Hypertensive disorders of pregnancy
Pereira Bernardes, Thomas Patrick Custodio Heinrich
DOI:
10.33612/diss.99788387
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Publication date: 2019
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Pereira Bernardes, T. P. C. H. (2019). Hypertensive disorders of pregnancy: occurrence, recurrence, and management. University of Groningen. https://doi.org/10.33612/diss.99788387
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Take-down policy
of pregnancy
Occurrence, recurrence, and management
Thomas Patrick Bernardes
2019
financially supported by the Abel Tasman Talent Program, University of Groningen. Printing of this thesis was financially supported by the University Library and the SHARE Research Institute of the Graduate School of Medical Sciences.
Hypertensive disorders of pregnancy Occurrence, recurrence, and management
ISBN (printed): 978-94-034-2123-0
ISBN (digital): 978-94-034-2122-3
Layout & cover design: Emilia Bigaeva
Hypertensive disorders of
pregnancy
Occurrence, recurrence, and management
PhD thesis
to obtain the degree of PhD at the University of Groningen
on the authority of the Rector Magnificus Prof. C. Wijmenga
and in accordance with the decision by the College of Deans. This thesis will be defended in public on Wednesday 6 November 2019 at 11.00 hours
by
Thomas Patrick Custodio Heinrich Pereira Bernardes
born on 09 April 1982Prof. P.P. van den Berg Prof. B.W. Mol
Co-supervisor
Dr. H. GroenAssessment Committee
Prof. J.J.H.M. Erwich Prof. M. Spaanderman Prof. Y.T. van der SchouwWhose hands can strike with such abandon That in a twinkling, life is sapped from the living
Yet those same hands can touch with such healing, irresistible tenderness That the haughty neck is happy to bow
And the proud back is glad to bend Out of such chaos, of such contradiction We learn that we are neither devils nor divines
When we come to it
We, this people, on this wayward, floating body Created on this earth, of this earth
(...)
Introduction
11
PA R T I
Recurrence risk of pre-eclampsia in a linked
population-based cohort: effects of first
pregnancy maximum diastolic blood pressure
and gestational age
Pregnancy Hypertension, 2019
29
Early and late onset pre-eclampsia and small for
gestational age risk in subsequent pregnancies
Submitted
47
PA R T I I
Relevance of individual participant data
meta-analysis for studies in obstetrics: delivery versus
expectant monitoring for hypertensive disorders
of pregnancy
European Journal of Obstetrics & Gynecology and Reproductive Biology, 2015
69
1
2
4
3
Contents
outcomes after induction of labor versus
expectant management in women with an unripe
cervix: a secondary analysis of the hypitat and
digitat trials
British Journal of Obstetrics and Gynaecology - BJOG, 2016
Summary, general discussion and perspectives
125
Nederlandse samenvatting
Sumário em Português do Brasil
Co-author affiliations
Acknowledgements
About the author
Research Institute SHARE
142
146
150
154
156
158
6
7
8
GENERAL INTRODUCTION
In science it often happens that scientists say, “You know that’s a really good argument; my position is mistaken,” and then they actually change their minds and you never hear that old view from them again. They really do it. It doesn’t happen as often as it should, because scientists are human and change is sometimes painful. But it happens every day.
- Excerpt from “The burden of skepticism”, Carl Sagan
Hypertensive disorders of pregnancy
Of the estimated 213 million pregnancies that occur worldwide annually, hypertensive disorders are present in 3 to 10%.1–4 These disorders remain important causes of maternal
and perinatal morbidity and mortality. It is estimated that 14% of maternal deaths as well as up to 10% of stillbirths can be attributed to hypertensive disorders.5–10 This thesis describes
studies that focus on their prevention and management.
Hypertensive disorders of pregnancy are classified under four major categories: gestational hypertension, eclampsia, chronic or preexisting hypertension and superimposed pre-eclampsia.12,13 Figure 1 provides an outline of their worldwide distribution.11
1
either proteinuria (300mg/dL or more in a 24h sample, a protein/creatinine ratio of 0.3 or more, or a dipstick reading of 2+ if quantitative methods are not available) or severe features present (American College of Obstetrics and Gynaecology 2019, Table 1).
Pre-eclampsia has a prevalence of 3 to 5% and it is more common in the 1st pregnancy, with prevalences approximately twice higher than that of subsequent pregnancies.1,2,14–16 The
presence of severe features or early onset of presentation, i.e. before 34 weeks, increases morbidity and mortality risks.17 Progression to eclampsia, the occurrence of grand mal
seizures inexplicable by a more compelling neurological cause, may occur in 0.6% of women who present pre-eclampsia with severe features despite magnesium sulfate prophylaxis.18
Differences in availability of magnesium sulfate may partly explain the wide difference in eclampsia prevalence found in the comparison between developing and developed countries, range of 90—157 and of about 6 in 10,000 pregnancies, respectively.19–23 It is of
note though that the relative proportion of maternal deaths attributable to hypertensive disorders in developing and developed regions is comparable at 14 and 12.9%, respectively.10
Table 1. Severe features of hypertensive disorders of pregnancy - ACOG 201912
a. Systolic blood pressure of 160 mm Hg or more, or diastolic blood pressure of 110 mm Hg or more on two occasions at least 4 hours apart (unless antihypertensive therapy is initiated before this time);
b. Thrombocytopenia (platelet count less than 100,000 x 109/L);
c. Impaired liver function as indicated by abnormally elevated blood concentrations of liver enzymes (to twice the upper limit normal concentration), and severe persistent right upper quadrant or epigastric pain unresponsive to medication and not accounted for by alternative diagnoses;
d. Renal insufficiency (serum creatinine concentration more than 1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease);
e. Pulmonary edema;
f. New-onset headache unresponsive to medication and not accounted for by alternative diagnoses;
g. Visual disturbances.
Gestational hypertension is defined by the new onset arterial blood pressure levels equal or above 140 mmHg systolic or 90 mmHg diastolic measured twice with a minimum interval of 4 hours between measurements, after completion of 20 weeks of gestation without proteinuria or severe features.
The prevalence in nulliparous women ranges from 6 to 17% and, as with pre-eclampsia, it is less common in multiparous women who present a prevalence between 2 and 4%.24–26 Up
to half of the women who present gestational hypertension may progress to pre-eclampsia, with higher rates of deterioration being associated with earlier onset of hypertension during
the pregnancy.27 The absence of proteinuria does not preclude progression to adverse
outcomes as there are reports of increased perinatal mortality, thrombocytopenia and liver dysfunction in women with nonproteinuric hypertension.28,29
Chronic or preexisting hypertension is characterized as hypertension diagnosed preceding the pregnancy, or hypertension present at a minimum of two evaluations before completion of 20 weeks of gestation, or hypertension that persists longer than 12 weeks postpartum. In the latter case, a previous diagnosis of gestational hypertension is updated to reflect its chronicity. Estimates to its prevalence in pregnancy vary from 0.9% up to 5%.30,31 Progressively
higher maternal ages and rates of obesity are reflected in an increase of 67% in the period of 2000 to 2009 in the prevalence of chronic hypertension during pregnancy in the US.13,32
Although most women who present chronic hypertension have uncomplicated pregnancies, some cases progress to hypertensive crises that are difficult to control, increasing maternal and neonatal risks.33 Low birthweights, preterm births as well as perinatal mortality are
more common in pregnancies complicated by chronic hypertension.34–36
Finally, women with chronic hypertension may experience superimposed pre-eclampsia, which involves new onset proteinuria or end-organ dysfunction characterized by severe features after completion of 20 weeks of gestation. Rates of progression to superimposed pre-eclampsia are estimated to be up to 20 to 50%.33,37,38 Maternal and fetal outcomes
in superimposed pre-eclampsia tend to be more severe when compared to outcomes in pregnancies complicated by either pre-eclampsia or chronic hypertension alone.39
Complications associated with hypertensive disorders in pregnancy
Incomplete or dysfunctional spiral artery remodeling that culminates in diminished blood flow to the fetus provides the pathophysiological link between hypertensive disorders of pregnancy – early onset pre-eclampsia in particular – and intrauterine growth restriction (IUGR).40,41 About a third of pregnancies complicated by pre-eclampsia are also affected by
IUGR.42 Fetal distress, impaired immune function, cerebral palsy, cardiovascular disease and
1
disorders of pregnancy. Although there is some controversy in the inclusion of HELLP syndrome as a distinct entity within the spectrum of hypertensive disorders, it is undisputed that the vast majority of women who develop this serious complication also present with hypertension, proteinuria or both.56–59
The usual although not consensual diagnostic criteria are: lactate dehydrogenase (LDH) equal or over 600 IU/L, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) higher than twice the normal upper limit of the particular test used and platelet count below 100,000 x 109/L. Progression to HELLP syndrome increases the risks of mortality and
of serious maternal complications such as placental abruption, disseminated intravascular coagulation, pulmonary edema, and also the need for blood products transfusion.60,61
HELLP syndrome is also associated with lower birthweights and increased rates of stillbirth when compared to pregnancies complicated by pre-eclampsia only. As progression to HELLP syndrome after 34 weeks of gestation prompts immediate delivery by current guidelines, long and short-term risks associated with preterm birth are also elevated. The associated perinatal mortality rates range from 7.4% to 20.4%, the latter being associated with earliest preterm deliveries.59,62,63
Prevention of hypertensive disorders of pregnancy
Considerable effort has been put forth in the search for preventive interventions that may benefit women at risk of hypertensive disorders of pregnancy. Supplementation with calcium, folic acid, vitamins E and C and the use of aspirin were all promising candidates, with plausible biological mechanisms. Although beneficial effects were found in small studies most of them were later found to be of either limited or no benefit.64,65 Exceptions
are calcium and aspirin, which are now part of standard antenatal care focused on the prevention of hypertensive disorders of pregnancy for specific groups of women.
In 2013 the WHO released a guideline that recommends calcium supplementation for the prevention of pre-eclampsia, in particular to women at high risk of hypertension, in populations with low calcium intake.66 This recommendation was based on a 2010
meta-analysis of 13 trials, updated in 2018 without inclusion of new trials, that showed pre-eclampsia risk was halved and gestational hypertension risk reduced by 35% with high-dose calcium supplementation. However, the authors of the meta-analysis recommend caution in the interpretation of these large effects. They suggest that potential small-study effect or publication bias may have occurred, in view of funnel plot asymmetry. Moreover, a considerably smaller 8% pre-eclampsia risk reduction with a confidence interval that crossed unity was observed in the largest study included.67
Aspirin use to prevent pre-eclampsia has now been extensively studied, with more than 18,000 women over 16 trials included in a 2018 meta-analysis.68 Authors found it reduced
preterm pre-eclampsia risk by 38% but also that there was no effect on the risk of term pre-eclampsia. Administration should be started at the latest in the 16th week of gestation in women who are at high-risk for pre-eclampsia. There is no current consensus on what constitutes this high-risk group. Current guidelines have so far resorted to listing known risk factors and recommend aspirin use either in the presence of a single factor highly associated with pre-eclampsia, such as occurrence in a previous pregnancy, or a combination of two or more moderate risk factors, such as nulliparity and BMI over 30. Figure 2 shows a comparison of pre-eclampsia occurrence rates in women presenting with and without numerous risk factors.69
Figure 2. Risk of pre-eclampsia among women with and without individual clinical risk factors determined by 16 weeks’ gestation.
IUGR: intrauterine growth restriction; SLE: systemic lupus erythematosus; ART: assisted reproductive technology; BMI: body mass index; aPL: antiphospholipid antibody syndrome. Reproduced with permission
1
are potentially more severe if hypertension occurs away from term as its management may involve delivery and consequently result in preterm birth, increasing rates of respiratory distress syndrome, intraventricular hemorrhage and neonatal mortality.70–75 Furthermore,
induction of labor was long held to be associated with an increased risk of cesarean section although recent meta-analyses of randomized clinical trials have shown otherwise.76–84 The
alternative of delaying delivery is not a solution as extending a pregnancy complicated by hypertensive disorders increases maternal morbidity and mortality risks.24,25
The dilemma posed by increased maternal and neonatal risks in both delivering too soon or too late suggests that an optimal timing may exist. Several randomized controlled trials have evaluated management strategies for hypertensive disorders of pregnancy covering different gestational age ranges and different subgroups.85–88 The succession of the trials that
were performed so far should be viewed in the light of developing evidence over the last 15 years. Uncertainty regarding the effectiveness and potential harm of the intervention, also regarding an unwanted potential increase of cesarean sections, prompted ethical concerns. Because of this, researchers independently approached these challenges in a gradual way. To circumvent the problem of the rarity of severe adverse neonatal and maternal outcomes associated with high mortality rates or long-term morbidity, which would require large sample sizes, composite adverse outcomes were constructed for the individual trials. Although initially informative, with time the need arose for more conclusive evidence for specific rare outcomes and for subgroup analyses in this diverse but interrelated group of disorders.
The HYPITAT trial randomized 756 women between October 2005 and March 2008 with gestational hypertension or pre-eclampsia without severe features and a gestational age from 36 weeks to either immediate delivery or expectant management, choosing at the start not to include women with chronic hypertension or earlier gestational ages.85
To tackle the rarity of very severe outcomes, the chosen primary outcome measure was a composite consisting of maternal mortality, eclampsia, HELLP syndrome, pulmonary edema, thromboembolic disease, placental abruption, major post-partum hemorrhage or progression to severe hypertensive disease (systolic blood pressure 170 mmHg, diastolic blood pressure 110 mmHg, or proteinuria 5 g per 24 h).
The “Deliver or Deliberate” trial focused instead on pre-eclampsia only, which resulted in a predictable longer recruitment period (March 2002—June 2008) and a smaller recruitment target of 220 women. Women presenting pre-eclampsia with gestational ages of 34+0 – 36+6 weeks were randomized to immediate delivery or expectant management until 37 weeks. Results favored delivery because of lower rates of progression to severe pre-eclampsia with no significant difference in neonatal morbidity.86
Superimposed pre-eclampsia was studied by Hamed et al. by randomization of pregnant women with mild to moderate chronic hypertension recruited between 24-36 weeks. This trial compared planned delivery at 37 weeks to expectant management until spontaneous labor, completion of 41 weeks of gestation, or development of superimposed pre-eclampsia without severe features after the 37th week of gestation or with severe features at any time.
They found no significant differences in maternal outcomes, but more NICU admissions and unsurprisingly smaller babies in the planned delivery group87.
Finally, the HYPITAT II trial followed the same design of “Deliver or Deliberate” but allowed for the inclusion of women presenting with gestational hypertension in addition to those presenting with pre-eclampsia. Women were randomized between 34 and 36+6 weeks of gestation to immediate delivery or expectant management until planned delivery at 37 weeks of gestation. Immediate delivery showed a not significant tendency towards less risk of maternal complications whereas respiratory distress syndrome risk was increased. The authors concluded that results favored a policy of expectant management up until 37 weeks of gestation or until the clinical situation deteriorates.
1
OUTLINE AND AIM OF THIS THESIS
The body of work composing this thesis was directed towards two main aspects of hypertensive disorders of pregnancy: their prevention and their management. However unclear the extent of the prevention potential of aspirin, it is now well established that women at high risk of developing hypertensive disorders benefit from its early introduction in pregnancy. Nonetheless, the uncertainty regarding what exactly constitutes this high-risk group naturally leads to the question of whether more women would benefit from this intervention if a better evaluation of their individual risk profile could be established. The first part of this thesis focuses on providing evidence that contributes towards this goal. This part is comprised of Chapters 2 and 3, with both studies based on large population-based cohort Dutch registry data. In Chapter 2, the impacts of max diastolic arterial pressure and gestational age at delivery in the first pregnancy were evaluated as risk factors for the occurrence and recurrence of pre-eclampsia in the following pregnancy. Chapter 3 is focused on the relationship between pre-eclampsia and delivery of small for gestational age infants across subsequent pregnancies.
The second part of this thesis uses randomized controlled trial data to tackle the dilemma of optimal delivery timing for women that have a potential indication for delivery in two scenarios. First, Chapter 4 doubles as a call-to-arms highlighting the value of individual patient meta-analyses (IPDMA) and as a protocol for their use in the study of the management of hypertensive disorders of pregnancy near term. Chapter 5 describes the IPDMA itself, which encompasses all available trial data that has so far been generated. Second, in so far as timely delivery may be beneficial in preventing maternal morbidity for women presenting with hypertensive disorders at term, Chapter 6 shows if for women with low Bishop scores any potential benefits are countered by potential increases in cesarean section and neonatal morbidity rates.
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a linked population-based cohort:
effects of first pregnancy maximum
diastolic blood pressure and
gestational age
Thomas P. Bernardes Ben W. Mol Anita C.J. Ravelli Paul P. van den Berg H. Marike Boezen Henk Groen
ABSTRACT
ObjectiveTo estimate pre-eclampsia occurrence and recurrence risk in the 2nd pregnancy and analyze associated risk factors such as 1st pregnancy maximum diastolic blood pressure (maxDBP) and gestational age at delivery (GA).
Study Design
Linked cohort of 1st and 2nd pregnancies of 272,551 women from the Dutch Perinatal Registry collected between 2000 and 2007. We defined pre-eclampsia as hypertension (maxDBP ≥ 90 mmHg or documented hypertension) plus proteinuria (≥ 300mg/ 24h) and analyzed its 2nd pregnancy occurrence with logistic regression. Early and late onset pre-eclampsia were defined by delivery before and after the 34th week, respectively.
Results
Pre-eclampsia prevalences in the 1st and 2nd pregnancies were 2.5% and 0.9%, respectively. Women with prior pre-eclampsia had a 10.5% risk of recurrence. For women with term 1st pregnancies and maxDBP < 80 mmHg, the 2nd pregnancy pre-eclampsia rate was 0.2% (95% CI 0.17% - 0.23%), while for those whom presented maxDBP ≥110 mmHg it was 4.2% (95% CI 3.6% - 4.8%). First pregnancy late onset eclampsia was associated with increased pre-eclampsia recurrence risk proportional to 1st pregnancy maxDBP: in women with a maxDBP between 100 and 109 mmHg the recurrence risk was 8.3%, while for women with a maxDBP ≥110 mmHg this risk was 11% (difference 2.7%; 95% CI 1.0% - 4.4%). In 1st pregnancy early onset pre-eclampsia corresponding rates were 14.8% and 19.3% (difference 4.5%; 95% CI -1.3% - 9.7%).
Conclusion
Pre-eclampsia recurrence risk is 10%. Pre-eclampsia risk in the 2nd pregnancy increases proportionally to 1st pregnancy maxDBP. Earlier onsets of 1st pregnancy pre-eclampsia further increase recurrence risk.
2
INTRODUCTION
Pre-eclampsia is a major contributor to maternal and fetal morbidity that affects approximately 3% of all pregnancies.1 Although its incidence is highest in the first pregnancy,
recurrence is still an important problem with estimates ranging from 12% to 38%.2–6 A wide
variety of factors such as previous early onset pre-eclampsia, preterm delivery, pre-eclampsia with severe features and maternal preexisting disease have been proposed as risk factors for pre-eclampsia which may help explain the wide range in recurrence rates.1,3,4,7,8 In any
case, once pre-eclampsia occurs, appropriate counseling targeted at patient reassurance and need for information about future pregnancies becomes paramount, as well as a better assessment of pertinent risk factors for the individual patient is required.
Considerable effort has recently been put forth in studying the effects of increasingly higher blood pressure levels during pregnancy on maternal and neonatal outcomes. In the CHIPS trial, severe hypertension was associated with poorer outcomes for newborns in both tight and less-tight blood pressure control groups as well as with poorer maternal outcomes in the less-tight group, such as increased risk of acute stroke during and post pregnancy, but follow-up into the next pregnancy was not performed. 9–11 On the other hand, the effects of
different hypertension levels on subsequent pregnancies have so far been left unexplored in the literature.
Therefore, in this study we analyzed pre-eclampsia recurrence and 2nd pregnancy
pre-eclampsia occurrence risks in a large cohort of the Dutch population using the longitudinal Netherlands Perinatal Registry (Perined) records. This population cohort allowed us to evaluate the influence of several factors previously suggested in the literature as well as that of gradually higher levels of pregnancy maximum diastolic blood pressure (maxDBP), which we hypothesized to be useful in further distinguishing patients in low or high risk of pre-eclampsia in a subsequent pregnancy.
METHODS
This study is based on a nationwide prospective cohort dataset extracted from Perined, the result of a validated linkage of three different registries: the midwifery registry (LVR1), the obstetrics registry (LVR2), and the neonatology registry (LNR). It consists of population-based data that covers approximately 96% of all deliveries in the Netherlands and contains information on pregnancies, deliveries and admissions until 28 days after birth.
Perined data is recorded at the child’s level and there is no unique maternal identifier to correlate siblings and follow up on subsequent pregnancies. Because of this, we submitted the data on all available 509,559 second deliveries from 2000 to 2007 to a linkage procedure based on the variables birth date of mother, birth date of previous child, and postal code of mother. The final linked cohort contained data on the first and second deliveries of 272,551 women. Further information on the linkage procedure can be found elsewhere.12
Pre-eclampsia was defined by the combined presence of hypertension (either maximum diastolic blood pressure ≥ 90 mm Hg or documented hypertension by the care provider) and proteinuria (≥300 mg in 24 hours). Chronic hypertension was defined by hypertension diagnosed before pregnancy or new onset hypertension before 20 weeks of pregnancy following the Dutch guidelines for hypertension in pregnancy (blood pressure ≥ 140/90 mmHg) and documented by the care provider, either a midwife or obstetrician. We also included obstetrician documented records of pre-eclampsia and eclampsia in the Perined database, as well as women with chronic hypertension that presented proteinuria (≥300 mg in 24 hours). In the Dutch perinatal system, blood pressure measurements are performed at every outpatient visit to the care provider and multiple times peripartum. While individual measurements are not recorded in the dataset, the maximum diastolic pressure available in the dataset is based on these measurements. The gestational age at which the highest blood pressure occurred is not recorded. Early onset pre-eclampsia was characterized by delivery before 34 weeks in cases with eclampsia. Late onset eclampsia was defined as pre-eclampsia cases delivered from the 34th week on.
We compared women who developed pre-eclampsia in their first pregnancy to those who did not according to their respective baseline demographic, clinical and obstetric
2
relevance and model parsimony.
To investigate the effects of GA at delivery in the 1st pregnancy to the pre-eclampsia risk
in the 2nd pregnancy, we further divided the two groups in three categories: extreme
preterm (22+0-29+6 weeks gestation), early preterm (30+0-33+6 weeks gestation) and late
preterm (34+0-36+6 weeks gestation). In the same manner, we also divided the two groups
in categories according to their maxDBP in the 1st pregnancy: < 80 mmHg, 80-89 mmHg,
90-99 mmHg, 100-109 mmHg and ≥ 110 mmHg. The variable for maximum diastolic blood pressure had 27.8% of missing values and no other covariates evaluated in the logistic regressions had missing values. To avoid potential bias introduced by listwise deletion of these cases in the logistic regressions, we performed a multiple imputation procedure with the aim of producing unbiased estimates as we assumed no systematic error in the registry. We generated five imputed sets using predictive mean matching and the following 1st and 2nd pregnancy variables: pre-eclampsia (yes or no), hypertension during pregnancy
(yes or no), GA (weeks), gestational diabetes (yes or no), multiple pregnancy (yes or no), maternal age (years), birthweight (grams), maxDBP (mmHg), 5th percentile small for GA (yes
or no), spontaneous birth (yes or no). In addition, we used the following demographic and clinical variables: low socioeconomic status (yes or no), ethnicity (Caucasian or not), chronic hypertension (yes or no) and diabetes (yes or no).
Student’s t or Mann-Whitney U tests were used in the statistical analyzes of continuous data. Categorical data were analyzed with chi-squared tests, and confidence intervals for proportions were found using the Wilson score interval.13 To assess pre-eclampsia risk, we
used logistic regression to adjust the odds ratios to differences in baseline characteristics and study the influence of maxDBPs and different GAs at delivery. We assessed potential interaction effects between pre-eclampsia occurrence and maximum diastolic blood pressure. Evidence of interaction effects was first evaluated by product terms. To obtain the relevant point estimates and generate appropriate confidence intervals for interaction effects, we followed the alternative coding scheme initially proposed by Rothman and further developed by Hosmer & Lemeshow.14 In this approach, interaction between two
risk factors (A and B) is evaluated through a single four level variable (-A-B, +A-B, -A+B, +A+B), with no loss of degrees of freedom. Point estimates for each combination and associated confidence intervals are then readily available in the output of most statistics software. Univariate models were run for each of the studied variables and compared to the fully adjusted model. Odds ratios obtained from the five multiple imputation sets were pooled following Rubin’s rules.15 The linkage procedure was performed using the R statistical
software environment (version 2.13.1; R Foundation for Statistical Computing, Vienna, Austria). The multiple imputation procedure was performed, and the data were analyzed with IBM SPSS Statistics software (version 20.0.0; IBM Corporation).
RESULTS
A total of 509,559 second deliveries were available for analyses. From this total we matched 272,551 (53%) to the corresponding first delivery. Of these, a total of 6,679 (2.4%) women developed pre-eclampsia in the 1st pregnancy, versus 2548 (0.9%) in the 2nd pregnancy. There were 702 women who presented pre-eclampsia in both pregnancies, a recurrence rate of 10.5% (95% CI 9.8% - 11.2%). Conversely, de novo pre-eclampsia in the 2nd pregnancy occurred in 1846 (72.4%) of the women. Of this group, 60% had presented gestational or chronic hypertension but not pre-eclampsia in the 1st pregnancy. Only 28% of the women that developed pre-eclampsia in the 2nd pregnancy presented no form of hypertension in the 1st pregnancy.
We present baseline characteristics of the two comparison groups in Table 1. Maternal ages were comparable, as well as the number of Caucasians and women with low socioeconomic status in each group. Women that did not present pre-eclampsia were less likely to have diabetes (0.9% vs 2.1%; p-value < 0.0001), chronic hypertension (0.9% vs 6.7%; p-value < 0.0001), and to have a multiple pregnancy (0.8% vs 2.6%; p-value < 0.0001). Women who presented pre-eclampsia had slightly higher interpregnancy intervals (2.5 years ± 1.2 vs 2.7 ± 1.3; p-value < 0.0001). Mean GAs were lower in women with pre-eclampsia (39.2 ± 2.2 vs 37.1 ± 3.0; p-value < 0.0001).
Table 1. Baseline maternal characteristics at 1st pregnancy delivery
No pre-eclampsia
(n=265,872) Pre-eclampsia(n=6,679) P value
Maternal age, years† 28.6 ± 4.2 28.5 ± 4.4 0.362
Interpregnancy interval, years† 2.5 ± 1.2 2.7 ± 1.2 <.0001
GA at delivery, weeks† 39.2 ± 2.2 37.1 ± 3.0 <.0001
Caucasian, n (%) 232,101 (87.3) 5,872 (87.9) 0.133
Low socioeconomic status, n (%) 71,258 (26.8) 1,753 (26.2) 0.548
Chronic Hypertension, n (%) 2,274 (0.9) 454 (6.8) <.0001
Diabetes, n (%) 2,561 (1.0) 142 (2.1) <.0001
2
occurrences were identified in the same way and the respective numbers are as follows: 873 (34,2%), 1010 (39,6%) and 662 (25,9%). Superimposed pre-eclampsia in the 2nd pregnancy
occurred in 222 (8.1%) women. Three did not fill the other criteria and were identified through documented proteinuria and chronic hypertension.
Figure 1 presents the risk of pre-eclampsia in the 2nd pregnancy in relation to different levels
of maxDBP in the 1st pregnancy, GA at delivery and history of pre-eclampsia. The presence
of severe hypertension (maxDBP ≥ 110 mmHg) in late onset 1st pregnancy pre-eclampsia
was associated with a 11% rate of recurrence, significantly higher than the 8.3% rate found for preeclamptic women whose maximum DPB levels were between 100 and 109 mmHg. A similar tendency was observed in women with early onset pre-eclampsia, although the smaller incidence resulted in overlapping confidence intervals. While the recurrence rate of those with maxDBP equal or above 110 mmHg after early onset pre-eclampsia was 19.3%, the rates of those within the 90-99 and 100-109 mmHg categories were 14% and 14.8%, respectively.
Figure 1. Rate of 2nd pregnancy PE by 1st pregnancy maxDBP, GA at delivery and PE occurrence.
Rate of 2nd pregnancy preeclampsia and 95% confidence interval by 1st pregnancy gestational age at delivery
(weeks), pre-eclampsia occurrence and maximum diastolic blood pressure (mmHg). PE: pre-eclampsia; maxDBP: maximum diastolic blood pressure; GA: gestational age.
As expected, women with term 1st pregnancies and low levels of maxDBP (<80 mmHg) had a
but still normal levels of maxDBP of 80-89 mmHg more than doubled this risk to 0.42% (95% CI 0.39% - 0.46%). Severe hypertension and no pre-eclampsia in these pregnancies raised 2nd
pregnancy pre-eclampsia risk to 4.1% (95% CI 3.6% - 4.8%).
Table 2 presents the results of the logistic regressions with pre-eclampsia in the 2nd pregnancy
as the outcome. Increasing levels of maxDBP in the 1st pregnancy were associated with
increased risks of pre-eclampsia in the 2nd pregnancy for women without prior history of
pre-eclampsia. Slightly elevated but not hypertensive levels of maxDBP were already associated with increased risks: women with levels between 80 and 89 mmHg had an adjusted odds ratio (aOR) of 2.3 (95% CI 1.9 - 2.7) for the occurrence of pre-eclampsia in the following pregnancy. Levels equal or above 110 mmHg were associated with higher risks, with an aOR of 20.7 (95% CI 16.7 - 25.6).
Pre-eclampsia history was identified as the main risk factor for recurrence. The aOR associated with severe hypertensive cases (≥ 110 mmHg) was 43.1 (95% CI 35.5 - 52.5). This risk is compounded by earlier preterm deliveries as these were also associated with increasing rates of 2nd pregnancy pre-eclampsia. The group of women whose 1st pregnancy
ended before 30 weeks had an aOR of 3.9 (95% CI 3.2 - 4.8), and the risk gradually decreased with increasing GA.
Women with chronic hypertension were at increased risk of superimposed pre-eclampsia in the 2nd pregnancy with an aOR of 2.3 (95% CI 2.0 - 2.7). History of pre-eclampsia in women
with chronic hypertension resulted in a 21.4% chance of recurrence on the 2nd pregnancy, as
opposed to 5.5% for those with only chronic hypertension (difference 15.9%; 95% CI 12.2% - 19.9%). Women with diabetes were also at increased risk as their aOR was 1.8 (95% CI 1.4 - 2.3). Prior pre-eclampsia and diabetes resulted in a 2nd pregnancy pre-eclampsia risk of
15.5%, while for isolated diabetes the risk to 1.8% (difference 13.7%; 95% CI 8.6% - 20.5%). In the univariate regression, a multiple 1st pregnancy was associated with increased
pre-eclampsia risk in the 2nd pregnancy with an OR of 1.5 (95% CI 1.2 - 1.8). However, in the
multivariate model there was an apparent protective effect as the aOR was 0.6 (95% CI 0.4 - 0.9).Stepwise adjustment of the univariate regression to additionally account for the effects
2
Table 2. Risk factors for pre-eclampsia in the second pregnancy
First pregnancy n N % Odds ratio (95% CI) Adjusted Odds ratio (95% CI)† Maximum diastolic pressure No pre-eclampsia 265,871 1,846 0.7 <80 mmHg 103,794 232 0.2 Reference Reference 80-89 mmHg 113,196 537 0.5 2.1 (1.8 - 2.5) 2.3 (1.9 - 2.7) 90-99 mmHg 30,630 422 1.4 6.2 (5.2 - 7.4) 6.7 (5.6 - 8.0) 100-109 mmHg 13,404 405 3.0 13.8 (11.5 - 16.7) 13.9 (11.5 - 16.8) ≥110 mmHg 4,847 250 5.2 24.2 (19.7 - 29.8) 20.7 (16.7 - 25.6) Pre-eclampsia 6,680 702 10.5 <90 mmHg 224 21 9.4 40.7 (24.4 - 68.0) 35.1 (21.3 - 57.7) 90-99 mmHg 1,234 115 9.2 45.2 (35.6 - 57.5) 40.7 (31.9 - 51.9) 100-109 mmHg 2,570 231 9.0 43.8 (36.1 - 53.2) 36.8 (30.2 - 44.9) ≥110 mmHg 2,652 335 12.6 64.0 (53.2 - 77.0) 43.1 (35.5 - 52.5) GA
Term 250,471 1,921 0.8 Reference Reference
34-366/7 weeks 15,404 314 2.0 2.7 (2.4 - 3.0) 1.6 (1.4 - 1.9) 30-336/7 weeks 4,335 189 4.4 5.9 (5.5 - 6.4) 2.6 (2.2 - 3.1) <30 weeks 2,341 124 5.3 7.2 (6.6 - 8.0) 3.9 (3.2 - 4.8) Chronic Hypertension 2,728 222 8.1 10.2 (9.5 - 11.0) 2.3 (2.0 - 2.7) Diabetes 2,703 68 2.5 2.8 (2.5 - 3.2) 1.8 (1.4 - 2.3) Multiple pregnancy 2,190 30 1.4 1.5 (1.2 - 1.8) 0.6 (0.4 - 0.9) Multiple pregnancy (2nd pregn.) 5,403 162 3.0 3.4 (3.2 - 3.7) 3.8 (3.2 - 4.5)
CI: confidence interval; n: total within category; N: 2nd pregnancy pre-eclampsia within category. All risk factors
present in the 1st pregnancy unless otherwise indicated.
† Fully adjusted model that also includes maternal ethnicity, socioeconomic status and maternal ages in both pregnancies.
DISCUSSION
We investigated the recurrence risk of pre-eclampsia and additional risk factors for its occurrence in 2nd pregnancies. Our main findings are that the maxDBP in the 1st pregnancy
is directly proportional to pre-eclampsia risk in the 2nd pregnancy for women with no history
of pre-eclampsia, and that GA at delivery is inversely proportional to this risk. We were also able to confirm that pre-eclampsia history is a major risk factor although there is no clear evidence that the degree of hypertension presented by itself further increases pre-eclampsia risk in the 2nd pregnancy.
Based on a retrospective cohort of 211 subsequent deliveries it was previously reported that increasing levels of hypertension in an early onset preeclamptic 1st pregnancy increased
early onset 2nd pregnancy pre-eclampsia risk.16 Our results do not support this claim as risk
confidence intervals found over different levels of hypertension overlapped considerably for women with history of pre-eclampsia. Additionally, three previous studies identified preterm birth as a risk factor for pre-eclampsia in the 2nd pregnancy. Two of them were
based on large cohorts and our results are consistent with them, although only one of the three reported on increased risks beyond very early preterm delivery as we did.3,7 Reporting
conflicting results, van Rijn et al found recurrence rates for pre-eclampsia not related to delivery before 28 weeks of gestation in 120 hospital-based subsequent pregnancies.2
Although chronic hypertension is generally identified as a risk factor for pre-eclampsia, the literature presents conflicting results regarding its effect on recurrence risk. Sibai et al. studied 369 women with chronic hypertension and concluded that a history of pre-eclampsia did not increase rates of superimposed pre-pre-eclampsia.17 On the other hand,
Langenveld et al. and van Rijn et al. reported higher recurrence risk in women with chronic hypertension.2,16 Our results concur with the latter.
We performed our study on data from Perined. The registry covers approximately 96% of all pregnancy and birth characteristics of the country. No a priori power calculation was performed due to the large sample size available. We were unfortunately unable to adjust for certain factors such as BMI, smoking, medication use (such as aspirin and anti-hypertensive drugs), pre-existing vascular and kidney disease, history of thrombophilia, paternal influence
2
Of these, BMI is the most relevant as, although the effect size associated with obesity is usually lower than that of chronic hypertension, it is widely more prevalent. Obesity rates in women of reproductive age in most developed countries range from 14 to 20%, reaching up to 60% in some countries. These account worldwide for about 30% of the pre-eclampsia cases.20–24 As modifiable risk factors, effects on pre-eclampsia risks in a subsequent pregnancy
imposed by high pre-pregnancy BMI as well as gestational weight gain in the index gestation are of interest. Whether these effects are causal or representative of a system prone both to metabolic syndrome and pre-eclampsia, and whether BMI reduction in the interpregnancy interval would be enough to lessen the associated risk are so far subject only to speculation. As we were interested in the pre-eclampsia risk in a subsequent pregnancy, a probabilistic linkage procedure was performed to identify siblings and the characteristics of their pregnancies and deliveries. Failure to match was because of missing values on the linkage variables or a first delivery prior to 1999. Changes in the home address also resulted in non-linkage as “postal code of mother” was one of the non-linkage variables. The linked dataset was comparable to the Dutch national data on both demographic characteristics and obstetric outcomes.25 The prevalence of pre-eclampsia in the 1st pregnancy in our database is most
likely underestimated as women that only had one child are not part of the longitudinal database. A large Swedish cohort reported an overall pre-eclampsia rate of 4.1% that dropped to 3.9% if these women were excluded.7
Systolic blood pressure is not available in the dataset. This restricted our definition of pre-eclampsia which may have further lowered pre-pre-eclampsia prevalence in our study. Perined’s independent recording of pre-eclampsia and eclampsia occurrences, which we made use of, in association with the inclusion of cases of documented hypertension and proteinuria mitigate this issue as women with pre-eclampsia limited to systolic blood pressure hypertension were counted in. Our sensitivity analysis showed consistent results when the model was restricted to these cases only. Similarly, the inclusion of proteinuria as a criterion in the pre-eclampsia definition was standard practice over the years of data collection.26
The recent increase in the use of aspirin during pregnancy has benefited women at high risk for pre-eclampsia.27 The US Preventive Task Force defines this high risk group as women who
present with a history of pre-eclampsia, multifetal gestation, chronic hypertension, diabetes, renal or autoimmune disease.28 Our results indicate that women with elevated maxDBP in
their 1st pregnancy have a pre-eclampsia risk at least in the same order of magnitude as
women in this high-risk group, whether they developed pre-eclampsia or not. As there is evidence that the intervention causes little harm to those without contraindications, and that the potential benefit is substantial, it is worth considering high diastolic blood pressure
in a previous pregnancy as a risk factor for which the recommendation to use of aspirin from the 12th week of gestation may be advisable.
CONCLUSION
We found that the degree of severity of hypertension in the 1st pregnancy has direct relation
to pre-eclampsia rates in the 2nd pregnancy in women with no pre-eclampsia history. Previous
pre-eclampsia remains the biggest risk factor for pre-eclampsia in a subsequent pregnancy. Furthermore, low 1st pregnancy GAs at delivery further increase pre-eclampsia risk in the
2nd pregnancy. These findings improve the awareness of individual risks of occurrence and
2
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2
SUPPLEMENTAL MATERIALS
Table S1. Risk factors for pre-eclampsia in the second pregnancy — no imputed data
First pregnancy n N % Odds ratio (95% CI) Adjusted Odds ratio (95% CI)†
Maximum diastolic pressure No pre-eclampsia 265,871 1,846 0.7 <80 mmHg 71,360 204 0.3 Reference Reference 80-89 mmHg 79,567 440 0.6 1.9 (1.6 - 2.3) 2.1 (1.8 - 2.5) 90-99 mmHg 23,188 343 1.5 5.2 (4.4 - 6.2) 5.6 (4.7 - 6.7) 100-109 mmHg 11,599 352 3.0 10.9 (9.2 - 13.0) 11.1 (9.3 - 13.2) ≥110 mmHg 4,220 221 5.2 19.3 (15.9 - 23.4) 16.7 (13.7 - 20.3) Pre-eclampsia 6,680 702 10.5 <90 mmHg 222 21 9.5 36.4 (22.8 - 58.3) 28.8 (17.7 - 46.7) 90-99 mmHg 1,226 115 9.4 36.1 (28.5 - 45.7) 33.5 (26.4 - 42.6) 100-109 mmHg 2,549 228 8.9 34.3 (28.2 - 41.6) 30.2 (24.8 - 36.7) ≥110 mmHg 2,637 332 12.6 50.2 (42.0 - 60.1) 35.9 (29.7 - 43.3) GA
Term 250,471 1,921 0.8 Reference Reference
34-366/7 weeks 15,404 314 2.0 2.7 (2.4 - 3.0) 1.5 (1.4 - 1.8) 30-336/7 weeks 4,335 189 4.4 5.9 (5.0 - 6.9) 2.5 (2.1 - 2.9) <30 weeks 2,341 124 5.3 7.2 (6.0 - 8.7) 3.7 (2.9 - 4.6) Chronic Hypertension 2,728 222 8.1 10.2 (8.8 - 11.8) 2.3 (1.9 - 2.7) Diabetes 2,703 68 2.5 2.8 (2.2 - 3.5) 1.7 (1.3 - 2.2) Multiple pregnancy 2,190 30 1.4 1.5 (1.0 - 2.1) 0.6 (0.4 - 0.9) Multiple pregnancy (2nd pregn.) 5,403 162 3.0 3.4 (2.9 - 4.0) 3.8 (3.2 - 4.5)
CI: confidence interval; n: total within category; N: 2nd pregnancy pre-eclampsia within category. All risk factors
present in the 1st pregnancy unless otherwise indicated.
† Fully adjusted model that also includes maternal ethnicity, socioeconomic status and maternal ages in both pregnancies.
