Chances of Getting Preeclampsia Again After 2 Pregnancies With It
Inquiry
Take a chance of pre-eclampsia in first and subsequent pregnancies: prospective accomplice study
BMJ 2009; 338 doi: https://doi.org/10.1136/bmj.b2255 (Published 18 June 2009) Cite this as: BMJ 2009;338:b2255 
- Sonia Hernández-Díaz , associate professor1,
- Sengwee Toh , doctoral student1,
- Sven Cnattingius , professorii
- oneDepartment of Epidemiology, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115, Us
- 2Department of Medical Epidemiology and Biostatistics and Clinical Epidemiology Unit, Department of Medicine, Karolinska Plant, Due south-171 77 Stockholm, Sweden
- Correspondence to: S Hernández-Díaz shernan{at}hsph.harvard.edu
- Accepted 26 February 2009
Abstruse
Objective To investigate whether pre-eclampsia is more than common in first pregnancies solely considering fewer affected women, who presumably have a college adventure of recurrence, keep to take subsequent pregnancies.
Design Prospective accomplice study.
Setting Swedish Medical Birth Register.
Participants 763 795 primiparous mothers who had their offset births in Sweden, 1987-2004.
Chief outcome measures Pre-eclampsia.
Results The adventure of pre-eclampsia was 4.ane% in the first pregnancy and ane.vii% in after pregnancies overall. Still, the adventure was 14.vii% in the second pregnancy for women who had had pre-eclampsia in their first pregnancy and 31.nine% for women who had had pre-eclampsia in the previous two pregnancies. The run a risk for multiparous women without a history of pre-eclampsia was around 1%. The incidence of pre-eclampsia associated with delivery before 34 weeks' gestation was 0.42% in primiparous women, 0.11% in multiparous women without a history of pre-eclampsia, and 6.8% and 12.5% in women who had had one or two previous pregnancies affected, respectively. The proportion of women who went on to take a further pregnancy was 4-v% lower after having a pregnancy with any pre-eclampsia but over x% lower if pre-eclampsia was associated with very preterm delivery. The estimated hazard of pre-eclampsia in parous women did not alter with standardisation for pregnancy rates.
Conclusions Having pre-eclampsia in i pregnancy is a poor predictor of subsequent pregnancy but a stiff predictor for recurrence of pre-eclampsia in future gestations. The lower overall risk of pre-eclampsia among parous women was not explained by fewer conceptions amid women who had had pre-eclampsia in a previous gestation. Early onset pre-eclampsia might be associated with a reduced likelihood of a future pregnancy and with more recurrences than late onset pre-eclampsia when there are further pregnancies. Findings are consistent with the being of ii distinct conditions: a severe recurrent early onset type affected by chronic factors, genetic or environmental, and a milder desultory grade affected past transient factors.
Introduction
Pre-eclampsia has been defined as a disease of start pregnancies.1 The association between primiparity and pre-eclampsia is so widely accepted that it is at the core of several pathophysiological theories. For example, it has been proposed that pre-eclampsia is the result of a maternal immune reaction against paternal antigens expressed in the placenta and that this reaction might result in defective trophoblast invasion and subsequent placental dysfunction. The lower risk of pre-eclampsia amidst multiparous women has been attributed to desensitisation after exposure to paternal antigens in the placenta during previous pregnancies.1 2 The lower gamble has also been attributed to smoother trophoblastic invasion after modification of maternal spiral arteries during the first pregnancy.3
We hypothesised that pre-eclampsia is more than common in first pregnancies because women who experience pre-eclampsia during their first pregnancy, whom might have an increased run a risk for genetic or ecology reasons, might decide non to accept further risks and have no more pregnancies. In addition, subfecundity has been associated with a college chance of pre-eclampsia.4 Thus an underlying disorder might result in both pre-eclampsia in the offset pregnancy and subsequent infertility.
Most previous studies included relatively small cohorts of pregnancies without prospective follow-upward of women from the beginning of their reproductive history.1 5 We used a big population based cohort to investigate the association betwixt parity and the risk of pre-eclampsia, before and after aligning for potential selection bias.
Methods
Written report population
The Swedish Medical Nascence Register is a population based registry that includes more than 98% of all births in Sweden.6 Starting with the first antenatal visit, commonly at 8-12 weeks' gestation, information is prospectively collected on maternal demographic data, reproductive history, pregnancy, and birth characteristics. Such information is recorded on the standardised antenatal, obstetric, and neonatal records, and copies of these records are forwarded to the nascence register, where the information is computerised. The current study included only women who had their first delivery on or subsequently 1 January 1987, with reproductive history followed until the end of 2004. During this period, the register recorded 763 795 primiparous mothers who had a total of i 430 464 deliveries (21 629 (1.5%) were multiple gestations).
Outcome definition and observation
The diagnoses are noted by a doctor at the time of belch from the infirmary, using ICD-9 and ICD-10 (international classification of diseases, 9th and tenth revisions). Pre-eclampsia is divers every bit a diastolic claret pressure of at least 90 mm Hg accompanied past proteinuria (≥0.3 g/24-hour interval or ≥1 on a urine dipstick) (ICD-9 codes 642 Due east-F and ICD-10 code O14). Eclampsia is defined as the occurrence of pre-eclampsia with seizures (ICD-ix code 642 Grand and ICD-10 code O15). We included pre-eclamptic and eclamptic pregnancies in our analysis. The quality of the diagnosis of pre-eclampsia has previously been validated: of 148 pregnancies coded every bit pre-eclampsia in the nativity annals, 137 (93%) had pre-eclampsia co-ordinate to the individual records.7
Early and late onset pre-eclampsia have different heritability, risk factors, clinical manifestations, and prognosis.8 9 10 eleven 12 13 As information on timing of onset was not available through the register, we used preterm delivery every bit a proxy for early onset and severity. Pre-eclampsia was considered "astringent" when delivery occurred before 34 completed gestational weeks.
Statistical analysis
We estimated the overall cumulative incidence of pre-eclampsia during the first pregnancy. Among those with and without a diagnosis, we estimated the proportion of women who had a second pregnancy and the incidence of pre-eclampsia during that pregnancy. Nosotros repeated the procedure upward to the fourth pregnancy. Nosotros calculated the interval between pregnancies with the difference between dates of terminal menstrual periods.
To compare the frequency of a 2nd pregnancy betwixt women with and without pre-eclampsia in their first pregnancy, we estimated the odds ratio and 95% confidence interval for a subsequent pregnancy. Multivariate logistic regression adapted for potential confounding factors—that is, factors associated with the take chances of both pre-eclampsia and subsequent pregnancies, including maternal age, body mass alphabetize, cigarette smoking, diabetes, and multiple gestations.7 11 14 15 To further assess the touch of multiple gestations, nosotros conducted a subanalysis restricting the sample to singleton births. To assess the impact of time trends, we conducted a subanalysis stratified by agenda years of offset pregnancy.
To quantify the contribution of any pick by history of pre-eclampsia to the difference in the incidence of pre-eclampsia between first and subsequent pregnancy, we standardised the analysis past the rates of subsequent pregnancy in women without pre-eclampsia. That is, nosotros simulated a population where the likelihood of a subsequent pregnancy was equal amongst women with and without a history of pre-eclampsia. We then estimated the gamble of pre-eclampsia amid multiparous women in such hypothetical population.
Results
The risk of pre-eclampsia in whatsoever pregnancy was iii.0%; the take chances was four.1% in the beginning pregnancy and ane.7% in afterwards pregnancies. The adventure during a given pregnancy, notwithstanding, was highly dependent on the history of pre-eclampsia (fig 1)⇓. During the 2nd pregnancy, the risk was 14.7% for women who had developed pre-eclampsia in their first pregnancy and 1.1% for those who had non. During the third pregnancy, the chance was 31.9% for women who had developed pre-eclampsia in the previous two pregnancies and remained 1.ane% for those without a history of pre-eclampsia. Similarly, for women with a kickoff occurrence of pre-eclampsia in their second pregnancy, the risk was 15.9% during the third pregnancy; and 29.0% during the fourth when they had adult pre-eclampsia in the previous 2 pregnancies. Likewise, for women with a outset occurrence of pre-eclampsia in their third pregnancy, the adventure was 14.7% during the fourth pregnancy. Among women without pre-eclampsia in their starting time pregnancy, the run a risk of pre-eclampsia was 0.83% if they became pregnant once again within two years and 2.ii% if they became meaning more than eight years afterwards their kickoff pregnancy; the corresponding risks were thirteen.ane% and 15.8% for women with pre-eclampsia in their first pregnancy (fig 2)⇓.
The proportion of women with 2 or more pregnancies was 62.2% and 66.3% amidst women with and without pre-eclampsia in their showtime pregnancy, respectively (fig 1).⇑ The proportion of women with three or more pregnancies ranged from 21.1% to 26.4% depending on history. If women with and without pre-eclampsia in their kickoff pregnancy had the same likelihood of another pregnancy (that is, if there were no selection of low hazard women in subsequent pregnancies), the estimated incidence of pre-eclampsia among multiparous women would have been 1.70%, similar to the observed ane.65%.
Impact of confounders
After having a get-go pregnancy with pre-eclampsia, the adjusted odds ratio for having another pregnancy was 0.91 (95% confidence interval 0.89 to 0.94) compared with women without pre-eclampsia in their showtime pregnancy. This adjusted odds ratio was closer to the aught than the crude odds ratio (0.84, 0.82 to 0.86), suggesting that the observed clan betwixt pre-eclampsia and the likelihood of subsequent pregnancies was partially explained by measured confounders.
Impact of multiple gestations
The results were like when we express our analysis to women with a singleton birth in the beginning pregnancy (data not shown). Among the 12 756 (one.7%) women who had twins (or more) during their first pregnancy, 12.three% developed pre-eclampsia during that pregnancy. During the second pregnancy, the risk was 6.3% for women who had adult pre-eclampsia in their first pregnancy and 1.1% for those who had not. The proportion of women with a second pregnancy was 25.iv% afterward having a outset twin pregnancy with pre-eclampsia and 26.4% later a twin pregnancy without pre-eclampsia.
Touch of temporal trends
The risk of pre-eclampsia during kickoff pregnancy was iii.2% in 1987-9, 4.0% in 1990-four, 4.8% in 1995-ix, and 4.2% in 2000-four. Amid women without pre-eclampsia in the showtime pregnancy, the proportion with a subsequent pregnancy by the end of follow-up was 83.5% in 1987-nine, eighty.5% in 1990-4, 73.eight% in 1995-9, and 31.0% in 2000-4. (Note the increasingly incomplete follow-up of women's reproductive life over report years.) The proportion of subsequent pregnancy amid women with pre-eclampsia in beginning pregnancy was three% to five% lower inside each time flow.
Impact of outcome definition
X percent of primiparous women with pre-eclampsia delivered earlier 34 weeks of gestation. The risk of such severe pre-eclampsia was 0.42% in the first pregnancy and 0.14% in later pregnancies (fig 3)⇓. Amongst women who had developed astringent pre-eclampsia in their kickoff pregnancy, the risk of any pre-eclampsia was 29% in their second pregnancy; and the take chances of severe pre-eclampsia was 62 times college (6.viii%) than in women without pre-eclampsia in their showtime pregnancy (0.xi%). During the 3rd pregnancy, the risk of severe pre-eclampsia was 12.5% for women who had developed this status in the previous ii pregnancies and 0.13% for those without a history of severe pre-eclampsia.
Fig 3 Adventure of astringent pre-eclampsia (divers as pre-eclampsia associated with delivery before 34 weeks) in given pregnancy by pregnancy gild and history of pre-eclampsia, Swedish Medical Birth Annals, 1987-2004
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The proportion of women having a second pregnancy was xi% lower after a first pregnancy with severe pre-eclampsia than in women without this condition in their first pregnancy; the proportion of women with three or more pregnancies ranged from 13.v% to 29.2%, depending on history. Despite this apparent selection of lower take a chance women, the estimated incidence of severe pre-eclampsia among multiparous women would take been just 0.xv% (rather than 0.14%) if women with and without severe pre-eclampsia in their first pregnancy had the same likelihood of another pregnancy. After having a first pregnancy with astringent pre-eclampsia, the adapted odds ratio of a subsequent pregnancy was 0.69 (0.64 to 0.75) compared with women without the status in their starting time pregnancy, which was closer to the nothing than the crude odds ratio (0.63, 0.59 to 0.68).
Discussion
In this large prospective cohort written report, the incidence of pre-eclampsia was 4.1% in primiparous women and ane.7% in parous women in Sweden betwixt 1987 and 2004. The increased risk of pre-eclampsia in primiparous compared with multiparous women was non explained past a biological or self choice of low take chances women throughout gestations. Then, is pre-eclampsia really a disease of primiparous women? It depends on the history. For multiparous women, the risk was significantly unlike for women who had pre-eclampsia in i (around fifteen%) or two (around thirty%) consecutive previous pregnancies than for those with no history (effectually one%). Although a longer interval between starting time and second pregnancies was associated with a higher incidence of pre-eclampsia, the hazard for women without pre-eclampsia during their kickoff pregnancy remained substantially lower even after eight years (2.2%), compared with women with pre-eclampsia in their first pregnancy.
Multiple gestations
Multiple gestations were associated with an increased hazard of pre-eclampsia (12%) and with a lower recurrence of pregnancy. All the same, multiple gestations did not explain the clan betwixt primiparity and pre-eclampsia. Interestingly, the proportion of women with subsequent pregnancies after having twins or triplets was like to that later 2 singleton births. This observation is compatible with families having a target number of children, likewise equally with a higher incidence of multiple gestations in subfertile couples undergoing infertility treatments. It is likewise worth noting that the recurrence of pre-eclampsia when the first afflicted pregnancy was a multiple gestation was half of that found when it was a singleton pregnancy. This finding suggests that a proportion of pre-eclampsias in multiple gestations might exist caused by the fetal multiplicity itself, rather than to underlying constant maternal hazard factors.
Temporal trends
The observed slight rise in the risk of pre-eclampsia over time could be acquired by an actual increase in the risk of pre-eclampsia (for case, because of an increase in multiple gestations) or to changes in diagnosis and coding practices. The proportion of women having two or more pregnancies decreased over the study menses, which could be partially explained by an increasing proportion of couples having a single child during the 1990s. At to the lowest degree part of the credible tendency, notwithstanding, is because of an increasing underestimation of the incidence of subsequent pregnancies induced past the study design. By the cease of 2004, when follow-upwards stopped, a considerable proportion of women had not completed their families, in particular those with a first pregnancy during the 2000s. Nevertheless, such trends in the recurrence of both pre-eclampsia and pregnancy did not explain the results. The clan between pre-eclampsia and a lower incidence of subsequent pregnancies was similarly modest, and the association between parity and pre-eclampsia remained inside each stratum of agenda years.
More than ane condition under the aforementioned term
Early and tardily onset pre-eclampsia differ in their risk factors and prognoses.9 10 eleven 12 13 I study has shown that the earlier pre-eclampsia develops in a given pregnancy, the greater the risk that pre-eclampsia will develop in subsequent pregnancies.8 Findings from the Swedish Medical Birth Register are consistent with this.7 In the current report, a history of early onset pre-eclampsia was a stronger predictor for the recurrence of pre-eclampsia than late onset events, in particular for the recurrence of early onset pre-eclampsia. For pre-eclampsia overall, the risk of recurrence was close to fifteen and 30 times higher subsequently one or two affected pregnancies, respectively. The relative risk of recurrence subsequently one or ii pregnancies with early onset pre-eclampsia was 60 and ninety, respectively. These observations suggest that early on and late onset events might indeed differ etiologically, with early onset pre-eclampsia existence affected by more than chronic risk factors.
Results also suggest that early on onset pre-eclampsia results more often in abstention of future pregnancies, presumably because of the more severe clinical presentation compared with late onset events. The incidence of a second pregnancy was 66% in women without pre-eclampsia in their first pregnancy, 63% when women developed pre-eclampsia without prematurity in the first pregnancy, and 55% if the pre-eclampsia was associated with very preterm delivery. Such pick was still insufficient to explain the association between severe pre-eclampsia and primiparity.
Interpretation of findings
Our findings back up the thought of two distinct entities, ane sporadic and another recurrent. We hypothesise that the sporadic type occurs in around 1% of pregnancies and is associated with transient risk factors (such equally twins), being therefore a poorer predictor of risk in future pregnancies and less predictable based on history. The recurrent blazon represents fifty-75% of the cases in primiparous women, tends to accept an early on onset, is more severe, causes preterm commitment and other fetal and maternal morbidities, has more familial aggregation, and is associated with unvarying risk factors (ecology or genetic) that confer a risk of around 30% in each pregnancy in that item grouping of women. Not every woman with these chronic risk factors, nevertheless, develops recurrent type pre-eclampsia, and non every woman with recurrent blazon pre-eclampsia in their first pregnancy has pre-eclampsia in further gestations. Moreover, with our electric current knowledge (and bachelor data), we cannot distinguish sporadic from recurrent types when we diagnose pre-eclampsia in a primiparous woman. A proportion of cases in primiparous women will be sporadic and would non tend to recur.
Clinical relevance
In add-on to contributing to our agreement of pre-eclampsia, our findings might influence the data women are given about the risk of pre-eclampsia in a subsequent pregnancy by providing risk estimates stratified past history. For example, when advising women who adult pre-eclampsia in their kickoff pregnancy and are contemplating a second pregnancy, we cannot say that their risk is low considering pre-eclampsia is a "disease of nulliparity," particularly if they had an early onset event.
Strengths and weaknesses of the study
Our report is based on a big, prospective, population based accomplice. The accuracy of diagnoses in the Swedish Medical Nascence Register was validated, and the positive predictive values were high.7 We evaluated the issue of well known risk factors as potential confounders and effect modifiers including multiple gestations, maternal age, diabetes, trunk mass index, and fourth dimension trends in incidence or diagnosis of pre-eclampsia.vii xi fourteen 15 Adjusted estimates of the effect of pre-eclampsia on the likelihood of future pregnancies were similar to crude ones, suggesting that misreckoning did not explain results. We were unable to straight assess the effect of timing of onset or clinical severity because data were non available in the register. Rather, we used a proxy for early onset and severity—that is, pre-eclampsia associated with delivery before 34 gestational weeks.
Further enquiry is needed to characterise the different disorders under the classification of gestational hypertension and proteinuria. A right diagnosis might help united states of america to predict the risk in future pregnancies for individual women, as well as to sympathize the etiology and notice ameliorate approaches to forbid and treat each disorder.
Conclusion
Having pre-eclampsia in one pregnancy is a poor predictor for subsequent pregnancy simply a strong predictor for recurrence of pre-eclampsia in futurity gestations. Contrary to what nosotros had hypothesised, the lower overall risk of pre-eclampsia amidst parous women was not explained by fewer conceptions amid women who experienced pre-eclampsia in a previous gestation. Early on onset pre-eclampsia was associated with more than recurrence of pre-eclampsia and fewer subsequent pregnancies than tardily onset events. Findings are consequent with the beingness of 2 distinct weather condition: a astringent early on onset blazon affected by chronic factors, genetic or environmental, and a milder desultory type affected by transient factors.
What is already known on this topic
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The risk of pre-eclampsia is higher in beginning pregnancies (4.one%) than in subsequent ones (ane.vii%)
What this study adds
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The lower overall take chances of pre-eclampsia amidst parous women is non explained by fewer pregnancies among women who experienced pre-eclampsia in a previous gestation
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The take a chance of recurrence is around 15% for women who had pre-eclampsia in one previous pregnancy and effectually 30% when 2 sequent previous pregnancies were affected
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Recurrence is higher for pre-eclampsias associated with very preterm delivery
Notes
Cite this as: BMJ 2009;338:b2255
Footnotes
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We thank Miguel Hernan for his useful comments.
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Contributors: All authors jointly designed the hypothesis, analysed and interpreted the information, and wrote the newspaper. SHD is guarantor.
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Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors had full access to all the information in the study and had the final responsibility for the conclusion to submit for publication.
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Competing interests: None declared.
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Upstanding approval: The report was approved past the research ethic committee at Karolinska Institute, Sweden (No 4863/2005).
This is an open-access article distributed under the terms of the Artistic Commons Attribution Non-commercial License, which permits unrestricted use, distribution, and reproduction in whatever medium, provided the original work is properly cited.
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Source: https://www.bmj.com/content/338/bmj.b2255
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