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Keywords:

  • Pre-eclampsia;
  • preterm recurrence;
  • severe

Abstract

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

Please cite this paper as: Langenveld J, Buttinger A, van der Post J, Wolf H, Mol B, Ganzevoort W. Recurrence risk and prediction of a delivery under 34 weeks of gestation after a history of a severe hypertensive disorder. BJOG 2011;118:589–595.

Objective  The aim of this study was to report outcomes of the subsequent pregnancy after early-onset pre-eclampsia in a first pregnancy (index), and to evaluate the potential risk factors for recurrence of pre-eclampsia and preterm delivery.

Design  We performed a retrospective cohort study of all women who developed early-onset pre-eclampsia (delivery before 34 weeks of gestation) in their first pregnancy between January 1996 and December 2004 in two perinatal centres with regional function. All patients were included consecutively. Information was retrieved on the course of subsequent pregnancies.

Setting  Two tertiair centres with regional function.

Population  Women with a delivery under 34 weeks due to a hypertensive disorder (N = 380).

Main outcome measures  We determined the absolute risk of recurrence of an adverse outcome, defined as a hypertensive complication resulting in delivery before 34 weeks of gestation. The available clinical parameters were evaluated as predictors for recurrence using logistic regression analysis.

Results  We identified 380 patients, of whom 46 were lost to follow-up. In total, 123 patients refrained from subsequent pregnancy (79 [64%] from fear of recurrence). Of the 211 patients with a subsequent pregnancy, 36 (17%, 95% CI 12–22%) had a recurrent delivery before 34 weeks of gestation, 30 (14%, 95% CI 9.5–19%) delivered between 34 and 37 weeks of gestation, and 145 (69%, 95% CI 62–75%) delivered later than 37 weeks of gestation. Of this last group, only 67 (32%, 95% CI 25–38%) pregnancies were completely uneventful. Chronic hypertension, maximum diastolic blood pressure, caesarean delivery and level of 24-h proteinuria were independent predictors for an adverse pregnancy outcome.

Conclusions  Women that had early severe pre-eclampsia in their first pregnancy have a 17% risk of recurrence, with a delivery before 34 weeks of gestation. Only 32% had a completely uneventful pregnancy.


Introduction

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

Hypertensive disorders of pregnancy, including pre-eclampsia and HELLP syndrome (haemolysis, elevated liver enzymes and low platelet count) affect 2–7% of pregnancies. Early-onset hypertensive disorders resulting in a delivery before 34 weeks of gestation constitute approximately 10% of this group.1,2 This subgroup is important because they contribute significantly to adverse maternal and perinatal outcomes, and psychosocial sequelae.3 Gestational age at admission and gestational age at delivery are the key factors in the prediction of adverse infant outcomes.4,5 Unfortunately, despite an abundance of early predictive tests for pre-eclampsia, with significant associations, the statistical accuracy of these tests is poor.6 Having a history of early-onset hypertensive disorders of pregnancy constitutes an increased risk of recurrence.7

For parents the psychosocial impact of a severe hypertensive complication of pregnancy and delivery before 34 weeks of gestation is often huge, and is associated with a high incidence of symptoms of post-traumatic stress disorder and depression, and anxiety of women before and during a subsequent pregnancy.8–10 Proper counselling regarding perinatal and maternal risk during future pregnancies is important to help couples in their consideration of a new pregnancy. The decision for future pregnancies largely depends on the information from the obstetrician gynaecologist on the estimated risk of recurrence of a preterm delivery, and the related severe maternal morbidity and serious neonatal morbidity. From a medical point of view, such counselling may influence management during the subsequent pregnancy, especially after early preterm delivery.

A common practical question from patients after these complicated pregnancies, and before engaging in a subsequent pregnancy, is: ‘what are my chances of delivering again early preterm (e.g. before 34 weeks of gestation) as a result of severe hypertensive disorder?’

In the absence of unselected, consecutively included and cohort studies of sufficient power, and in the absence of individual risk prediction models, we performed a cohort study of significant population size, without other selection than by gestational age and hypertension. As patients and doctors are mostly interested in the recurrence of a delivery earlier than 34 weeks, our primary aim was to study the recurrence risk of a delivery before 34 weeks of pregnancy as a result of a hypertensive disorder of pregnancy. Additionally, we identified independent related factors using a multivariate analysis for recurrence of early-onset pre-eclampsia.

Methods

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

Study population

We retrospectively identified patients from electronic databases from January 1996 to December 2004 in two perinatal centres with a regional function: the Maxima Medical Centre (MMC) in Veldhoven, the Netherlands, and the Academic Medical Centre (AMC) in Amsterdam, the Netherlands. All patients who were diagnosed with hypertension (including patients with chronic hypertension), pre-eclampsia or HELLP syndrome, and delivered before 34 weeks of gestation in the study period were included if they were primiparous with a singleton pregnancy without fetal abnormalities in the first pregnancy. Demographic, medical and obstetric data were extracted from the medical files. Information on subsequent pregnancies was first gained through the medical files. A subsequent pregnancy was defined as an ongoing pregnancy beyond 16 weeks of gestation. If no such information was available in the records of the institution, all individual women were contacted. If the patient reported an ongoing subsequent pregnancy, her gynaecologists and family doctor were contacted for data after informed consent. If the woman did not report a subsequent pregnancy, they were asked if there was a specific reason for not becoming pregnant again. All ethically available public resources were consulted if patients were lost to follow-up.

Primary outcome (adverse pregnancy outcome) among women with a subsequent pregnancy was defined as recurrence of a delivery before 34 weeks of gestation as a result of a hypertensive disorder. Secondary outcomes were delivery between 34 and 37 weeks of gestation, and the incidence of hypertensive disorders and delivery after 37 weeks, and related term disease.

Pre-eclampsia was defined as hypertension (diastolic blood pressure ≥90 mmHg or systolic blood pressure ≥140 mmHg measured on two occasions, 4–5 hours apart) in combination with proteinuria (defined as ≥1 + [0.3 g/l] in a proteinuria dipstick test, a protein/creatinine ratio of ≥30 mg/mmol in a random sample or a urine protein excretion of ≥300 mg per 24 hours) after 20 weeks of gestation. Women without proteinuria were considered to have gestational hypertension. Chronic hypertension is defined as the presence or history of hypertension preconception, or in the first half of pregnancy. HELLP syndrome was defined by haemolysis (elevated lactate dehydrogenase [LDH] levels [≥600 units/l], elevated liver enzymes by levels of aspartate transaminase [ASAT] or alanine transferase [ALAT] ≥ 70 units/l and low platelets <100 000/mm).3,11,12 Small for gestational age (SGA) was defined as a birthweight below the tenth percentile, adjusted for gestational age based on a local reference population.13 Routine diagnostic work-up in the postpartum period after an early-onset pre-eclampsia or HELLP includes thrombophilia investigation. This includes factor-V Leiden or prothrombin mutations, protein-C, -S or antithrombin deficiency, or the presence of lupus anticoagulant and anticardiolipine antibodies.

Statistics

Clinical characteristics were compared between women who refrained from subsequent pregnancies and women who did have a subsequent pregnancy. Primary and secondary outcome are presented as n (%) and the 95% confidence interval (95% CI). We calculated the time interval between the two subsequent deliveries with dates of delivery taken as the reference point. Continuous variables are expressed as means with standard deviations, and are compared with an unpaired Student’s t-test. Categorical variables within the general characteristics were compared with analysis of variance and chi-square tests. P values <0.05 were considered to indicate statistical significance.

Subsequently, we analysed which clinical characteristics (known at the start of the subsequent pregnancy) were related to the primary outcome (recurrence of a delivery before 34 weeks of gestation in the presence of a hypertensive disorder). We used univariable and multivariable logistic regression analysis, with P values of 0.50 and 0.20 for variables for model entry and model stay, respectively. Demographic variables considered as relevant clinical variables were age and body mass index (BMI). Relevant obstetric variables known after the first pregnancy were the maximum systolic and diastolic blood pressures, proteinuria, chronic hypertension, gestational age at time of delivery, caesarean section in the first pregnancy, diagnosis of pre-eclampsia, HELLP and/or SGA in the first pregnancy. The results were expressed as odds ratios and 95% confidence intervals. All data were analysed using spss v16.0 for windows (SPSS Inc. Corp., Chicago, IL, USA).

Results

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

The study profile is shown in Figure 1. We identified 380 women (MMC = 181; AMC = 199). Of these, 46 (12%) were lost to follow-up, 211 (56%) had a subsequent pregnancy and 123 (32%) did not conceive again. All of these 123 women were contacted and asked for the reason for not conceiving again. Seventy-nine (64%) of the 123 women expressed a fear of recurrence as the main reason. The other 44 women of this group (36%) expressed other reasons for not conceiving again: having a complete family, no partner or subfertility (Figure 1).

image

Figure 1.  Flow-chart of consecutively included patients with a history of a delivery before 34 weeks of gestation as a result of a hypertensive disorder in two perinatal hospitals: AMC, Academic Medical Centre (Amsterdam, the Netherlands); MMC, Máxima Medical Centre (Veldhoven, the Netherlands).

Download figure to PowerPoint

To test for selection bias, baseline clinical characteristics of the 380 first pregnancies are summarised in Table 1, subdivided by category: patients with a subsequent pregnancy, loss to follow-up and patients without a subsequent pregnancy. There were no relevant clinical differences in severity of disease in the first pregnancy between the three groups. There were a few statistically significant but clinically unimportant differences: the group of patients that did not conceive delivered significantly later, were older, had a higher BMI and had had more caesarean deliveries.

Table 1.   Baseline clinical characteristics for the first pregnancy (delivery before 34 weeks of gestation as a result of a hypertensive disorder) of the 380 included patients subdivided by category: with a subsequent pregnancy, lost to follow-up and without a subsequent pregnancy
Demographic characteristic in the first pregnancyPatients with a subsequent pregnancy (n = 211)Patients who were lost to follow-up (n = 46)Patients without a subsequent pregnancy (n = 123)P*
  1. *Comparing patients with a subsequent pregnancy against patients without a subsequent pregnancy; P < 0.05 is considered to be statistically significant.

  2. **Data are presented as mean (SD) or n (%), as appropriate.

  3. ***Thrombophilia: factor-V Leiden or prothrombin mutations, protein-C, -S or antithrombin deficiency, or the presence of lupus anticoagulant and anticardiolipine antibodies.

Age at delivery (years)**28.6 (3.9)27.3 (5.4)30.4 (4.5)0.0001
Smoking30 (14%)4 (9%)16 (13%)0.87
White177 (84%)27 (59%)103 (84%)1.00
Other ethnicity22 (10%)10 (22%)10 (8%)0.57
Unknown ethnicity12 (6%)9 (20%)10 (8%)0.49
BMI (kg/m2) for index pregnancy**24 (4.4)24 (5.5)25 (4.6)0.049
Chronic hypertension (diagnoses for complete period)45 (21%)9 (20%)25 (20%)0.89
Maximum systolic blood pressure (mmHg**) for index pregnancy174 (20)176 (20)175 (24)0.68
Maximum diastolic blood pressure (mmHg**) for index pregnancy111 (12)114 (13)110 (12)0.46
Thrombophilia tested positive***31 (15%)UnknownUnknown 
Index pregnancy characteristics
Gestational age at delivery (weeks)**30 (2)30 (2)31 (2)0.0001
Caesarean delivery175 (83%)42 (91%)117 (95%)0.002
Delivery before 30 weeks of gestation106 (50%)22 (48%)51 (42%)0.14
Birthweight (g)**1070 (379)1026 (379)1105 (327)0.39
Small for gestational age (below tenth percentile)82 (39%)26 (39%)52 (42%)0.56
Diagnosis of pre-eclampsia183 (87%)37 (80%)109 (89%)0.73
Diagnosis of eclampsia10 (5%)4 (9%)4 (3%)0.58
Diagnosis of HELLP syndrome122 (58%)20 (44%)62 (50%)0.21

Table 2 outlines the baseline demographic and clinical characteristics of the 211 subsequent pregnancies, subcategorised based on gestational age at delivery in the subsequent pregnancy.

Table 2.   Baseline clinical characteristics of the subsequent pregnancies of all 211 included patients who became pregnant after they delivered before 34 weeks of gestation due to a hypertensive disorder in the first pregnancy
Baseline maternal characteristics in the subsequent pregnancyPatients in their subsequent pregnancy subdivided into categories by gestational age in weeks
All patients (n = 211)Delivery <34 (n = 36)Delivery <340–366> (n = 30)Delivery ≥37 (n = 145)
  1. *Data expressed as mean (SD) or as n (%), as appropriate.

  2. **Thrombophilia: factor-V Leiden or prothrombin mutations, protein-C, -S or antithrombin deficiency, or the presence of lupus anticoagulant and anticardiolipine antibodies.

Age at delivery index pregnancy (years)*31.4 (4.0)31.8 (4.7)31.7 (2.9)31.3 (3.9)
Smoking19 (9%)2 (6%)1 (3%)16 (11%)
White177 (84%)28 (78%)23 (77%)126 (87%)
Other ethnicity22 (10%)6 (17%)6 (20%)10 (7%)
Unknown ethnicity12 (6%)2 (5%)1 (3%)9 (6%)
BMI (kg/m2) in subsequent pregnancy*25.2 (5.3)23.4 (3.5)25.3 (5.0)25.6 (5.6)
Chronic hypertension (diagnoses for complete period)45 (21%)12 (33%)11 (37%)22 (15%)
Thrombophilia**31 (15%)4 (11%)4 (13%)23 (16%)
Maternal pregnancy outcome in the subsequent pregnancy
Maximum systolic blood pressure (mmHg*) in subsequent pregnancy145 (23)163 (26)147 (19)138 (19)
Maximum diastolic blood pressure (mmHg*) in subsequent pregnancy94 (13)103 (15)99 (14)90 (11)
Diagnosis of pre-eclampsia54 (26%)23 (64%)14 (47%)17 (12%)
Diagnosis of eclampsia
Diagnosis of HELLP syndrome18 (9%)9 (25%)5 (17%)4 (3%)
Fetal outcome in the subsequent pregnancy
Gestational age at delivery (weeks)*37 (4)30 (3)36 (1)39 (1)
Delivery before 30 weeks of gestation17 (8%)17 (47%)
Birthweight (g)*2791 (950)1190 (580)2466 (568)3251 (529)
Small for gestational age (below tenth percentile)53 (25%)9 (25%)6 (20%)38 (26%)

Adverse pregnancy outcome (recurrence of a delivery before 34 weeks of gestation as a result of a hypertensive disorder) occurred in 36 women (17%, 95% CI 12–22%). Thirty (14%, 95% CI 9.5–19%) of the women delivered between 34 and 37 weeks, and 145 (69%, 95% CI 62–75%) delivered after 37 weeks of gestation. Of this last group that delivered after 37 weeks of gestation, only 67 women (32%, 95% CI 25–38%) had a completely uneventful pregnancy.

Of the women with an adverse pregnancy outcome, nine (25%, 95% CI 11–39%) were diagnosed with HELLP and 23 (64%, 95% CI 48–80%) were diagnosed with pre-eclampsia, compared with four (3%, 95% CI 0.09–5.4%) and 17 (12%, 95% CI 6.5–17%), respectively, who delivered after 37 weeks of gestation. The mean interval time between pregnancies was 31 ± 19 months (SD), which was not different between gestational age groups. The mean gestational age at delivery of the subsequent pregnancy was 37 ± 4 weeks (SD).

In multivariable logistic regression analysis, chronic hypertension, and index pregnancy maximum diastolic blood pressure, 24-h proteinuria and caesarean delivery, were independently correlated with an adverse outcome of a delivery before 34 weeks of gestation as a result of a hypertensive disorder in the subsequent pregnancy. BMI was excluded into the multivariable analysis because of too many missing values (Table 3). Chronic hypertension had a strong correlation with the outcome (OR 5.2, 95% CI 0.72–41), and the maximum diastolic blood pressure had an odds ratio of 12.0 per 12 mmHg (95% CI 10–13).

Table 3.   Results of the univariable and multivariable analyses for the primary endpoint: delivery before 34 weeks of gestation as a result of a hypertensive disorder in the subsequent pregnancy after the first pregnancy. The first index pregnancy was defined as a delivery before 34 weeks of gestation as a result of a hypertensive disorder
 Number of patients with missing dataUnivariable analysisMultivariable analysis
OR95% CIP valueOR95% CIP value
Demographic characteristics
Maternal age (years)41.030.94–1.130.54   
BMI (per point increase, kg/m2)1130.910.80–1.050.20   
Chronic hypertension (yes or no)22.20.96–4.900.065.20.72–360.08
Index pregnancy characteristics
Gestational age at delivery (per increment of 1-day gestational age)20.970.95–0.970.02   
RR systolic maximum (per increment of 1 mmHg)761.010.99–1.030.26   
RR diastolic maximum (per increment of 1 mmHg)201.051.01–1.080.011.21.04–1.310.03
Proteinuria (per increment of 1 g/24 hours)560.980.94–1.040.530.700.56–0.910.04
Caesarean section20.460.19–1.110.080.410.19–1.010.08
Pre-eclampsia32.60.58–11.50.21   
HELLP syndrome20.640.30–1.340.23   
Small for gestational age20.790.37–1.700.54   

Discussion

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

This large cohort study adds data from 211 patients to the available literature on the course of pregnancies after premature deliveries resulting from hypertensive disorders of pregnancy. The recurrence rate of a delivery before 34 weeks of gestation in this group was 17%, which fits well within the spectrum of recurrence rates in other studies.14 Fourteen percent delivered at between 34 and 37 weeks of gestation, and 69% of the women delivered after 37 weeks of gestation. Of this last group only 67 of them (32%) had a completely uneventful pregnancy. Although this 32% might seem a low percentage, the question of interest for the patient and the obstetrician is the recurrence of early preterm delivery. Morbidity of the mother and her child is mainly related to this early gestational age (e.g. under 34 weeks). From this point of view a recurrence rate of 17% is most relevant.

The group of women without subsequent pregnancies counts for 32% of the index group, which is in agreement with other studies.9,10 Of these women, 64% did not conceive again because of the fear of recurrence. It might be hypothesised beforehand that this group of women had more severe disease in the first pregnancy, but this was not apparent in the data. The statistically significant differences calculated between the groups, such as BMI, age at time of delivery, greater number of caesarean deliveries and an average extra 1 week of gestational age at time of delivery, have no clinical relevance in our opinion. This finding remains unexplained, therefore, and there may be speculations on the role of baseline psychosocial differences.

The main study for comparison, by Van Rijn et al.,15 also from the Netherlands, reported a lower recurrence rate of 5%. As background populations of both studies are more or less comparable for socio-geographical reasons, the shorter minimum follow-up time of 2 years (compared with our minimum follow-up time of 4 years) may explain the differences. It might be speculated that women who experienced more severe complications (such as maternal disease and early gestational age) take more time to engage in a subsequent pregnancy, and Van Rijn might have missed this group of patients.

A possible interpretation problem may be the confounding factor that women with more severe disease in the first pregnancy are more likely to end up at tertiary university centres. However, this effect is limited, because in principle all women before 32 weeks of gestation are referred to tertiary university centres in the Netherlands, according to the national guidelines. If second pregnancies were not handled in the tertiary care centres, data would be retrieved regardless.

Information about recurrence was until recently fragmentary and outdated, with the most quoted study of Sibai et al.16 dating from 1991. This study was the main reference for counselling, and concerned a highly selected population with a high recurrence rate of pre-eclampsia, of 65%, and a 21% recurrence rate of early pre-eclampsia, compared with the 5% recurrence rate reported by van Rijn et al.15 This variation probably arises as a result of population selection differences, and the small numbers involved. This also holds true for the bigger aspirin and antioxidant prospective prevention trials, such as the CLASP trial and the VIP or INTAPP trials, where secondary and primary prevention are the main concern, and not the specific recurrence rate of a preterm delivery.17–19 The study of Spinnato et al. included an unselected and heterogeneous group of patients, and mentioned a recurrence rate of 11.5% in 338 patients with a history of pre-eclampsia. They did not give the recurrence rate of severe pre-eclampsia resulting in delivery before 34 weeks of gestation.20 Caritis et al. selected a patient population that was at higher risk for developing pre-eclampsia. They included patients with previous pre-eclampsia and mentioned recurrence rates of 17% in the low-dose aspirin group versus 19% in the placebo group.21 These studies assessed the overall recurrence of pre-eclampsia without distinguishing between mild pre-eclampsia and the more clinically relevant category of severe pre-eclampsia. Recently, more specific data on the recurrence rate of an early delivery as a result of a hypertensive disorder became available, and a systematic review was published.14 Eleven studies with a total of 2461 patients (range 18–1754 patients per study) were available. For methodological reasons (heterogeneity), only seven studies (2188 patients) could be included for pooling. The pooled risk of recurrence of hypertension, pre-eclampsia or HELLP resulting in delivery before 34 weeks was 7.8% (95% CI 6.7–9.0%). Variation between studies was significant, probably because of variation in patient selection and the wide variation in population size. Selection bias could be the reason that the smallest studies had a higher risk estimate than our pooled result, whereas bigger trials like Hernández-Diaz et al.7 were more comparable with a 6.8% recurrence rate. No data were available on women who decided to refrain from future pregnancies. Translation to clinical everyday practice therefore remains uncertain. The main point of the present study is that it consecutively included all patients who matched the inclusion criteria from 1996 to 2004. The study is well numbered and another strong point is the fact that for the first time data are shown on women who did not become pregnant again. A fourth point of advantage is the high follow-up rate and that there was an adequately long follow-up time. Preconception care becomes increasingly important, and this study adds clinical information for motivated counselling. Because anxiety and fear experienced is related to the preterm delivery, as well as the neonatal and maternal mortality and morbidity, patients want information before their subsequent pregnancy.

With increasing data becoming available, counselling becomes more informed and patients might make better decisions for further pregnancies. However, individual tailored advice and simple prediction models are still unavailable. In this study, we took the first step towards a prediction model based on simple clinical parameters that will be available for each obstetrician. We identified four simple factors in predicting adverse pregnancy outcome. A high diastolic blood pressure at the index pregnancy and chronic hypertension are related to an adverse outcome in the subsequent pregnancy. Chronic hypertension after the first pregnancy was associated with a five-fold increased risk of recurrence. However simple, the model needs elaborate perfection before aiding patient counselling and obstetric care. Given the surprising and not easily explained finding that caesarean section is a protective parameter, the model probably needs adjustments, indicating the limitation of this study. Another limitation is the retrospective character of the study. Factors that may have been interesting for the model might not have been available. Missing values in the multivariable model are another disadvantage arising from the retrospective design. An individual patient data meta-analysis of patients from comparable cohorts is planned. Subsequently, validation in the clinical setting would be the logical next step in the development of such a model.

Disclosure of interests

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

None of the authors report a conflict of interest related to the findings reported in this manuscript.

Contribution to authorship

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

All authors fulfilled the requirements for authorship. JL, BWM, WG and JvdP conceived and designed the study. JL, AB and WG performed the data collection. JL, BWM and HW analysed the data. JL, BWM and WG wrote the paper.

Details of ethics approval

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

Ethical approval was not needed as the retrospective observational character of our study does not require such approval in the Netherlands.

Funding

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

This study was solely funded by the department of Obstetrics and Gynaecology of the Academic Medical Centre Amsterdam, the Netherlands.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of interests
  8. Contribution to authorship
  9. Details of ethics approval
  10. Funding
  11. References
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    Langenveld J, Jansen S, van der Post JA, Wolf H, Mol BW, Ganzevoort W. Recurrence risk of a delivery before 34 weeks of pregnancy due to a severe hypertensive disorder: a systematic review. Am J Perinatol 2010;27:56571.
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    Spinnato JA II, Freire S, Pinto E Silva JL, Cunha Rudge MV, Martins-Costa S, Koch MA, et al. Antioxidant therapy to prevent preeclampsia: a randomized controlled trial. Obstet Gynecol 2007;110:13118.
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    Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, Thom E, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1998;338:7015.