The recurrence risk of severe de novo pre-eclampsia in singleton pregnancies: a population-based cohort

Authors


Dr SD McDonald, Division of Maternal-Fetal Medicine, Departments of Obstetrics & Gynecology, Diagnostic Imaging and Clinical Epidemiology & Biostatistics, McMaster University, 1200 Main St. West, HSC 3N52B, Hamilton, ON L8N 3Z5, Canada. Email mcdonals@mcmaster.ca

Abstract

Objective  Previous studies have found recurrence risks of severe pre-eclampsia as high as 40%. Our objective was to determine both the recurrence risk of severe de novo pre-eclampsia and risk factors associated with it in a contemporaneous population.

Study design  Population-based retrospective cohort study.

Population  Women who had two or more singleton liveborn or stillborn hospital deliveries in Ontario, Canada between April 1994 and March 2002 and without a history of chronic hypertension

Methods  International Classification of Disease codes were used to identify patients in the Canadian Institute for Health Information Discharge Abstract Database.

Main outcome measures  The absolute and adjusted risks of recurrent severe de novo pre-eclampsia were determined.

Results  Between 1 April 1994 and 30 March 2002, there were 185 098 women with two or more singleton deliveries >20 weeks in the province of Ontario, Canada. There were 1954 women who had severe de novo pre-eclampsia in the index pregnancy, 133 of whom had recurrent severe pre-eclampsia, for a risk of recurrent severe pre-eclampsia of 6.8% (95% CI 5.7–7.9%). The risk of recurrent severe de novo pre-eclampsia was increased in women with pre-existing renal disease (adjusted OR 17.98, 95% CI 3.50–92.52) and those >35 years of age (adjusted OR 3.79, 95% CI 2.04–7.04, reference 20–25 years).

Conclusions  The recurrence risk of severe de novo pre-eclampsia in our population-based cohort study (6.8%) is lower than previously published reports in selected populations.

Introduction

The potential recurrence of severe pre-eclampsia is a matter of grave concern for patients, their families, and healthcare providers, however, there is currently insufficient evidence to be able to counsel women who do not fit the profile in most previously published studies. Pre-eclampsia, in its severe form, continues to be a significant cause of maternal and perinatal morbidity and mortality. Maternal morbidity includes severe hypertension with or without seizures (eclampsia), cerebrovascular accidents, placental abruption, pulmonary edema, renal failure, hepatic dysfunction and rupture.1 Fetal risks include growth restriction (in approximately 25% of cases), premature delivery, and death either in utero or as a result of prematurity (in approximately 20 per 1000 cases).2

Published recurrence rates of pre-eclampsia vary from 5% to 65%.3–14 The wide range of recurrence is likely because of variations in severity, patient populations and diagnostic criteria. Most studies assessed the overall recurrence of pre-eclampsia without distinguishing between mild pre-eclampsia and the more clinically relevant category of severe pre-eclampsia.

One of the most widely quoted recurrence risks of severe pre-eclampsia comes from a landmark study published by Sibai and colleagues in 1991.3 After developing severe pre-eclampsia between 18 and 27 weeks gestation in the index pregnancy, 40% of the 108 women who had subsequent pregnancies developed preterm pre-eclampsia (<37 weeks). Limitations of the study include the fact that it was hospital-based and hence prone to selection bias, the gestational age at delivery in either pregnancy was not stated and the participants were relatively young (23.6 ± 4.9 years at the time of the index pregnancy), limiting the generaliseability of their results. Finally, only an unadjusted risk was reported, without exploration of predictive factors. In two other studies based in single referral centres, van Rijn et al.12 found a much lower recurrence risk of pre-eclampsia requiring delivery <34 weeks of 5% and <37 weeks of 22% and Koike et al.15 reported that five of 19 women had recurrence of preterm pre-eclampsia.

The impact of severe pre-eclampsia, both physical and psychosocial, can be devastating, and the concern that the condition may recur may prevent some couples from trying to conceive again. Given the increase in delayed childbearing during the last two decades,16 and the youthful age of patients in most previous studies3,4 current estimates of the recurrence risk of severe pre-eclampsia are required. The aim of this study is to determine the recurrence rate of severe de novo pre-eclampsia in a contemporaneous population of women who undertake a subsequent pregnancy and to explore predictive factors.

Methods

Cohort definition

A population-based retrospective cohort study was performed. All women who had two or more liveborn or stillborn singleton hospital deliveries >22 weeks gestation in the province of Ontario, Canada between the years of 1 April 1994 and 30 March 2001 were identified from the Canadian Institute for Health Information Discharge Abstract Database (CIHI-DAD). All hospital admissions in Canada are captured in this database which contains a unique encrypted healthcare number, the age of the patient and up to 16 diagnoses coded by ICD-9 coding. Data audit occur at each individual institution prior to submission of data to CIHI, and as needed subsequent to this for invalid or inconsistent data. We used the database both to identify admissions and to study covariates. We excluded women with chronic hypertension as we were focusing on pre-eclampsia, not superimposed pre-eclampsia on chronic hypertension. If a woman had greater than two deliveries during the time period above, the first two were examined. Certain variables such as paternity, smoking, gestational age at the onset of pre-eclampsia or delivery, obesity and race were not available in the database.

Outcome definition

The primary outcome was the risk of recurrent severe pre-eclampsia in the subsequent pregnancy in women who were diagnosed with severe pre-eclampsia in the index pregnancy. Severe pre-eclampsia was a clinically defined composite outcome including (i) the standard ACOG definition (systolic blood pressure ≥160 mmHg or a diastolic blood pressure ≥110 mmHg; or hypertension (≥140/90) with proteinuria occuring after 20 weeks gestation and one or more of: proteinuria ≥5 g/24 hours or ≥3+; oliguria; pulmonary edema or cyanosis; impairment of liver function; visual or cerebral disturbances; epigastric or right upper quadrant pain; thrombocytopenia; intrauterine growth restriction)17 or pre-eclampsia complicated by (ii) fetal death or (iii) premature birth or (iv) eclampsia. We focused on severe de novo pre-eclampsia, not severe pre-eclampsia superimposed on chronic hypertension which has previously been examined12 and hence women with chronic hypertension were excluded.

Secondary outcomes included the adjusted risk of recurrent severe de novo pre-eclampsia, and the adjusted risk of severe de novo pre-eclampsia in a subsequent pregnancy regardless of pre-eclamptic status during the index delivery (to be able to explore the impact of severe pre-eclampsia during the index pregnancy). All pregnancy diagnoses and outcomes were identified with the use of the International Classification of Diseases 9th edition (ICD-9) coding system (Supplementary Material S1).

Statistical analysis

Continuous baseline characteristics such as maternal age at the index and subsequent deliveries were compared using analysis of variance (ANOVA), and chi-square tests were conducted to compare the risk of dichotomous predictor variables of severe pe-eclampsia: pre-existing renal disease, connective tissue disease, deep vein thrombosis or pulmonary embolus, diabetes mellitus, gestational diabetes, interpregnancy interval (>5 years), previous fetal growth restriction, previous intrauterine fetal death and maternal age (<20.0 years, 20.0 to 25.0 years, >25.0 to 30.0 years, >30.0 to 35.0 years, >35.0 years), with the 20.0- to 25.0-year-old age group as the reference. Factors significant at the < 0.1 level and biologically plausible variables were used in the multivariable logistic model to determine the adjusted odds ratio (OR) of recurrent severe pre-eclampsia in the group of women with severe pre-eclampsia in both the index and subsequent pregnancies. In a separate, second multivariable analysis, factors significant at the < 0.1 level and biologically plausible variables were used to determine the adjusted OR of severe pre-eclampsia in the subsequent pregnancy to be able to include the impact of having had severe pre-eclampsia in the index pregnancy in the regression model. Analyses were performed using SAS® Version 9.2 (SAS Institute, Cary, NC, USA) on Sun Solaris™ Unix operating system. Patient identifiers were removed prior to data extraction. Permission to conduct the study was granted by the Research Ethics Board at McMaster University (CR #302-S).

Power calculation

With approximately 130 cases of recurrent de novo pre-eclampsia, we had sufficient data to fit a model with approximately 13 predictor variables maintaining the minimum requirements of ten events per variable. Moreover, we calculated that with approximately 130 patients with severe pre-eclampsia in both the index and subsequent pregnancies, and approximately 1800 patients with severe pre-eclampsia in the index pregnancy alone would yield approximately 93% power to find a recurrence odds if at least 2.5 for severe de novo pre-eclampsia.

Results

Between 1 April 1994 and 30 March 2002, there were 188 768 women with two or more hospital deliveries in the province of Ontario, Canada without chronic hypertension (Figure 1), of whom 185 098 had singleton deliveries. There were 1954 women who had severe pre-eclampsia in the index pregnancy (1.1%, 95% CI 1.01–1.10%). One hundred and thirty-three of these women or 6.8% (95% CI 5.7–7.9%) had recurrent severe de novo pre-eclampsia in the following pregnancy. Women with severe de novo pre-eclampsia had lower household income (< 0.0001) than women without, although their ages were similar (= 0.3176) (Table 1). The mean age of women at delivery with severe de novo pre-eclampsia during both their index and subsequent deliveries (recurrent severe de novo pre-eclampsia), was 28.9 ± 5.3 years and 31.5 ± 5.5 years, respectively, similar to women who were not pre-eclamptic (27.6 ± 5.0 and 30.2 ± 5.0 years respectively).

Figure 1.

 Flow diagram of patients in this population-based cohort of women with recurrent severe de novo pre-eclampsia in at least two singleton liveborn or stillborn pregnancies in the province of Ontario, Canada between 1 April 1994 and 30 March 2001.

Table 1.   Baseline characteristics of a population-based cohort of women with at least two singleton liveborn or stillborn deliveries and without a history of chronic hypertension in the province of Ontario, Canada between 1 April 1994 and 30 March 2001
Maternal characteristicWomen with 2 or more pregnancies without severe de novo pre-eclampsia (%)Women with 2 or more pregnancies with severe de novo pre-eclampsia (%)P value
Income quintile
1 (lowest)22.225.3<0.0001
219.921.6
319.619.2
419.719.0
5 (highest)18.715.0
Maternal age at index delivery
≥357.88.80.3176
30 to 3429.028.8
25 to 2937.637.0
20 to 2419.518.9
<207.17.5

The majority of women with severe de novo pre-eclampsia in the index pregnancy had much better outcomes in the following pregnancy, with 80.7% (95% CI 29.0–82.4%) not developing pre-eclampsia and 11.4% (95% CI 10.0–12.8%) having pre-eclampsia that was not severe.

To determine risk factors for recurrent severe de novo pre-eclampsia, we examined the group of women with severe de novo pre-eclampsia in both the index and subsequent pregnancies (= 133). Maternal age >35 years and renal disease predicted recurrent severe pre-eclampsia in both univariable and multivariable analyses [adjusted OR’s 3.79 (95% CI 2.04–7.04) and 17.98 (95% CI 3.50–92.52) respectively] (Table 2).

Table 2.   Univariable and multivariable analyses of maternal characteristics and previous pregnancy characteristics in a population-based cohort of women with recurrent severe de novo pre-eclampsia in at least two singleton liveborn or stillborn pregnancies in the province of Ontario, Canada between 1 April 1994 and 30 March 2001 compared with women without severe pre-eclampsia the subsequent pregnancy
Predictor variable assessed during index pregnancyUnadjusted OR (95% confidence interval)Adjusted odds ratio (95% confidence interval)
Renal disease13.69 (2.79–67.18)17.98 (3.50–92.52)
Gestational diabetes mellitus1.10 (0.45–2.70)1.04 (0.41–2.66)
Diabetes1.71 (0.22–13.58)2.00 (0.25–16.28)
Deep vein thrombosis or pulmonary embolus4.56 (0.48–43.58)6.29 (0.63–63.04)
Interpregnancy interval >5 years 1.35 (0.70–2.62)1.61 (0.78–3.30)
Previous fetal death1.04 (0.46–2.34)1.02 (0.43–2.42)
Previous fetal growth restriction0.90 (0.65–1.24)0.91 (0.60–1.39)
Age 20–25 years ReferenceReference
Age >35 years 3.16 (1.82–5.50)3.79 (2.04–7.04)
Age 30–35 years1.31 (0.77–2.23)1.36 (0.77–2.38)
Age 25–30 years1.22 (0.73–2.04)1.25 (0.72–2.15)
Age <20 years0.65 (0.25–1.69)0.58 (0.21–1.61)

To determine risk factors for severe de novo pre-eclampsia in a subsequent pregnancy regardless of pre-eclampsia status in the index pregnancy (= 718, 464 of whom had no pre-eclampsia in the index gestation and 114 had mild), we included the impact of having had severe pre-eclampsia in the index pregnancy in the regression model (adjusted OR 18.97, 95% CI 15.29–23.53). Other predictor variables included advanced maternal age (adjusted OR 2.14, 95% CI 1.61–2.85) and renal disease (adjusted OR 12.89, 95% CI 5.12–32.44), as well as interpregnancy interval >5 years (adjusted OR 2.37, 95% CI 1.88–2.99), gestational diabetes (adjusted OR 2.20, 95% CI 1.54–3.13), diabetes mellitus (adjusted OR 2.87, 95% CI 1.01–8.14), connective tissue disease (adjusted OR 7.63, 95% CI 2.70–21.60), fetal growth restriction (adjusted OR 1.65, 95% CI 1.23–2.20) and fetal death (adjusted OR 2.54, 95% CI 1.68–3.82) (Table 3).

Table 3.   Multivariable analyses of predictor variables and adjusted odds ratio of severe pre-eclampsia in a subsequent pregnancy (including women with and without severe pre-eclampsia in the index gestation)
Predictor variable assessed during index pregnancyAdjusted odds ratio (95% confidence interval)
Severe pre-eclampsia during index pregnancy18.97 (15.29–23.53)
Renal disease12.89 (5.12–32.44)
Connective tissue7.63 (2.70–21.60)
Deep vein thrombosis or pulmonary embolus1.79 (0.24–13.22)
Gestational diabetes mellitus2.20 (1.54–3.13)
Diabetes2.87 (1.01–8.14)
Interpregnancy interval >5 years2.37 (1.88–2.99)
Previous fetal death2.54 (1.68–3.82)
Previous fetal growth restriction1.65 (1.23–2.20)
Age >35 years (reference 20–25 years)2.14 (1.61–2.85)
Age 30 to 35 years1.39 (1.10–1.76)
Age 25 to 30 years1.30 (1.04–1.64)
Age <20 years1.05 (0.73–1.50)

Discussion

The risk of recurrent severe de novo pre-eclampsia in our population-based cohort of singleton pregnancies, the largest study to date, was 6.8% (95% CI 5.7–7.9%). Our recurrence risk was lower than that in Sibai’s landmark study3 (40%) conducted in a single referral centre in younger patients (23.6 years compared to our patients’ mean age of 28.9 years), with onset of pre-eclampsia between 18–27 weeks gestation and which included some women with chronic hypertension. Other differences including ethnicity, the possible use of low dose aspirin to prevent recurrence (a practice more common now than during the period of Sibai’s study) and universal health care including prenatal care in Canada may also contribute. A study by van Rijn of women with pre-eclampsia who delivered at a single university centre prior to 34 weeks in the index pregnancy (and with similar maternal ages as those in our study), found a recurrence risk of delivery <34 weeks of 5% and 22% <37 weeks12 (Table 4).

Table 4.   Summary table of previous studies on the recurrence rate of severe* pre-eclampsia
First authorYearNumber of severe pre-eclampticsAge at index delivery (years)Definition of severe* PETRecurrence rate severe PET in the subsequent pregnancyFactors adjusted or matched for
  1. *Severe pre-eclampsia included classical definition17 or eclampsia or pre-eclampsia with intrauterine fetal demise or requiring preterm delivery or; PET, pre-eclampsia; cHTN, chronic hypertension; BP, blood pressure; UP, urine protein; ND, not described; mmHg, millimeters of mercury; >, greater than.

Lopez–Leira181974110 eclampticsNDBP >160/110 mmHg or >3 g (with >140/90) Severe PET: 14.5%None
Sibai41986287 severe PET, 119 eclampsia17.0 ± 2.5 BP >160/110 mmHg twice 6 hours apart and either edema or >3 + UPSevere PET: 25.9% Eclampsia: 1.7%None
Sibai141992183 eclampticsNDBP >160/110 mmHg on 2 occasions 6 hours apart and either edema or >3 + UP Severe PET: 8.8%None
Koike15200219 women with preterm birth due to PET or eclampsia28 ± 3.7PET: BP >140/90 with proteinuriaPreterm PET: 5/19 (26%) None
van Rijn 122006120 women with PET <34 weeks 1st pregnancy29.0 ± 4PET: BP 140/90 mmHg + UP >3 mg/24 h or 2 + dipstick.22% delivered <37 weeks (<28 weeks 2.5%, 28–34 weeks 2.5%, 34–37 weeks 17%)Age, interval between pregnancies, BMI, cHTN, thrombophilia did not alter results. Smoking increased risk (HR 1.4, 95%CI 1.1–5.6)

Recurrent severe pre-eclampsia was predicted by advanced maternal age and pre-existing renal disease in our study. Most studies did not examine any predictors.4,14,15,18,19 (Table 4) van Rijn explored a number of factors including chronic hypertension, age, BMI, gestational age at first delivery and fetal growth restriction, but found none predictive of delivery <34 weeks, and only smoking was predictive of delivery <37 weeks (adjusted HR 2.4, 95% CI 1.1–5.6).12 Factors previously associated with recurrent pre-eclampsia in general (not specifically recurrent severe pre-eclampsia) including pre-existing diabetes mellitus, gestational diabetes, connective tissue disease or deep vein thrombosis or pulmonary embolus, poor fetal growth, previous intrauterine fetal death and interpregnancy interval were not predictive of recurrent severe pre-eclampsia in our study, nor were they in van Rijn’s study,12 which may be because of the low incidence of these conditions and the relatively small number of recurrent severe pre-eclamptics in both studies leading to a type II error, or limitations of ICD coding in our study.

Limitations of our study include the fact that we did not have access to the patients’ medical charts. We had access to maternal disease states coded at the time of the admission for delivery. Certain variables (e.g. paternity, smoking, obesity and race) were not available in the database, nor were medical interventions such as aspirin. The fact that our study’s focus was on recurrent, not initial pre-eclampsia, minimised the impact that we did not have access to parity. Although the exact gestational age at delivery was not obtainable, whether or not the delivery was preterm or term delivery was available. There is no single universally agreed upon definition of severe pre-eclampsia and existing published definitions have limitations.20 Hence, we selected a clinical definition that would be relevant to clinicians and patients, including severity from both a maternal perspective (a standard definition including severe blood pressure elevations and end-organ manifestations including eclampsia) and a fetal perspective (fetal demise, growth restriction and prematurity). Although we are not aware of an audit of the CIHI data in terms of pre-eclampsia, the validity of using databases to study pre-eclampsia was confirmed in a large Swedish study comparing a birth registry, similar to CIHI, with that of individual medical records.21 The positive predictive value for the presence of normotension in the database was 95% and for pre-eclampsia the predictive values was 96%.

Strengths of this study include the fact that it was population-based, minimising the possibility of selection bias, which may have occurred in all previously published studies that all found higher recurrence risks of severe pre-eclampsia. This is the largest study to date on recurrent severe de novo pre-eclampsia. Together with van Rijn et al.,12 ours is the only other study to examine predictive factors for recurrent severe pre-eclampsia.

Conclusions

Severe pre-eclampsia may not only compromise a woman’s health, but may also affect her decision to have more children. In this large province-wide population-based cohort study, the recurrence risk of severe de novo pre-eclampsia in women who undertook a subsequent pregnancy was not as high as in previously published studies of select populations.

Disclosure of interests

The authors do not have any conflict of interest.

Contribution to authorship

Each of the authors (a) made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; and (b) was involved in drafting the article or revising it critically for important intellectual content; and (c) gave final approval of the version to be published.

Details of ethics approval

Permission to conduct the study was granted by the Research Ethics Board at McMaster University (CR #302-S).

Funding

This study was supported by a grant from the Regional Medical Association Fund of Hamilton Health Sciences.

Acknowledgement

None.

Ancillary