Objective
We sought to compare maternal and neonatal outcomes of expectantly managed pregnancies complicated by chronic hypertension with superimposed preeclampsia vs mild preeclampsia up to 37 weeks of gestation.
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 34-36 6/7 weeks of gestation.
Results
We found no significant differences in rates of neonatal composite morbidity or latency periods between women with superimposed preeclampsia and mild preeclampsia. Adverse neonatal outcomes were significantly higher at <34 compared to 34-36 6/7 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 = .003; relative risk, 3.0; 95% confidence interval, 1.45–6.29).
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.
Hypertensive 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. These conditions markedly increase the risk of both maternal and neonatal morbidity and mortality.
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. 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. 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 management. The ACOG Practice Bulletin, addressing chronic hypertension in pregnancy, recommends delivery at 34 weeks of gestation for patients with superimposed preeclampsia. Management and delivery timing in this patient population is based on indirect conclusions from severe preeclampsia studies. 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. 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.
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. 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. 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. 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.
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 expectantly in the hospital <37 weeks of gestation. Secondary goal of this study is to analyze outcomes of pregnancies that are stratified between 34-36 6/7 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.
Materials and Methods
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.
This study was approved by the institutional review board at the University of Cincinnati, Cincinnati, OH (#12-03-02-01) 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 24 0/7 and 36 6/7 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 >34 0/7 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 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 24-hour 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 well-being. 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/μL) 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 were compared after stratification by gestational age into pregnancies that delivered <34 and between 34-36 6/7 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 >36 6/7 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.
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 χ 2 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.
Results
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 women diagnosed with mild preeclampsia, primary cesarean delivery rates were not significantly different between the 2 groups.
| Characteristic | Superimpose preeclampsia, 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 antihypertensive medications | 128 (75) | 15 (1) | < .001 |
| Regimen with ≥1 medication | 43 (25) | 0 (0) | < .001 |
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 34-36 6/7 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, 1.45–6.29). The rate of adverse maternal outcome was significantly higher in women with superimposed preeclampsia delivered at later preterm gestational ages between 34-36 6/7 weeks (RR, 4.0; 95% CI, 1.13–14.39), as compared to <34 weeks of gestation (RR, 2.3; 95% CI, 0.95–5.64; Table 3 ).
| Outcome variable | Superimposed preeclampsia, n = 171 | Preeclampsia, n = 186 | P value |
|---|---|---|---|
| EGA at diagnosis, wk | 31 4/7 ± 3 3/7 | 32 4/7 ± 3 1/7 | .004 |
| Latency, d | 10 ± 13 5 [2–11] | 8 ± 8 5 [3–10] | .12 |
| Days in hospital | 13 ± 12 9 [6–16] | 10 ± 7 8 [6–11] | < .001 |
| Severe preeclampsia | 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 |
| Elevated liver enzymes | 24 (14) | 29 (16) | .79 |
| Oliguria | 7 (4) | 5 (3) | .66 |
| HELLP | 2 (1) | 7 (4) | .22 |
| Eclampsia | 1 (1) | 1 (1) | 1.0 |
| Maternal composite a | 25 (15) | 9 (5) | .003 |
a Morbidity defined as ≥1 of the following: pulmonary edema, placental abruption, eclampsia, oliguria.
| Outcome variable | <34 0/7 wks of gestation | 34-36 6/7 wks of gestation | ||||
|---|---|---|---|---|---|---|
| Superimposed preeclampsia, n = 92 | Preeclampsia, n = 80 | P value | Superimposed preeclampsia, n = 79 | Preeclampsia, n = 106 | P value | |
| EGA at diagnosis, wk | 29 2/7 ± 2 5/7 | 30 1/7 ± 2 5/7 | .08 | 33 6/7 ± 2 4/7 | 34 4/7 ± 1 6/7 | .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 composite a | 16 (17) | 6 (8) | .08 | 9 (11) | 3 (2) | .04 |
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