronic hypertension.1-4 These conditions markedly increase the risk of both maternal and neonatal morbidity and mortality.1,5 Expectant management with close maternal and fetal surveillance and
planned delivery at 37 weeks of gestation is recommended for patients with mild preeclampsia in the absence of other delivery indications.6-8 The recent American Congress of Obstetricians and Gynecologists (ACOG) Task Force on Hypertension in Pregnancy states that preterm preeclampsia without severe features may be followed expectantly with inpatient or outpatient management.7 However, many expert
authorities recommend hospitalization with a diagnosis of preeclampsia as significant morbidity and mortality are increased even without progression to severe disease. The broad disease spectrum, especially in the setting of concomitant organ insult, and the challenge of diagnosing preeclampsia in the presence of chronic hypertension has led to a paucity of quality studies regarding optimal
From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Cincinnati School of Medicine (Drs Valent and DeFranco); Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical Center (Drs DeFranco and Habli); and Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Good Samaritan Hospital (Drs Salem, Klarquist, and Habli), Cincinnati, OH; Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of South Alabama Children’s and Women’s Hospital, Mobile, AL (Drs Allison and Lewis and Ms Armistead); Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Tennessee College of Medicine, Chattanooga, TN (Drs Gonzales and Adair); Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center, Shreveport, LA (Dr Wang); and Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Health, University 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 Association of Obstetricians and Gynecologists, Chicago, IL, Oct. 17-20, 2012. Corresponding author: Amy M. Valent, DO. [email protected] 0002-9378/$36.00 ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2014.10.1090
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management. The ACOG Practice Bulletin, addressing chronic hypertension in pregnancy, recommends delivery at 34 weeks of gestation for patients with superimposed preeclampsia.9 Management and delivery timing in this patient population is based on indirect conclusions from severe preeclampsia studies.10-12 Patient surveillance and expectant management of severe preeclampsia and chronic hypertension with superimposed preeclampsia at tertiary care institutions are similarly associated with prolonged pregnancy, decreased neonatal intensive care unit stays, and respiratory distress syndrome (RDS) without significant maternal compromise <34 weeks.10,11,13 Evidence supporting that delivery at 34 weeks of gestation is superior to expectant management until 37 weeks of gestation for superimposed preeclampsia without severe disease is lacking.7 Despite the inconsistent recommendations regarding the optimal delivery timing for superimposed preeclampsia diagnosed in the preterm period compared to mild preeclampsia, surprisingly few studies have compared the maternal and fetal outcomes of these 2 conditions.13,14 Women with chronic hypertension even without subsequent superimposed preeclampsia have increased adverse perinatal outcomes including but not limited to gestational diabetes, fetal growth restriction, cesarean delivery, and worsening hypertension.1,3,15 Preeclampsia is a risk factor for long-term cardiovascular conditions and it is biologically plausible that superimposed preeclampsia represents further cardiovascular disease and endothelial dysfunction progression, which places women at higher risk of adverse outcomes.16 Although there are promising studies using imaging and biomarkers to predict preeclampsia and potential disease progression, we still do not fully understand the natural disease process or etiology of preeclampsia, especially superimposed preeclampsia.17,18 The purpose of this study is to compare the rates of adverse maternal and neonatal outcomes in patients with mild preeclampsia and superimposed preeclampsia who are managed
ajog.org expectantly in the hospital <37 weeks of gestation. Secondary goal of this study is to analyze outcomes of pregnancies that are stratified between 34-366/7 vs <34 weeks of gestation to gain a better understanding of the natural history of these 2 disease processes. We hypothesize that in the hospital setting with close monitoring, patients with superimposed preeclampsia can be managed safely with similar perinatal risks as patients with mild preeclampsia without a hypertensive history.
M ATERIALS
AND
M ETHODS
This was a multicenter retrospective cohort study including 4 tertiary care teaching hospitals. All patients admitted to the University of Cincinnati Medical Center; University of South Alabama Children’s and Women’s Hospital; Good Samaritan Hospital, Cincinnati; and University of Tennessee College of Medicine, Chattanooga, from January 2008 through December 2011 with a diagnosis of mild preeclampsia or chronic hypertension with superimposed preeclampsia were evaluated for inclusion in this study. The study period was prior to the ACOG Task Force on Hypertension in Pregnancy recommendations for the change in terminology from “mild preeclampsia” to “preeclampsia” and to distinguish superimposed preeclampsia with and without severe features.7 This study was approved by the institutional review board at the University of Cincinnati, Cincinnati, OH (#1203-02-01) and individual institutional review board approval was obtained at all participating centers. International Classification of Diseases, Ninth Revision codes and/or antepartum and unit recording systems were used to identify all maternal and associated neonatal charts with the diagnosis of preeclampsia, chronic hypertension, superimposed preeclampsia, and/or preterm birth. Coinvestigators at the individual institutions reviewed all potentially eligible charts, and collected data regarding maternal demographic characteristics, gestational age at diagnosis and delivery, latency period, mode of delivery, indications for delivery, and maternal and
neonatal outcomes. Inclusion criteria comprised all singleton pregnancies between 240/7 and 366/7 weeks of gestation with the diagnosis of mild preeclampsia and chronic hypertension with superimposed preeclampsia that were managed expectantly in the hospital. Exclusion criteria were the diagnosis of severe preeclampsia >340/7 weeks of gestation at the time of admission, preeclampsia requiring delivery immediately after corticosteroids or maternal stabilization, preterm labor or prelabor rupture of membranes on admission, major medical comorbidities not including chronic hypertension, multifetal gestation, congenital anomalies, or other maternal or fetal contraindications to expectant management. The primary outcomes of the study were composites of maternal and neonatal adverse morbidities. The maternal composite was defined as 1 of the following: pulmonary edema, placental abruption, oliguria, and eclampsia. The composite of neonatal morbidities included 1 of the following: RDS, intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, 5-minute Apgar score of <7, and neonatal death. Secondary outcome was the latency duration from day of admission to delivery. Other maternal morbidities of interest included progression to severe preeclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, abnormal liver enzymes, thrombocytopenia, and maternal death. Additional neonatal complications studied comprised admission to the neonatal intensive care unit and suspected neonatal sepsis. Suspected neonatal sepsis was defined as a neonate receiving antibiotics during a sepsis evaluation regardless of the culture result. All neonatal complications were diagnosed by a board-certified neonatologist. The collected cohort consisted of minimal missing information for primary outcomes of interest, exposure variables, and covariates (<5%). Patients included in this study were categorized into 2 groups based on the presence or absence of chronic hypertension. Hypertension was defined as
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ajog.org systolic blood pressure 140 mm Hg or diastolic blood pressure 90 mm Hg on 2 different occasions >4-6 hours apart or persistent, elevated pressures requiring antihypertensive therapy. Chronic hypertension was defined as the use of antihypertensive medications prior to conception, diagnosis of hypertension <20 weeks’ gestation, or the presence of hypertension for >12 weeks postpartum in a previous pregnancy. Superimposed preeclampsia was defined as women with chronic hypertension who subsequently developed preeclampsia with an acute exacerbation of preexisting hypertension in addition to either new-onset proteinuria defined by 0.3 g of total urinary protein excretion over a 24-hour period or a substantial increase in baseline proteinuria if present early in pregnancy. Mild preeclampsia was defined as hypertension >20 weeks’ gestation with the presence of proteinuria. Upon admission, the patient was evaluated to ensure she did not meet criteria for severe preeclampsia. Fetal viability was confirmed, baseline laboratory values (including but not limited to liver enzyme tests, renal panel, urinalysis for protein evaluation, and complete blood cell count) and a 24hour urine collection for total protein excretion were subsequently completed in the hospital. Serial ultrasound biometry every 3-4 weeks was performed to assess fetal growth. Antenatal surveillance with nonstress test, biophysical profile, Doppler studies, fetal kick counts, or a combination of these modalities was used to determine fetal wellbeing. Laboratory assessments and careful maternal clinical evaluations of vital signs, urine output, symptoms, or signs of disease progression were routinely performed. Patients admitted at <34 weeks of gestation received antenatal corticosteroids for fetal lung maturity. Women without evidence of advancing, severe disease received oral antihypertensive medications for management of severe range blood pressures (systolic 160 mm Hg and/or diastolic 110 mm Hg). For women with mild preeclampsia or superimposed preeclampsia, expectant
management was continued unless fetal or maternal indications required immediate intervention. Isolated fetal growth restriction and isolated proteinuria >5 g/d without the presence of other severe signs or symptoms were not indications for delivery at the study institutions. The progression of severe disease 34 weeks of gestation was an indication for delivery for all patients. Fetal reasons for delivery included nonreassuring fetal heart tracing or abnormal fetal testing, which involved fetal growth restriction with persistent oligohydramnios, umbilical artery Doppler velocimetry with reversed end-diastolic flow, or nonreassuring biophysical profile score. Maternal indications for delivery included the development of renal insufficiency, eclampsia, placental abruption, pulmonary edema, persistent gastrointestinal or neurologic symptoms, uncontrollable hypertension with intravenous and/or orally titrated antihypertensive therapy, or laboratory values suggesting thrombocytopenia (<100,000/mL) or HELLP syndrome (hemolysis, elevated liver enzymes [2 times the normal transaminase concentrations], and low platelet). The criteria for severe preeclampsia included the presence of 1 of the following: 2 systolic blood pressures 160 mm Hg or diastolic blood pressures 110 mm Hg >4-6 hours apart after administration of intravenous antihypertensive therapy, oliguria (<500 mL or <0.5 mL/kg/h over 24 hours), cyanosis, thrombocytopenia, elevated liver enzymes, pulmonary edema, eclampsia, or worsening/persistent gastrointestinal or neurologic symptoms (ie, headache, epigastric pain, visual disturbances, altered mental status). The development of HELLP syndrome was defined by evidence of hemolysis on a peripheral blood smear, elevated lactate dehydrogenase per institutional laboratory standards, decreased platelets, and elevated liver enzyme tests. The frequency of maternal and neonatal adverse composite outcomes were compared between pregnancies complicated by mild preeclampsia and superimposed preeclampsia. Both composite outcomes and integrated variables
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were compared after stratification by gestational age into pregnancies that delivered <34 and between 34-366/7 weeks of gestation. Estimated gestational age was determined with a combination of last menstrual period, ultrasound imaging, and clinical assessment, which is commonly accepted in general practice. Gestational weeks >366/7 were not included in the data analysis because expectant management of preeclampsia is not the advocated approach due to the progressive risk for adverse perinatal outcomes.7,8 Statistical analysis was performed using StatView (SAS Institute Inc, Cary, NC) and GraphPad Prism, version 5.00 for Windows (GraphPad Software, San Diego, CA). Demographic characteristics were compared using Student t test for continuous variables and c2 or Fisher exact test for categorical variables. Comparisons with a P value < .05 or 95% confidence interval (CI) without inclusion of the null were considered statistically significant.
R ESULTS Over the 3-year study period, 357 patients met inclusion criteria for this study; 171 pregnancies complicated by chronic hypertension with superimposed preeclampsia and 186 women with mild preeclampsia. University of South Alabama Children’s and Women’s Hospital contributed 109 mother-infant pairs; the University of Cincinnati Medical Center contributed 100 pairs; Good Samaritan Hospital contributed 95 pairs; and University of Tennessee College of Medicine, Chattanooga, provided 53 mother-infant outcome data. The demographic characteristics of the 2 groups are presented in Table 1. Patients with chronic hypertension with superimposed preeclampsia were older, more commonly multiparous, and black. Higher rates of oral antihypertensive therapy during pregnancy and postpartum period were observed among women with superimposed preeclampsia compared to women without a history of chronic hypertension. Although patients with superimposed preeclampsia were diagnosed and delivered at an earlier gestational age than
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TABLE 1
Maternal characteristics Superimpose preeclampsia, n [ 171
Characteristic
Preeclampsia, n [ 186
P value
30 6
26 6
< .001
Caucasian
83 (49)
114 (61)
.02
Black
85 (50)
68 (39)
.01
Other
3 (2)
4 (2)
1.0
64 (32)
115 (62)
< .001
Vaginal
35 (21)
72 (38)
< .001
Repeat cesarean
51 (30)
26 (14)
< .001
Primary cesarean
85 (50)
88 (47)
.73
Oral antenatal antihypertensive medications
128 (75)
15 (1)
< .001
Regimen with 1 medication
43 (25)
0 (0)
< .001
Age, y Race and ethnicity
Primigravida Mode of delivery
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 preeclampsia, primary cesarean delivery rates were not significantly different between the 2 groups. The Figure demonstrates the most common indications for delivery among this cohort. Women with superimposed preeclampsia were more likely to be delivered for uncontrollable, elevated blood pressures (57% vs 39%, P <.001), and pregnancies complicated by mild preeclampsia were delivered more commonly for the development of persistent neurologic or gastrointestinal symptoms (20% vs 6%, P < .001). Although patients with mild preeclampsia had significantly shorter hospitalization stays compared to women with superimposed preeclampsia, no difference in the latency periods between diagnosis and delivery among the 2 groups were appreciated, even after stratification at <34 or 34-366/7 weeks of gestation (Tables 1 and 2). Pulmonary edema was more frequently observed in pregnancies with superimposed preeclampsia, particularly deliveries <34 weeks of gestation. Maternal adverse composite outcome occurred more frequently in women with superimposed preeclampsia (15%) compared to those
with preeclampsia (5%) (relative risk [RR], 3.0; 95% CI, 1.45e6.29). The rate of adverse maternal outcome was significantly higher in women with superimposed preeclampsia delivered at later preterm gestational ages between 34-366/7 weeks (RR, 4.0; 95% CI, 1.13e14.39), as compared to <34 weeks of gestation (RR, 2.3; 95% CI, 0.95e5.64; Table 3). Prior to stratification into 2 preterm gestational age categories, small for gestational age (26% vs 16%, P ¼ .02) and low birthweight (1941 790 vs 2161 834 g, P < .001) were more frequent among neonates born to mothers with superimposed preeclampsia, but no significant difference in the frequency of critical neonatal complications such as necrotizing enterocolitis, RDS, neonatal mortality, or intraventricular hemorrhage was appreciated between the 2 groups. Table 4 presents differences in neonatal outcomes between the 2 groups stratified by gestational age at delivery. Aside from a 5-minute Apgar score <7, no significant differences in estimated gestational age at delivery or neonatal outcomes were detected between women with preeclampsia and superimposed preeclampsia when
stratified between <34 or 34-366/7 weeks of gestation. However, compared to 34-366/7 weeks, both cohorts delivering <34 weeks of gestation had higher rates of adverse neonatal composite morbidity and mortality. A total of 8 perinatal losses occurred in the study cohort with all deliveries <34 weeks of gestation. There were 2 cases of stillbirth in the 24th week of pregnancy, both complicated by intrauterine growth restriction with estimated fetal weights of <300 g in the superimposed preeclampsia cohort. Five neonatal deaths were among extremely preterm births at <26 weeks of gestation in both study groups.
C OMMENT This study is one of the first and largest to compare the maternal and neonatal outcomes following expectant management of pregnancies with mild preeclampsia and superimposed preeclampsia up to 37 weeks of gestation. Our multicenter, observational study demonstrates that expectant, inpatient management of these 2 diseases result in similar neonatal outcomes. Without the presence of severe disease at the time of admission, they have comparable mean latency periods from diagnosis to delivery irrespective of the gestational age at diagnosis. We found that women with superimposed preeclampsia were more commonly black, older, multiparous, and required oral antihypertensive therapy, which is consistent with previous studies.19 This higher frequency of antihypertensive treatment may be indicative of ongoing chronic treatment of their underlying disorder rather than a marker of progressive, severe disease during pregnancy. Antihypertensive therapy has not been shown to improve rates of preterm birth or progression to superimposed preeclampsia but is recommended to reduce the risk of severe hypertension, worsening end-organ damage, and maternal complications including cerebral hemorrhage and infarction.12,20,21 Physicians are aware of the increased perinatal risks among chronic hypertensive women, likely resulting in a lower threshold for
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FIGURE web 4C=FPO
Indications for delivery
Bar graph representing common indications for delivery in pregnancies complicated by superimposed 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 fetal surveillance. *Persistent neurological or gastrointestinal symptoms. Valent. Expectant management of preeclampsia. Am J Obstet Gynecol 2014.
conservative inpatient supervision, aggressive blood pressure management, and longer hospitalizations. Hypertensive exacerbations and undiagnosed
microvascular disease can complicate the clinical picture, diagnosis, and management strategies. However, our study shows that with careful inpatient
TABLE 2
Maternal outcomes Superimposed preeclampsia, n [ 171
Outcome variable EGA at diagnosis, wk
314/7 33/7
Latency, d Days in hospital Severe preeclampsia
Preeclampsia, n [ 186
P value
324/7 31/7
.004
10 13 5 [2e11]
88 5 [3e10]
.12
13 12 9 [6e16]
10 7 8 [6e11]
< .001
149 (87)
157 (84)
.56
Pulmonary edema
7 (4)
0 (0)
.01
Placental abruption
11 (6)
5 (3)
.18
Thrombocytopenia
8 (5)
12 (6)
.62
24 (14)
29 (16)
.79
Oliguria
7 (4)
5 (3)
.66
HELLP
2 (1)
7 (4)
.22
1 (1)
1 (1)
25 (15)
9 (5)
Elevated liver enzymes
Eclampsia Maternal composite
a
1.0 .003
Continuous variable are presented as mean SD or median [interquartile range]. Dichotomous variables are presented as number (percent). 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.
Valent. Expectant management of preeclampsia. Am J Obstet Gynecol 2014.
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management, women with superimposed preeclampsia can continue pregnancy >34 weeks of gestation with titrating doses of antihypertensives as long as the blood pressure responds to these increases. Women in both groups were found to have high rates of neonatal mortality and respiratory morbidities, especially deliveries <34 weeks of gestation. Hypertensive disorders may contribute to impaired fetal growth and increase the risk for birth of small-for-gestational-age infants.22,23 Consistent with previously published studies, we found that women with superimposed preeclampsia had higher rates of small for gestational age and overall lower average birthweights than patients with mild preeclampsia, but no difference was observed when stratified by gestational age at delivery.3,9,24 This could be explained in part by the increased use of oral antihypertensive maintenance therapy in superimposed preeclamptic patients, which is known to reduce mean arterial pressure and is associated with small for gestational age independent of duration of therapy.25 Given the minimal observed difference in frequency of these adverse neonatal outcomes with a probability value >5%, we conclude that no significant difference in neonatal outcomes occurs following births to superimposed preeclampsia and mild preeclampsia pregnancies managed expectantly in the late preterm period. Similarly, the likelihood of an adverse neonatal outcome for births <34 weeks of gestation did not differ between the 2 cohorts but the frequency of adverse neonatal morbidity was significantly higher (94-97%) than those managed and delivered between 34-366/7 weeks of gestation. We did observe a higher frequency of RDS in late preterm infants than is commonly reported in prospectively performed studies.26 This may be related to misclassification of some cases of oxygen requirement or respiratory complications as RDS that may not have not have met strict criteria for RDS if defined as such prospectively. Despite this, it is unlikely that RDS cases were
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TABLE 3
Maternal outcomes stratified by preterm gestational age groups <340/7 wks of gestation Superimposed preeclampsia, n [ 92
Outcome variable EGA at diagnosis, wk
29
2/7
2
5/7
8.6 11.1
Latency, d Days in hospital
12.2 9.1
Severe preeclampsia
34-366/7 wks of gestation Preeclampsia, n [ 80 30
1/7
2
5/7
P value
Superimposed preeclampsia, n [ 79 6/7
2
4/7
Preeclampsia, n [ 106
P value
1
.22
34
4/7
6/7
.08
33
6.2 4.1
.06
11.7 15.6
8.5 9.6
.09
9.6 3.7
.02
14.6 14.2
9.1 7.7
< .001
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
1.0
Elevated liver enzymes
12 (13)
10 (12)
12 (15)
19 (18)
Oliguria
4 (4)
2 (2)
.82
3 (4)
3 (3)
1.0
HELLP
1 (1)
5 (6)
.15
1 (1)
2 (2)
1.0
1 (1)
1 (1)
0 (0)
0 (0)
1.0
16 (17)
6 (8)
9 (11)
3 (2)
Eclampsia Maternal composite
a
1.0 .08
.77
.04
Continuous variable are presented as mean SD. Dichotomous variables are presented as number (percent). 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.
Valent. Expectant management of preeclampsia. Am J Obstet Gynecol 2014.
differentially misclassified between the superimposed preeclampsia and mild preeclampsia groups. The majority of pregnancies in this study complicated by superimposed preeclampsia and mild preeclampsia developed severe preeclampsia. Compared to previous severe preeclampsia studies and acknowledging variance in sample sizes, similar rates of HELLP and placental abruption were observed in this study.11,13 Tuuli et al19 retrospectively studied the same pregnancy populations but observed lower rates of placental abruption. However, their study included patients over an 18 year period and disease management has changed progressively during this time. Although a higher frequency of overall composite maternal morbidity was observed in women with superimposed preeclampsia, the statistical differences in the overall composite morbidity between 34-366/7 weeks of gestation were driven by increased rates of placental abruption without a significant difference in neonatal outcome compared to pregnancies with mild preeclampsia. Expectant management >34 weeks of
gestation did not increase the risk of serious maternal complications such as HELLP, eclampsia, or pulmonary edema. Higher rates of pulmonary edema were observed among women with superimposed preeclampsia but all of the events occurred <34 weeks and not in later gestational ages. Severe hypertension was a more frequent delivery indication for women with superimposed preeclampsia compared to worsening neurologic or gastrointestinal symptoms in those women with mild preeclampsia. An acute hypertensive crisis commonly precipitates pulmonary edema causing significant vasoconstriction, increased afterload, and redistribution of fluid centrally into pulmonary circulation, placing all women with preeclampsia at increased risk.27,28 Alternatively, these women may represent advanced endothelial dysfunction predisposing them to disease progression or insufficient maternal immunologic response or tolerance at an early gestation. The latency duration found in this study is consistent with previously
published studies reporting an average duration between 8.4-9.7 days in pregnancies complicated by superimposed preeclampsia.13,14 However, prior studies followed management recommendations suggested for severe preeclampsia in women diagnosed with superimposed preeclampsia, delivering at 34 weeks of gestation even in the absence of signs or symptoms of severe disease. The practice of planned early delivery at 34 weeks for women with superimposed preeclampsia in the previously reported studies may have influenced the reported outcomes, possibly demonstrating shorter latency periods and more adverse neonatal outcomes related to prematurity. Expectant management in the preterm period and delivery at 37 weeks, unless earlier delivery was indicated due to the development of signs or symptoms of severe disease, is consistent with the most recent recommendations from the ACOG Task Force on Hypertension in Pregnancy.7 This study was performed prior to the institution of the task force guidelines for management. However, removal of 5 g of proteinuria and fetal
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TABLE 4
Neonatal outcomes <340/7 wks of gestation Superimposed preeclampsia, n [ 92
Outcome variable
4/7
2
4/7
34-366/7 wks of gestation Preeclampsia, n [ 80 0/7
2
P value
Superimposed preeclampsia, n [ 79
4/7
.18
35
5/7
1
0/7
EGA at delivery
30
Days in hospital
34.4 28.2
39.8 32.3
.25
6.0 4.6
NICU admission
86 (93)
71 (89)
.41
35 (44)
5-min Apgar 7
31
Preeclampsia, n [ 106 35
6/7
1
0/7
7.3 9.0
P value .17 .24
49 (46)
.91
15 (16)
16 (20)
.67
16 (20)
7 (7)
.01
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 (1)
2 (2)
1.0
NEC
7 (8)
4 (5)
.71
0 (0)
1 (1)
1.0
13 (14)
13 (16)
.86
14 (18)
20 (19)
1.0
9 (10)
7 (9)
1 (1)
3 (3)
6 (7)
2 (3)
.38
0 (0)
0 (0)
89 (97)
75 (94)
.57
38 (48)
53 (50)
Birthweight, g
a
Suspected sepsis IVH Death
Neonatal composite
b
1.0
1.0
.87 1.0 .92
Continuous variable are presented as mean SD. Dichotomous variables are presented as number (percent). BPD, bronchopulmonary dysplasia; EGA, estimated gestational age; IVH, intraventricular hemorrhage of any grade; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; RDS, respiratory distress 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).
Valent. Expectant management of preeclampsia. Am J Obstet Gynecol 2014.
growth restriction as indications for delivery in the new recommendations would not have changed the outcomes of this study as they were not direct indications for delivery at any participating center. Although the old criteria had oliguria as a sign of severe disease, the frequencies of oliguria were not statistically significant between the 2 groups and would not have changed the rate of adverse maternal outcome in our study. A major strength of this study is the large number of patients managed at 4 tertiary level centers, representing wide national demographic regions and populations; therefore, we believe our findings are widely generalizable. This study addresses an issue that is not well studied and important in perinatal management. We specifically excluded patients from this study with other serious disease comorbidities such as renal disease, systemic lupus erythematosus, and other end-organ dysfunction. Likely through different disease processes, women with these disease states have risks for
worse perinatal outcomes regardless of inclusion in either group and would not represent the risks and outcomes specifically of these hypertensive diseases focused in this study. This study faces the inherent weaknesses of any observational study. Relying on International Classification of Diseases, Ninth Revision codes for hypertensive diseases and preterm birth, not all patients who meet inclusion criteria may have been identified at all participating centers. The maternal-fetal medicine specialists at each institution may have variations in management and practicing styles despite all centers consistently managing both patient cohorts expectantly until 37 weeks of gestation during the study period. Exclusion of other comorbidities, especially pregestational diabetes, may somewhat limit the generalizability of our findings to all patient populations presenting with chronic hypertension and preeclampsia; however, we believe these patients represent a unique
high-risk population who warrant individualized management regardless of additional pregnancy complications. Selection bias could influence the study findings as physicians may have chosen to deliver women with superimposed preeclampsia who were perceived to be at higher risk immediately, leaving a lower risk study population that may not represent the risks and outcomes of this entire cohort. When the 2 groups were further stratified by gestational age at delivery (<34 and 34-366/7 weeks), our study groups were further restricted in numbers and limited the sample size to detect a true difference for more rare adverse outcomes. However, the statistically significant findings represent true risk differences. We found considerable perinatal morbidity and mortality risks associated with preeclampsia and chronic hypertension with superimposed preeclampsia. However, compared to each other, neonatal complication rates do not differ irrespective of gestational age. Although
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at later gestational ages maternal adverse outcomes are increased predominantly in women with superimposed preeclampsia, overall adverse neonatal morbidity is much lower without an increase in serious maternal morbidities. This study further supports both cohorts and especially superimposed preeclampsia should be managed at centers where appropriate maternal and neonatal resources are available. As currently practiced among women with mild preeclampsia, it is reasonable and safe to manage superimposed preeclampsia similarly with close inpatient observation and delivery at 37 weeks of gestation, unless an earlier indication arises based on worsening disease, to decrease neonatal morbidity. This retrospective study creates the basic platform to study both populations prospectively with larger cohorts to clearly determine if these are 2 different disease processes and truly require different delivery management and timing. ACKNOWLEDGMENT The authors thank Suneet Chauhan, MD, for his contribution to the study design and support for the development of this study.
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