Objective
The purpose of this study was to assess recurrence rates of preeclampsia and neonatal outcomes in women with a history of preeclampsia that required preterm delivery.
Study Design
Five hundred women with previous preeclampsia that required delivery at <37 weeks’ gestation were followed prospectively.
Results
Preeclampsia reoccurred in 117 women (23%). Predictive factors included black (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.16–4.53) or Asian (OR, 2.98; 95% CI, 1.33–6.59) ethnicity, enrollment systolic blood pressure of >130 mm Hg (OR, 2.89; 95% CI, 1.52–5.50), current antihypertensive use (OR, 6.39; 95% CI, 2.38–17.16), and proteinuria of ≥2+ on enrollment urinalysis (OR, 12.35; 95% CI, 3.45–44.21). Women who previously delivered at <34 weeks’ gestation were more likely to deliver preterm again (29% vs 17%; relative risk, 1.69; 95% CI, 1.19–2.40) than were those women with previous delivery between 34 and 37 weeks’ gestation.
Conclusion
Although this study confirms that women with previous preeclampsia that required early delivery are at high risk of the development of preeclampsia, the study identifies risk factors for recurrence and illustrates that women with previous preeclampsia are at greater risk of adverse neonatal outcome.
Preeclampsia is a multisystem disorder that complicates approximately 4-6% of pregnancies in the United Kingdom and is associated with maternal and fetal death and morbidity. Women with a history of preeclampsia have a higher risk of the development of preeclampsia in subsequent pregnancies, but the likelihood or recurrence is poorly defined; previous studies have either included a majority of women who delivered at >37 weeks’ gestation in whom the risk of recurrence is low or have relied on information that was drawn from routinely collected clinical data in which the accuracy of diagnosis may be imprecise. Women with previous preeclampsia that required delivery at <34 weeks’ gestation are of particular concern because it is recognized that they are at greater risk of recurrent disease and worse fetal outcome. The risk of the development of preeclampsia in these women is also uncertain because previous reports have been of atypical populations and/ or small numbers of women.
Recurrent preeclampsia has also been associated with increased rates of preterm delivery, delivery of a small-for-gestational-age (SGA) infant, and perinatal death in women with recurrent preeclampsia when compared with preeclampsia in a first pregnancy. Although a higher rate of associated neonatal complications might be anticipated, this has not been investigated formally.
In this study, we report the results of a planned secondary analysis of women with a history of preeclampsia who were recruited as part of a prospective randomized control trial of vitamin C and E supplementation in women who were at increased risk of preeclampsia, for whom previous preeclampsia (delivery at <37 weeks’ gestation) was 1 of 8 entry criteria. The objectives of this analysis were to determine the incidence of recurrent disease in women with previous preeclampsia and to identify predictive risk factors for subsequent preeclampsia. A further objective was to define the neonatal outcome in those who did and did not experience recurrent disease, in particular for those who previously delivered at <34 weeks’ gestation.
Materials and Methods
A randomized placebo controlled trial of vitamin C and E supplementation (the Vitamins in Preeclampsia trial, VIP no. ISRCTN 62368611) was completed between August 2003 and June 2005. All 2404 women who were recruited were considered to be at increased risk for the development of preeclampsia according to at least 1 of 8 defined criteria ( Figure ). They included 500 women with singleton pregnancies who had preeclampsia at <37 weeks’ gestation in their most recent pregnancy.
After recruitment at 14 +0 -21 +6 weeks’ gestation, women were assigned randomly to receive placebo preparations or 1000 mg vitamin C and 400 IU vitamin E daily until delivery. There was no significant difference in the primary outcome of preeclampsia between women who received placebo or treatment. In subgroup analyses of women with previous preeclampsia, there were no significant differences in preeclampsia, low birthweight, or SGA infants in the control and intervention arms; consequently, data for women in the placebo and intervention arms were analyzed together. Trial participants with multiple pregnancies were excluded from the analysis.
Personal and demographic details, which were obtained at the enrollment visit, and pregnancy outcome were recorded in a customized secure password-protected internet-based study-specific database. Urinalysis was confirmed by a routine visual dipstick from a midstream urine sample that was collected by clinical midwives.
The South East Multi Ethics Research Committee provided ethics approval (no. 00/01/027), and site-specific approval was obtained from all participating centers.
Definitions
Inclusion criteria for this analysis were previous preeclampsia that was defined as preeclampsia in the pregnancy preceding the index pregnancy that required delivery at <37 completed weeks’ gestation. Chronic hypertension was defined as a diastolic blood pressure of ≥90 mm Hg (Korotkoff Stage 5) at the enrollment visit or at <20 weeks’ gestation or the use of current or previous antihypertensive medication. For women with chronic hypertension and no proteinuria, a diagnosis of preeclampsia was defined as the new development of proteinuria in accordance with the International Society of Study of Hypertension in Pregnancy (ISSHP) guidelines. In women with preexisting proteinuria or hypertension, a diagnosis of preeclampsia was based on the development of gestational hypertension or proteinuria or after the identification of clinical or biochemical markers or at least 1 additional feature of preeclampsia (eg, HELLP [hemolysis, elevated liver enzymes, low platelets] syndrome or eclampsia). In women with both essential hypertension and preexisting proteinuria, the diagnosis was confirmed by 2 senior clinical staff members who acted independently who sought additional features of preeclampsia, as outlined in the ISSHP guidelines. Severe preeclampsia was defined according to ISSHP guidelines as diastolic blood pressure of >110 mm Hg with proteinuria as defined earlier.
Birthweights were assessed by customized birthweight percentile charts ( www.gestation.net/birthweight_centiles/centile_online.htm ); SGA was considered to be <10th percentile. The following available data were also used in analysis: preterm birth (<37 and <34 weeks’ gestation, both spontaneous and iatrogenic), gestational age at delivery, perinatal death (intrauterine death at >24 weeks’ gestation or postnatal by 7 days), antenatal inpatient nights and mode of delivery, and admission to neonatal unit.
Statistical analysis
Categoric variables were summarized with the use of percentages and compared with the use of the χ 2 test. Risk ratios with 95% confidence interval (CI) were calculated to determine the relationship between maternal and neonatal endpoints. Bootstrapping was used to develop confidence intervals for the difference in the arithmetic mean for indices of health care resources (maternal and neonatal inpatient stay). Risk factors for continuous outcome were analyzed by linear regression with robust standard errors and for binary outcome by logistic regression, which is expressed as odds ratio (OR) with 95% CI. A probability value of < .05 was determined to be statistically significant. Analysis was conducted with SPSS software (version 16; SPSS Inc, Chicago, IL) and Stata software (version 10.1; StataCorp, College Station, TX).
Results
Baseline demographics and management characteristics are provided in Table 1 for the 500 women with previous preeclampsia, according to the development of recurrent preeclampsia that occurred in 117 women (23%). Table 2 gives a comparison of maternal and neonatal outcomes in women who had preeclampsia in the index pregnancy and those who did not. The one maternal death occurred in a woman with chronic hypertension and human immunodeficiency virus who had recurrent preeclampsia. The death was subsequent to and unrelated to the pregnancy.
| Characteristic | No preeclampsia (n = 383; 77%) | Preeclampsia (n = 117; 23%) |
|---|---|---|
| Maternal age, y a | 31.1 ± 5.5 | 31.9 ± 5.4 |
| Gestational age at randomization, wk b | 18.2 (15.7–20.6) | 18.1 (15.6–20.4) |
| Ethnicity, n (%) | ||
| White | 309 (81) | 72 (61) |
| Black | 42 (11) | 26 (22) c |
| Asian | 23 (6) | 14 (12) d |
| Other | 9 (2) | 5 (3) |
| Smoking status, n (%) | ||
| Never | 228 (60) | 80 (68) |
| Current smoker (including occasional/social smoker) | 46 (12) | 10 (9) |
| Stopped before present pregnancy | 82 (21) | 21 (18) |
| Stopped during present pregnancy | 27 (7) | 6 (5) |
| Maternal weight, kg a | 28.0 ± 6.1 | 27.9 ± 5.6 |
| Body mass index, n (%) | ||
| <25 kg/m 2 | 137 (36) | 41 (35) |
| 25-30 kg/m 2 | 122 (32) | 43 (37) |
| 31-35 kg/m 2 | 71 (18) | 19 (16) |
| ≥35 kg/m 2 | 53 (14) | 14 (12) |
| Maternal baseline systolic blood pressure, mm Hg a | 121 ± 15 | 127 ± 14 e |
| <130 mm Hg, n (%) | 265 (69) | 58 (50) |
| 130-139 mm Hg | 64 (17) | 31 (26) f |
| ≥140 mm Hg | 54 (14) | 28 (24) f |
| Maternal baseline diastolic blood pressure, mm Hg | 73 (10) | 77 (10) c |
| <80 mm Hg, n (%) | 253 (66) | 55 (47) |
| 80-89 mm Hg, n (%) | 100 (26) | 46 (39) c |
| ≥90 mm Hg, n (%) | 30 (8) | 16 (14) g |
| Dipstick proteinuria | ||
| Normal/trace | 365 (95) | 96 (82) |
| + | 13 (3) | 9 (8) h |
| ≥ + + | 5 (1) | 12 (10) e |
| Additional risk factors at enrollment, n (%) i | ||
| Previous HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome | 40 (10) | 6 (5) |
| Previous eclampsia | 28 (7) | 5 (4) |
| Diabetes mellitus | 15 (4) | 3 (3) |
| Chronic kidney disease | 3 (0.8) | 4 (3.4) |
| Antiphospholipid syndrome | 6 (1.6) | 1 (0.9) |
| Chronic hypertension | 112 (29) | 49 (42) |
| Medication at enrollment, n (%) | ||
| Aspirin | 182 (48) | 71 (61) d |
| Heparin | 6 (1.6) | 0 |
| Current antihypertensive use | 41 (11) | 32 (27) e |
| Previous antihypertensive use | 67 (18) | 25 (21) |
| Subsequent additional medication after enrollment, n (%) | ||
| Oral antihypertensive use | 46 (58) | 53 (68) |
| Parenteral antihypertensive use | 1 (0.3) | 8 (6.8) e |
| Magnesium sulfate use | 5 (1.3) | 20 (17.1) e |
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