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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama; The Emmes Corporation, Potomac, Maryland; Division of Epidemiology, Statistics, and Prevention Research, National Institute of Child Health and Human Development, Bethesda, Maryland; Department of Obstetrics and Gynecology, University of Tennessee College of Medicine, Memphis, Tennessee; Department of Obstetrics and Gynecology, University of New Mexico Health Sciences Center Albuquerque, New Mexico; Department of Obstetrics and Gynecology, Metro Health Medical Center, Case Western Reserve University, Cleveland, Ohio; and Department of Medicine, Oregon Health Sciences University, Portland, Oregon.
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Abstract |
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Methods: We conducted (and reported elsewhere) a randomized, double-masked, placebo-controlled trial calcium supplementation of 4589 healthy nulliparas assigned at 13–21 weeks’ gestation. This well-defined and characterized data set provided an opportunity to detail more precisely adverse maternal, fetal, and newborn outcomes in women who developed hypertension among a prospective series of healthy nulliparas.
Results: Of 4302 women observed to or beyond 20 weeks’ gestation, 1073 (24.9%) developed mild or severe pregnancy-associated hypertension or preeclampsia. One hundred sixteen women of the 1073 with hypertension (10.8%) and 336 of the 3229 without hypertension (10.4%) were delivered before 37 weeks’ gestation. Fetal and neonatal mortality were similar in those groups; however, selected maternal and newborn morbidities were significantly greater in women with hypertension. Significantly increased maternal morbidities included increased cesarean deliveries, abruptio placentae, and acute renal dysfunction; and significantly increased perinatal morbidities included respiratory distress syndrome, ventilatory support, and fetal growth restriction. Adverse outcomes were highest in women with severe pregnancy-associated hypertension or preeclampsia.
Conclusion: Hypertension, especially severe hypertension, was associated with an appreciable increase in important maternal and perinatal morbidity but not perinatal mortality.
In a recent randomized, double-masked trial of daily maternal dietary calcium supplementation,1 we found that treatment did not alter the occurrence of preeclampsia, pregnancy-associated hypertension, or small for gestational age births. For this planned secondary analysis we combined outcomes in women who received calcium or placebo daily supplementation. The well-defined and characterized data set provided us more precisely detailed adverse maternal and perinatal outcomes. Our objectives in this secondary analysis were to determine whether there was increased frequency of maternal, fetal, or newborn sequelae among women who developed hypertension compared with normotensive women, and to evaluate the relationship between the severity of hypertension with and without proteinuria and frequency of those sequelae.
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Materials and Methods |
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The study included only women who had blood pressures (BPs) below 135/85 mmHg and no proteinuria by dipstick at randomization. Women with medical or obstetric complications and those with known fetal complications (multifetal gestation, hydatidiform mole, or chromosomal or major congenital anomalies) at baseline were excluded. At initial visits, medical histories and demographic data were collected. Subjects were seen then by trained research staff at clinic visits scheduled every 4 weeks through 29 weeks’ gestation, every 2 weeks between 30 and 35 weeks, and weekly thereafter. Seated BP was measured by the same research staff using a standard mercury sphygmomanometer according to a published protocol. Two measurements taken at least 1 minute apart were averaged. Diastolic BP was determined using the fifth Korotkoff sound unless one or both measurements were zero, in which case the fourth sound was used. Voided urine specimens were collected for measurement of protein by dipstick. Dipsticks indicating proteinuria at least 1+ (300 mg/L) were confirmed in clean-catch, midstream urine samples. A dipstick of zero or trace in the confirmatory sample was considered negative.
Pregnancy-associated hypertension was defined as diastolic BP at least 90 mmHg on two occasions 4–168 hours apart. Severe pregnancy-associated hypertension was defined as diastolic BP of at least 110 mmHg on two occasions 4–168 hours apart, or one occasion if the woman received antihypertensive medications before diastolic BP of 110 mmHg or during the ensuing 168 hours. Severe pregnancy-associated hypertension also was diagnosed when hypertension was complicated by oliguria (one subject) (under 400 mL per 24 hours), pulmonary edema (one subject), or thrombocytopenia (seven subjects) (two platelet counts under 100,000/mm3) without other known causes. Proteinuria was defined as at least 300 mg protein in a 24-hour urine collection, two random urine specimens 4–168 hours apart containing at least 1+ protein by dipstick, a single urine sample with a protein/creatinine ratio at least 0.35, or a single random urine specimen containing at least 2+ protein by dipstick. After rupture of the membranes or with vaginitis, urine specimens were collected by catheter. Severe proteinuria was diagnosed by 24-hour urine containing at least 3.5 g protein or two random urine specimens with at least 3+ protein by dipstick. Preeclampsia was defined as pregnancy-associated hypertension plus proteinuria within 7 days of each other. Severe preeclampsia was defined as severe hypertension with proteinuria; mild hypertension with severe proteinuria; development of hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome (nine subjects); or eclampsia (eight subjects).
Comparative end points included clinically diagnosed abruptio placentae, acute renal dysfunction (increase in serum creatinine at least 0.5 mg/dL over baseline), cesarean delivery, and preterm birth (before 37 weeks’ gestation). Selected perinatal outcomes were documented by newborn chart review and included admission to the neonatal intensive care unit (NICU), respiratory distress syndrome (RDS), ventilatory support, intraventricular hemorrhage, birth weight under 2500 g, fetal growth restriction (FGR) (below the tenth percentile according to the standards of Brenner et al3), and fetal or neonatal death.
Incidence rates of perinatal and maternal outcomes were computed with respect to hypertensive disease status. Rates were computed for the normotensive, mild pregnancy-associated hypertension, severe pregnancy-associated hypertension, mild preeclampsia, and severe preeclampsia groups. After preliminary examination of results, the mild pregnancy-associated hypertension and mild preeclampsia groups and the severe pregnancy-associated hypertension and severe preeclampsia groups were combined and are presented separately.
Effect estimates (not shown) for each category of hypertensive disease with reference to normotensive women were estimated from logistic regression models fit to dichotomous outcomes and linear regression models fit to continuous outcomes. The logistic regression model could not be fitted to some of the rarer perinatal outcomes using large sample methods, so exact conditional inference was done using the LOGXACT (Cytel Software Corp., Cambridge, MA) package. Effects found to be significant at the .005 or .001 level are highlighted in the tables.
Odds ratios (ORs) and linear effect estimates were reported after adjustment for potential confounding from clinical centers (Albuquerque, Birmingham, Cleveland, Memphis, and Portland), randomized treatment assignment (calcium or placebo), and race-ethnicity (white non-Hispanic, white Hispanic, black, and other–Missing). The confounders appear as strata in the conditional logistic regression models and as main effects in the linear regression models. To avoid spurious results, a confidence coefficient of 99.9% was used for all reported confidence intervals (CIs).
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for all five groups. Fetal and neonatal mortalities were similar in all groups. In each of the four hypertensive categories, various maternal or perinatal outcomes were significantly higher than in normotensive women. The outcomes listed in Table 2 were generally of similar frequency in the subgroups of mild pregnancy-associated hypertension or preeclampsia and among women with severe pregnancy-associated hypertension or severe preeclampsia. To increase the population among groups and increase assurance of the associations in Table 2, we analyzed selected maternal and perinatal outcomes in women who remained normotensive compared with those in the mild or severe categories of hypertension diagnoses in Table 3. Fetal and neonatal deaths were not increased in women with severe hypertension diagnoses and were significantly less (P < .05) in women with mild hypertension or preeclampsia compared with women with no hypertension. Selected adverse maternal and perinatal outcomes were increased in women who developed hypertension. Women with severe hypertension were at highest risk for adverse maternal or perinatal outcomes (Table 3). Adjusted ORs with 99.9% CIs for selected maternal and perinatal outcomes are presented in Tables 4 and 5.
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Discussion |
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Perinatal and fetal death rates were similar among our three groups, in contrast to the report of Friedman and Neff.4 We believe the similarities might be due to improvements in antepartum surveillance, assessments of fetal well-being, and newborn care over the 2 decades since their report. In our trial, even in women with severe pregnancy-associated hypertension or severe preeclampsia, the fetal death rate was 14.2 per 1000, similar to that reported by Friedman and Neff in women with mild hypertension. In our study, the fetal death rate in normotensive women or those who developed only mild pregnancy-associated hypertension or preeclampsia was 7.45 per 1000, which corresponds to the rate reported by Friedman and Neff in women with no hypertension or proteinuria. Ferrazzani et al5 reported a perinatal mortality rate of 129 per 1000 in 147 women with proteinuric preeclampsia, and Lin et al6 reported a rate of 127 per 1000 in 79 nulliparas with preeclampsia. In our nulliparas, the perinatal mortality rate was similar in each of the three groups (range 6–21 per 1000). It is not likely that future interventions to reduce pregnancy-associated hypertension or preeclampsia will associate with concomitant reductions in perinatal mortality. However, successful interventions could reduce important maternal and neonatal morbidities that increased in women who developed pregnancy-associated hypertension or preeclampsia, especially in those who developed severe hypertension diagnoses. In a clinical trial of an intervention to prevent preeclampsia, incidence of morbidities in this population will allow calculation of the sample needed to find a significant reduction of those morbidities.
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Footnotes |
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Received November 3, 1998. Received in revised form June 11, 1999. Accepted June 24, 1999.
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2. Levine RJ, Esterlitz JR, Raymond EG, DerSimonian R, Hauth JC, Curet B, et al. Trial of calcium for preeclampsia prevention (CPEP): Rationale, design, and methods. Control Clin Trials 1996;17:442–9.[Medline]
3. Brenner WE, Edelman DA, Hendricks CH. A standard of fetal growth for the United States of America. Am J Obstet 1976;126:555–64.[Medline]
4. Friedman EA, Neff RK. Pregnancy outcome as related to hypertension, edema, and proteinuria. In: Lindheimer MD, Katz AI, Zuspan FP, eds. Hypertension in pregnancy. New York: Wiley, 1976:13.
5. Ferrazzani, Caruso A, De Carolis S, Martino IV, Mancuso S. Proteinuria and outcome of 444 pregnancies complicated by hypertension. Am J Obstet Gynecol 1990;162:366–71.[Medline]
6. Lin CC, Lindheimer MD, River P, Moawad AH. Fetal outcome in hypertensive disorders of pregnancy. Am J Obstet Gynecol 1982; 142:255–60.[Medline]
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