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Keywords:

  • Caesarean section;
  • early-onset pre-eclampsia;
  • fetal death;
  • placental abruption;
  • pre-eclampsia;
  • preterm birth;
  • small for gestational age

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References

Please cite this paper as: Chang J, Muglia L, Macones G. Association of early-onset pre-eclampsia in first pregnancy with normotensive second pregnancy outcomes: a population-based study. BJOG 2010;117:946–953.

Objective  To evaluate pregnancy outcomes in normotensive second pregnancy following pre-eclampsia in first pregnancy.

Design  Population-based retrospective cohort study.

Setting  State of Missouri in the USA.

Sample  White European origin or African-American women who delivered their first two non-anomalous singleton pregnancies between 20 and 44 weeks of gestation in Missouri, USA, 1989–2005, without chronic hypertension, renal disease or diabetes mellitus (n = 12 835).

Methods  Pre-eclampsia or delivery at 34 weeks of gestation or less in first pregnancy was defined as early-onset pre-eclampsia, whereas late-onset pre-eclampsia was defined as pre-eclampsia with delivery after 34 weeks of gestation. Multivariate regression models were fitted to estimate the crude and adjusted odds ratios and 95% confidence intervals.

Main outcome measures  Preterm delivery, large and small-for-gestational-age infant, Apgar scores at 5 minutes, fetal death, caesarean section, placental abruption.

Results  Women with early-onset pre-eclampsia in first pregnancy were more likely to be younger, African-American, recipients of Medicaid, unmarried and smokers. Despite a second normotensive pregnancy, women with early-onset pre-eclampsia in their first pregnancy had greater odds of a small-for-gestational-age infant, preterm birth, fetal death, caesarean section and placental abruption in the second pregnancy, relative to women with late-onset pre-eclampsia, after controlling for confounders. Moreover, maternal ethnic origin modified the association between early-onset pre-eclampsia in the first pregnancy and preterm births in the second pregnancy. Having a history of early-onset pre-eclampsia reduces the odds of having a large-for-gestational-age infant in the second pregnancy.

Conclusion  A history of early-onset pre-eclampsia is associated with increased odds of adverse pregnancy outcomes despite a normotensive second pregnancy.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References

Pre-eclampsia occurs in approximately 5–10% of nulliparous pregnancies.1 It is amongst the top three causes of maternal mortality in both developed and developing countries2,3 and is one of the leading causes of maternal and fetal morbidity.4 Women who experience pre-eclampsia are at increased risk for adverse pregnancy outcomes, with the prognosis depending on the severity of the disease and the gestational age at the time of disease onset and at delivery.5 Most pre-eclampsia has an onset near term, but approximately 10% of cases have an early onset before 34 weeks of gestation.6 It is believed that early-onset pre-eclampsia that requires preterm delivery has underlying pathology that differs and is more severe than that of late-onset pre-eclampsia.7 Early-onset pre-eclampsia has been associated with worse perinatal outcomes, such as small-for-gestational-age (SGA) infants, than pre-eclampsia that has onset at term.8,9 Early-onset pre-eclampsia is also characterised by increased severity, including HELLP (haemolysis, elevated liver enzymes and low platelet count) syndrome and placental abruption.9

Several studies have investigated the recurrence risk and subsequent pregnancy outcomes of women with a history of pre-eclampsia and eclampsia.9–11 However, few studies have examined the outcomes of a normotensive second pregnancy following pre-eclampsia. Even though the recurrence risk for pre-eclampsia is high, particularly among those with a history of early-onset pre-eclampsia, it does not recur in about 80% of women with a history of pre-eclampsia.12 It has been observed that, when pre-eclampsia does not reoccur in the second pregnancy, the overall obstetric outcome is favourable.13 Nonetheless, amongst the few studies that have examined pregnancy outcomes in subsequent normotensive pregnancy following pre-eclampsia in first pregnancy, these findings have been limited by the inclusion of women with chronic hypertension, lack of statistical power, failure to control for potential confounders and failure to classify women by gestational age at delivery or early- versus late-onset pre-eclampsia in first pregnancy.

Information regarding pre-eclampsia and its effects on subsequent pregnancy outcomes is essential in providing counselling to women with a history of pre-eclampsia and their caregivers to help them make important decisions pertaining to future pregnancies. Previous research has indicated that the mechanism of disease may be different in pregnancies that are complicated by pre-eclampsia at term compared with pregnancies that are preterm.7 In studying the effect of pre-eclampsia on subsequent pregnancy outcomes, it is important to stratify women by gestational age at delivery in pre-eclamptic pregnancies. The objective of the present study was to investigate the association between early-onset pre-eclampsia in first pregnancy and adverse maternal and perinatal outcomes in normotensive second pregnancy. The ethnic disparity in adverse maternal and fetal outcomes between African-American women and women of white European origin has been recognised for decades, and remains a major public health concern. Maternal ethnic origin has consistently been shown to be a contributing factor in maternal complications and adverse birth outcomes, including diabetes mellitus, pre-eclampsia, low-birth-weight infants and preterm delivery.14–17 Therefore, we further evaluated whether maternal ethnic origin is an effect modifier. Although racial group implies a specific genetic inheritance, ethnicity reflects culture and is therefore changeable. When analysing groups, such as a white European population versus an African-American population in the present study based on a US population, it is difficult to ascertain whether there is a genetic or environmental effect. In this study, no attempt has been made to distinguish between these two effects in the role of maternal ethnic origin as an effect modifier.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References

We conducted a population-based, retrospective cohort study of pregnancy outcomes in normotensive second pregnancy following pre-eclampsia in first pregnancy among women who reside in the state of Missouri, USA. The study was based on data from the Missouri maternally linked cohort, which links sibling birth certificate data with the use of maternal identifiers. The database includes a large quantity of data regarding each birth that occurs in the state, including parental demographic information, medical and obstetric characteristics and complications, and neonatal status at birth. Details on the methods used to link records of successive pregnancies, as well as the validation process of the linked reproductive histories, have been described elsewhere.18 Briefly, the degree of agreement across a set of common variables for two pregnancies (i.e. a ‘pair’) was used to calculate statistical weights.18 The pairs of pregnancies with the highest overall weights were selected on the basis of the level of agreement and a priority indicator of variables (i.e. birth date, maternal name) with exact matches.18 The linkage rate was 93% for women born in Missouri. The Missouri vital record system is considered to be very reliable and has been adopted as a ‘gold standard’ to validate other vital statistics datasets in the USA that involve matching and linking procedures.19 This research was reviewed by the Saint Louis University Institutional Review Board and was classified as exempt.

All women who had the condition ‘pregnancy-induced hypertension (pre-eclampsia)’ or ‘eclampsia’ checked for the first birth on the Missouri birth certificate were eligible for the present study. The entire cohort of Missouri maternally linked data, based on the old 1989 revision of birth certificates form, included all women who gave birth in the state between 1979 and 2005. Gestational age from the present study was based on the variable ‘clinical estimate of gestation’ from the birth certificate, because it is a more accurate reflection of gestational age at delivery than is the length of pregnancy calculated using the last menstrual period. However, the clinical estimated gestational age variable did not become a required field on the birth certificate until 1989. Therefore, we limited the analysis to the years from 1989 to 2005. Our study sample consists of women of white European origin or African-American women who delivered their first two non-anomalous singleton pregnancies between 20 and 44 weeks of gestation in Missouri between January 1, 1989 and December 31, 2005. In our study sample, about 7% (n = 16 920) of women experienced pre-eclampsia in the first pregnancy and, of those, 84% of women (n = 14 146) had a normotensive second pregnancy after having pre-eclampsia in the first pregnancy (Figure 1). In order to reduce the heterogeneity of the study population, multiple gestational births were excluded because of their potential confounding effect on the outcomes of interest. Women with medical problems in second pregnancy, such as chronic hypertension, renal disease and diabetes mellitus, were also excluded. Specifically, 9% (n = 1313) of women with normotensive second pregnancy and 13% (n = 370) of women with recurrent pre-eclampsia were excluded because of medical problems, such as chronic hypertension, renal disease and diabetes mellitus, in second pregnancy. This resulted in an analytical sample of 12 835 women with a history of pre-eclampsia in first pregnancy who had a normotensive second pregnancy (Figure 1).

image

Figure 1.  Study population.

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The outcomes of interest for the present study included preterm births, SGA infant, large-for-gestational-age (LGA) infant, low Apgar scores at 5 minutes (<7), fetal death, caesarean section and placental abruption in the second pregnancy. Preterm birth, as defined by the World Health Organisation (WHO), is delivery at <37 weeks of gestation.20 We focused our analysis on those preterm births occurring at <35 weeks in order to avoid borderline gestational ages, which are more prone to misclassification bias, and to identify the population of infants born at the earliest gestational age when prognoses are often poor. SGA and LGA infants were measured as those with birth weights below the 10th percentile and above the 90th percentile, respectively, for gestational age and ethnicity, with the US population serving as the reference for fetal growth.21 In accordance with the WHO definition of fetal death, cases were defined as those pregnancies that had a gestational age of 22 completed weeks with a fetal weight of 500 g or more.22 The caesarean section outcome referred to primary elective and emergency caesarean section as indicated on the birth certificate for the second pregnancy after a vaginal delivery in the first prengnacy. Pre-eclampsia with delivery at or before 34 weeks of gestation in first pregnancy was defined as early-onset pre-eclampsia, whereas late-onset pre-eclampsia was defined as pre-eclampsia with delivery after 34 weeks of gestation.23

Factors that may be associated with early-onset pre-eclampsia and the outcomes of interest were evaluated as potential confounders. Data for the following maternal demographic and lifestyle variables from the second pregnancy were obtained from the birth certificate: maternal age, ethnic origin (white European origin or African-American), marital status (single or married), smoking during pregnancy (yes or no), Medicaid use (yes or no), pre-pregnancy body mass index (BMI) and inter-pregnancy interval. For easier parameter estimate interpretation, maternal age was mean centred.24 BMI, calculated as weight (kilograms) per height squared (square metres), was categorised as underweight (BMI < 18.5 kg/m2), normal weight (BMI = 18.5–24.9 kg/m2), overweight (BMI = 25–29.9 kg/m2) and obese (BMI ≥ 30 kg/m2). Inter-pregnancy interval was calculated as the time (in years) from the first birth until conception of the second pregnancy (estimated from clinical gestational age), and was categorised as <1, 1–2, >2 to 4 and >4 years.

Statistical analysis

Differences in sample characteristics by gestational timing of pre-eclampsia in the first pregnancy were assessed using the Pearson chi-squared (χ2) test for categorical variables and the t-test for continuous variables. Multivariate binary logistic regression models were used to estimate the odds of SGA, LGA, preterm delivery, low Apgar scores, fetal death and placental abruption in the second pregnancy. A Poisson regression model with robust error variance was constructed to estimate the relative risk and 95% confidence intervals (95% CI) for caesarean section to avoid the pitfall of using the odds ratio to estimate the risk ratio when the outcome is common (greater than 10%).25 The estimated relative risk and 95% CI for caesarean section were further verified with a negative log-binomial regression model for common outcome.25,26 To reduce the bias in the estimation of risk, potential confounders were included in the multivariate analysis, including maternal age, marital status, smoking during pregnancy, Medicaid use, BMI and inter-pregnancy interval. To evaluate whether maternal ethnic origin is an effect modifier, the Wald test was used to test whether the regression coefficient of the product term of gestational timing of pre-eclampsia in the first pregnancy and maternal ethnic origin was statistically significantly different from zero. All tests were two-tailed and P < 0.05 was considered to be significant. All statistical analyses were performed with STATA (version 10.0, STATA Corp., College Station, TX, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References

The characteristics of the study participants are summarised by gestational timing of pre-eclampsia in the first pregnancy in Table 1. Compared with women with late-onset pre-eclampsia in first pregnancy, those who had a history of early-onset pre-eclampsia were younger and more likely to be African-American, to smoke during pregnancy, to be Medicaid recipients, to be unmarried and to have infants with a shorter inter-pregnancy interval and lower mean birth weight. We also compared the normotensive second pregnancy outcomes by early or late onset of pre-eclampsia in the first pregnancy, and the results are detailed in Table 2. Women who experienced early-onset pre-eclampsia in the first pregnancy were less likely to have LGA infants, but were more likely to have SGA infants, premature infants, fetal deaths, caesarean sections and placental abruption in the second normotensive pregnancy, compared with those who had late-onset pre-eclampsia in the first pregnancy.

Table 1.   Characteristics of study sample by gestational timing of pre-eclampsia in first pregnancy (n = 12 835)
CharacteristicPre-eclampsia (first pregnancy)*P value**
Early onset n (%)Late onset n (%)
  1. *Pre-eclampsia with delivery at or before 34 weeks of gestation in first pregnancy was defined as early-onset pre-eclampsia, whereas late-onset pre-eclampsia was defined as pre-eclampsia with delivery after 34 weeks.

  2. **P value for a chi-squared test for categorical variables and for a t-test for continuous variables.

Maternal age (years), mean (SD)25.6 (5.32)26.0 (5.2)<0.01
<20121 (11.7)1049 (8.9)0.03
20–29657 (63.5)7666 (65.0) 
30–34191 (18.5)2317 (19.6) 
35–3960 (5.8)675 (5.7) 
≥405 (0.5)94 (0.8) 
Maternal ethnic origin
White European origin795 (76.9)10018 (84.9)<0.01
African-American239 (23.1)1783 (15.1)
Smoking during pregnancy
No843 (81.69)9 913 (84.1)0.04
Yes189 (18.3)1871 (15.9)
Pre-pregnancy body mass index
Underweight51 (5.2)358 (3.1)<0.01
Normal433 (43.9)4502 (39.2)
Overweight226 (22.9)2972 (25.9)
Obese276 (28.0)3644 (31.8)
Medicaid use
No547 (53.1)7087 (60.2)<0.01
Yes483 (46.9)4686 (39.8)
Marital status
Married668 (64.6)8595 (72.9)<0.01
Unmarried366 (35.4)3202 (27.1)
Inter-pregnancy interval
<1 year253 (24.5)2460 (20.9)<0.01
1–2 years278 (26.9)3608 (30.6)
2+  to 4 years331 (32.1)3800 (32.3)
>4 years170 (16.5)1915 (16.3)
Mean birth weight in grams (SD)3086 (708.5)3417 (558.5)<0.01
Table 2.   Normotensive second pregnancy outcomes by gestational age of pre-eclampsia in first pregnancy (n = 12 835)
Perinatal outcome in second pregnancyPre-eclampsia status in first pregnancyP value*
Early onset n (%)Late onset n (%)
  1. *P value for a chi-squared test.

  2. **Restricted to live births.

  3. ***Among women who had a vaginal delivery in first pregnancy.

Small for gestational age**144 (14.1)894 (7.6)<0.01
Large for gestational age**82 (8.1)1477 (12.6)<0.01
Preterm delivery (<35 weeks)**97 (9.6)349 (3.0)<0.01
Low Apgar scores (<7 at 5 minutes)16 (1.6)124 (1.1)0.13
Fetal death10 (1.0)48 (0.4)0.01
Caesarean section***63 (14.4)712 (9.0)<0.01
Placental abruption24 (2.3)91 (0.8)<0.01

Because of the differences in the distribution of risk factors between the two study groups by gestational timing of pre-eclampsia in the first pregnancy, the analyses were adjusted for variables potentially associated with the outcomes of interest. After controlling for confounding, having a history of early-onset pre-eclampsia in the first pregnancy increased the odds of SGA by 75%, but reduced the odds of LGA by 36%, in a normotensive second pregnancy, compared with women who had late-onset pre-eclampsia in the first pregnancy (Table 3). Furthermore, the odds of having a preterm birth in the second normotensive pregnancy were three times as great in women with early-onset pre-eclampsia in the first pregnancy than in those with late-onset pre-eclampsia in the first pregnancy. For fetal death in a normotensive second pregnancy, our findings showed that women who had early-onset pre-eclampsia in the first pregnancy had more than twice the odds of those who had late-onset pre-eclampsia in the first pregnancy. Furthermore, having early-onset pre-eclampsia in the first pregnancy increased the odds of placental abruption by 140% in a normotensive second pregnancy, after controlling for covariates. To reduce the heterogeneity of our study sample in the analysis of outcomes in the second pregnancy, we further estimated the odds of the first occurrence of the outcomes of interest in the second pregnancy and obtained similar results. Specifically, having early-onset pre-eclampsia in the first pregnancy yielded an adjusted odds ratio of 1.94 (95% CI: 1.48, 2.53) for SGA, 0.73 (95% CI: 0.56, 0.94) for LGA, 1.28 (95% CI: 0.68, 2.40) for a low Apgar score, 2.22 (95% CI: 1.07, 4.60) for fetal death and 2.26 (95% CI: 1.33, 3.83) for placental abruption in the normotensive second pregnancy (results not shown).

Table 3.   Odds ratios for normotensive second pregnancy outcomes among women who experienced early-onset pre-eclampsia in first pregnancy, Missouri, USA, 1989–2005 (n = 12 835)
Perinatal outcomes in second pregnancycOR (95% CI)**aOR (95% CI)*,**
  1. *Analysis adjusted for maternal age, ethnic origin, marital status, smoking during pregnancy, Medicaid use, body mass index and inter-pregnancy interval.

  2. **Adjusted odds ratios and 95% confidence intervals.

  3. ***Relative risk estimated by Poisson regression model with a robust error variance among women who had vaginal delivery in first pregnancy.

  4. ****Restricted to live births.

Small for gestational age****2.00 (1.65, 2.41)1.75 (1.43, 2.15)
Large for gestational age****0.61 (0.48, 0.77)0.64 (0.50, 0.81)
Preterm delivery (<35 weeks)****3.43 (2.71, 4.34)3.00 (2.35, 3.85)
Low Apgar scores (<7 at 5 minutes)1.50 (0.89, 2.53)1.31 (0.75, 2.29)
Fetal death2.40 (1.21, 4.75)2.43 (1.21, 4.89)
Caesarean section***1.60 (1.26, 2.04)1.65 (1.29, 2.10)
Placental abruption3.06 (1.94, 4.82)2.40 (1.46, 3.94)

Table 4 details the results of our analysis on whether the effect of gestational age of pre-eclampsia on adverse maternal and fetal outcomes was modified by maternal ethnic origin; we detected a significant additive interaction. The effect of gestational timing of pre-eclampsia in first pregnancy on preterm delivery in second normotensive pregnancy varied by maternal ethnic origin (interaction term P = 0.04). Having a history of early-onset pre-eclampsia alone carried a more than three-fold increased odds of preterm delivery in a normotensive second pregnancy relative to late-onset pre-eclampsia (Table 4). Being African-American alone carried a 2.43-fold increased odds of preterm delivery. Being African-American with a history of early-onset pre-eclampsia carried a markedly increased odds of preterm delivery, with an adjusted odds ratio of 5.45, albeit this is a weak positive (i.e. synergistic) interaction on the additive scale as the observed joint odds ratio is slightly greater than the expected joint odds ratio of 5.14 (=3.71 + 2.43 – 1).27

Table 4.   Multivariate adjusted interaction between gestational age of pre-eclampsia in first pregnancy and maternal ethnic origin on preterm delivery in normotensive second pregnancy, Missouri, USA, 1989–2005 (n = 12 835)
Gestational timing of pre-eclampsia in first pregnancy by maternal ethnic originPreterm delivery
aOR*,**95% CI*
  1. *Adjusted odds ratios and 95% confidence intervals.

  2. **The multivariate model includes gestational timing of pre-eclampsia in first pregnancy, maternal age, ethnic origin, marital status, smoking during pregnancy, Medicaid use, body mass index and inter-pregnancy interval, and gestational timing of pre-eclampsia in first pregnancy and maternal ethnic origin product term.

Non-Hispanic white and late onset1.0Reference
Early-onset pre-eclampsia only3.712.81, 4.90
African-American only2.431.86, 3.17
Early-onset pre-eclampsia and African-American5.453.62, 8.21

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References

In our study, we evaluated the perinatal outcomes in a normotensive second pregnancy of women with early-onset pre-eclampsia in the first pregnancy. Despite a normotensive second pregnancy, we observed that having a history of early-onset pre-eclampsia, relative to late-onset pre-eclampsia, in first pregnancy increased the odds of SGA, preterm birth, fetal death, caesarean section and placental abruption, after controlling for confounders. It is noteworthy that, in the second normotensive pregnancies of women with late-onset pre-eclampsia, the incidence of SGA babies was less than that in those with early-onset pre-eclampsia (7.6% versus 14.1%), whereas the incidence of LGA babies was greater (12.6% versus 8.1%). These findings support the hypothesis that pre-eclampsia is an aetiologically heterogeneous disorder with two subtypes: late-onset pre-eclampsia with normal fetal growth, indicating normal placental function; and early-onset pre-eclampsia with fetal growth restriction, implying placental dysfunction. In the early-onset subtype, it has been hypothesised that placental hypoperfusion is caused by the shallow invasion of fetal trophoblast in early pregnancy, leading to fetal growth restriction in early-onset pre-eclampsia.28 Decreased perfusion of the feto-placental unit decreases fetal size, even before the appearance of the defining criteria of pre-eclampsia (hypertension and proteinuria).29 The higher rate of LGA infants in late-onset pre-eclampsia in the present study may suggest that placental dysfunction is absent or plays only a minor role in late-onset pre-eclamptic pregnancies. The excess of LGA infants could be explained by increased cardiac output in late-onset pre-eclamptic pregnancies, as late-onset pre-eclampsia is believed to be a maternal reaction to a greater than average rapid fetal growth, secondary to impaired placental perfusion and abnormal placentation.30,31

Our findings also indicated that maternal ethnic origin modified the association between early-onset pre-eclampsia in first pregnancy and the risk of preterm delivery in a normotensive second pregnancy. Specifically, the risk of preterm birth was even more pronounced among African-American women who had a history of early-onset pre-eclampsia, relative to women of white European origin who had late-onset pre-eclampsia (Table 4). Numerous studies have documented that African-American women are at increased risk for preterm labour and preterm delivery.15 Our findings showed that the risk of preterm delivery was markedly increased among African-American women when the maternal obstetric risk factor was superimposed on early-onset pre-eclampsia in first pregnancy.

Our results are similar to those from previous research. In a hospital-based sample, Lain et al.23 compared second pregnancy outcomes among 130 women with and 6148 women without pre-eclampsia in their first pregnancies, who all had second pregnancies without pre-eclampsia. They reported that women with early-onset pre-eclampsia delivered earlier in their second non-pre-eclamptic pregnancy relative to women with late-onset pre-eclampsia or no pre-eclampsia in the first pregnancy. However, the findings of Lain et al.23 were limited by a lack of adjustment of important confounders, such as BMI, pregnancy interval and smoking during pregnancy. In another study, Makkonen et al.13 reported that infants of mothers with pre-eclampsia in the first pregnancy had an increased risk of admission to a neonatal unit and intrauterine fetal death in the normotensive second pregnancy, relative to secundagravid women without a previous pre-eclamptic history. On the contrary, they also observed that a history of pre-eclampsia had no significant effects on infant birth weight, fetal distress or prematurity rate.13 The differences in findings may be attributed to the observation that women in the study by Makkonen et al.13 were not stratified by the gestational timing of pre-eclampsia, which could mask the underlying risk of a previous early-onset pre-eclampsia on pregnancy outcomes. In another study, Sibai et al.5 observed that women with pre-eclampsia in the first pregnancy had a significantly higher incidence than the normotensive control group of placental abruption, perinatal mortality, fetal growth retardation and premature delivery in subsequent pregnancies. However, the pre-eclamptic status in subsequent pregnancies was not reported in this study. The findings of Sibai et al.5 were also limited by incorrect statistical modelling for clustered data, which underestimates the standard error of the risk estimate.

Early-onset pre-eclampsia is often defined as a syndrome of first pregnancies and its underlying cause is largely unknown.32,33 It has been suggested that early-onset and late-onset pre-eclampsia should be regarded as different forms of the disease.33 Egbor et al.34 evaluated morphometric placental villous and vascular abnormalities in early- and late-onset pre-eclampsia. It was observed that late-onset pre-eclampsia had a minimal influence on placental villous and vascular morphology (i.e. reduced stem vein volume) compared with gestational age-matched controls. In contrast, early-onset pre-eclampsia was associated with placental dysfunction marked by a reduction in placental weight, volume or intervillous space, terminal villous volume and surface area.34 In another study, Moldenhauer et al.7 studied placental lesions according to gestational age at delivery. The study found that the rate of placental lesions was higher the earlier the gestational age at the time of delivery, compared with normotensive control subjects. It is not clear whether the implantation and placental abnormality recur and affect fetal birth weight and length of gestation despite a normotensive second pregnancy.

Previous research has shown that early-onset pre-eclampsia in first pregnancy has long-term health implications to the mother. After pre-eclamptic pregnancies, metabolic syndrome markers often remain elevated, as does the cardiovascular risk.33 Women followed up after pre-eclampsia also show higher levels of 8-isoprostane, a marker of oxidative stress, and plasma von Willebrand factor, a marker of endothelial dysfunction.33,35 Women with a history of early-onset pre-eclampsia seen 6 months to 20 years postpartum have also been noted to have an increased risk of later hypertension, heart disease and associated metabolic disturbances, including higher insulin levels and reduced endothelial function, when compared with women with uncomplicated pregnancies.5,33,36–38 In turn, cardiac disease, chronic hypertension and diabetes are significant maternal chronic medical risk factors associated with preterm birth, low birth weight and infant mortality.39 In our study, women who had recurrent pre-eclampsia had a higher rate of chronic hypertension, renal disease or diabetes mellitus relative to those who were normotensive in the second pregnancy (Figure 1).

Some methodological limitations of this study need to be considered in interpreting the study findings. They include the potential for inaccurate reporting, residual confounding by socioeconomic and other maternal characteristics, the lack of information regarding the diagnosis and severity of pre-eclampsia, and the misclassification of medical and obstetric conditions. However, a previous validation study has indicated that the reporting rate of pre-eclampsia on birth certificates with a check-box format (such as that used in Missouri) is fairly good, ranging from 85% to 97% when compared with risks based on hospital discharge data.40 In addition, the generalisability of this study is limited to Caucasian American and African-American women who reside in Missouri, or other populations of women with demographics and characteristics similar to those of Missouri women. Furthermore, potential confounding caused by changes in the management and treatment of women during and after pre-eclampsia in the 16-year study period cannot be excluded. The strength of this study lies in the classification of pre-eclampsia in first pregnancy by gestational age at delivery as early onset or late onset, its use of a large population-based sample of women with pre-eclampsia in the first pregnancy, and the availability of information on many potential confounders that may affect the risk of adverse pregnancy outcomes in the second pregnancy. The large sample size provided the study with adequate statistical power to detect significant associations and increased the precision in the risk estimates. To the authors’ knowledge, the present study is the first to examine the role of maternal ethnic origin in the association between early-onset pre-eclampsia and pregnancy outcomes in subsequent normotensive pregnancies. Our results indicated the presence of health disparity in the risk of preterm delivery in normotensive second pregnancy among women with a history of early-onset pre-eclampsia.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References

We have shown that women with a normotensive second pregnancy following early-onset pre-eclampsia in the first pregnancy are at increased risk of adverse maternal and fetal outcomes relative to women with late-onset pre-eclampsia in the first pregnancy. The magnitude of risk for these conditions also varied by maternal ethnic origin, with a worse prognosis associated with African-American women with earlier onset pre-eclampsia in the first pregnancy. It is increasingly accepted that early-onset and late-onset pre-eclampsia may have different underlying aetiologies, and our findings lend support to this theory. Our findings have clinical relevance for the management of subsequent pregnancy for women with a history of pre-eclampsia. Given the increased odds of SGA in a normotensive second pregnancy after early-onset pre-eclampsia in a first pregnancy, obstetricians should consider an ultrasound to evaluate fetal growth, in addition to clinical follow-up, in the second pregnancy. Increased awareness of the association between early-onset pre-eclampsia in the first pregnancy and adverse maternal and fetal outcomes in subsequent nomotensive pregnancies is needed among healthcare professionals to optimise maternal and fetal outcome.

Contribution to authorship

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References

JJC wrote the study protocol, performed the analyses and wrote the first draft of the manuscript. LJM and GAM both made substantial contributions to the study design, interpretation of the results and manuscript revision.

Details of ethics approval

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References

This research was reviewed by the Saint Louis University Institutional Review Board and was classified as exempt.

Funding

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References

This study was supported by a KL2 Multidisciplinary Clinical Research Career Development Program Scholar award from the National Institutes of Health.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References

The authors acknowledge and appreciate the Missouri Department of Health and Senior Services, Section of Public Health Practice and Administrative Support as the original source of the data. The analysis, interpretations and conclusions in the present study are those of the authors and not of the Missouri Department of Health and Senior Services, Secition of Public Health Practice and Administrative Support.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure of interest
  9. Contribution to authorship
  10. Details of ethics approval
  11. Funding
  12. Acknowledgements
  13. References
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