Sources

We performed a literature search in the electronic libraries PubMed (Medline) and Embase. Language restrictions or restrictions on publication date were not applied. The search covered all records until August 2012. The following terms were used: ‘‘preeclampsia’’ [MeSH] AND [early OR severe OR pre-term OR early onset OR 32 OR 34 OR 37] AND [history OR previous OR secondary OR subsequent OR recurrence]. Cross-references of the selected studies were checked to identify other studies of interest. All studies that described cohorts of women with a history of a hypertensive disorder that resulted in a delivery at any gestational age were eligible for inclusion. Inclusion was not restricted to any study design, apart from for case-control studies, where recurrence was a prerequisite. Studies that did not report recurrence of preeclampsia in the publication, but was thought to have this information in the original data, were also considered eligible. If data between studies overlapped, only the larger of the 2 studies was included. Two independent reviewers (M.F.vO. and J.L.) screened the identified articles for eligibility based on title and abstract. Discrepancies were resolved by a third reviewer (W.G.).

Data collection

For each of the eligible articles, contact information of the first, second, or last author was obtained through Medline, Embase, or the Internet. We approached the authors by email to inform them about the IPD metaanalysis project and to invite them to share their data. If authors were willing to participate, they were provided a more detailed study proposal and asked to send their original database. Variables and categories needed to be labeled adequately within the original database or in a separate data dictionary. Data of women who had a subsequent pregnancy after the hypertensive pregnancy were included. We focused on collecting demographic characteristics that included age, body mass index (BMI), cardiovascular risk factors, and the clinical syndrome of the index pregnancy. The quality of all studies that were included was evaluated with the Newcastle Ottawa Scale for cohort studies.

Definitions

HDP were defined as GH, preeclampsia, superimposed preeclampsia, or HELLP syndrome. Nonhypertensive pregnancies with an SGA child were excluded. Chronic hypertension was not an exclusion criterion for the IPD but was in some individual studies.

Preeclampsia was defined as hypertension (diastolic blood pressure ≥90 mm Hg or systolic blood pressure ≥140 mm Hg on 2 occasions that were 4-5 hours apart) in combination with proteinuria (defined as a positive [0.3 g/L] proteinuria dipstick test, a protein/creatinine ratio of ≥30 mg/mmol in a random sample or an urine protein excretion of ≥300 mg for 24 hrs) after 20 weeks’ gestation. Mild or severe preeclampsia was not separately defined, because only some of the studies made this distinction in their data. Women with hypertension at >20 weeks’ gestation without proteinuria or a significant rise in blood pressure (if a woman had known chronic hypertension) were considered to have GH. Chronic hypertension was defined as the presence or a history of preconceptional hypertension or detection of hypertension in the first one-half of the pregnancy. De novo proteinuria or a sudden increase in proteinuria if already present, qualified women with chronic hypertension for superimposed preeclampsia. HELLP syndrome was defined by hemolysis (elevated lactate dehydrogenase levels [≥600 U/L], elevated liver enzymes by levels of aspartate transaminase or alanine transferase ≥70 U/L, and low platelets <100,000/mm). HELLP syndrome in combination with hypertension was also classified as preeclampsia. SGA was defined as birthweight <10th percentile, according to the American College of Obstetricians and Gynecologists practice bulletin, and adjusted for gestational age based on a local reference population. The exact definitions for the hypertensive syndromes that were used in the included studies were not retrievable for a few studies that were published as abstracts. Nevertheless, we presume that the authors concur about the international accepted criteria, which were described earlier.

The primary outcome was the recurrence of any HDP in the next subsequent pregnancy. Secondarily, we aimed to show the recurrence of individual hypertensive syndromes.

Statistical analysis

Most studies focused on detailed data of the subsequent pregnancy, whereas some studies registered only details of the index pregnancy. To use the data as best as possible, we combined data of the index and subsequent pregnancy for BMI, smoking, medical history, and chronic hypertension. If, for example, BMI was recorded at the time of the second pregnancy, but not at the index pregnancy, then we copied the second pregnancy BMI information.

Not all the dependent or independent variables have been registered in every database. Results therefore are accompanied with the number of cases in which the variable was registered (n). Proportions are presented as percentages of n, rather than as percentages of the total population. For descriptive analysis, we expressed continuous variables as mean with standard deviation or median with interquartile range, as appropriate. We decided not to use imputation because the pattern of systematic missing values cannot be extrapolated between databases.

Differences in outcomes between the index and subsequent pregnancy were investigated with the use of a random intercept/random effects binomial regression model for dichotomous outcomes and of a random intercept random/effects linear regression model for continuous outcomes. A random intercept was fitted per study to account for the fact that the baseline risk between studies may differ. Based on Akaike’s information criterion, the random effects model was compared with a fixed effects model, and the model with the lowest Akaike’s information criterion was used as the final model for analysis for that outcome. Heterogeneity across studies was assessed with the I ² measure, and the values were interpreted in the following manner: 0% indicates no observed heterogeneity; 25%, 50%, and 75% indicate low, moderate, and high heterogeneity, respectively. Probability values < .05 were considered to indicate statistical significance.

We have performed 3 post hoc sensitivity analyses: in one of them, we performed separate analysis for studies with < or >200 inclusions; in one of them, we excluded retrospective studies; and in 1 of them, we excluded studies with high or unclear risk of bias.

Statistical analysis was performed with SPSS software (version 20.0; SPSS Inc, Chicago, IL) and R software (version 3.0.1; The R Foundation for Statistical Computing).

Study selection

Our search of PubMed and Embase for eligible articles until August 2012 yielded 2819 nonduplicate hits. After screening title and abstract, a total of 94 articles were included. Of these articles, 6 were excluded because of overlapping databases; 39 were excluded because of failure to make contact; 14 were excluded because of unavailable data; 2 were excluded because of judgment of data as not useful by the authors; and 11 authors decided not to share their data. Reasons for declining to share data included no interest in participation, still in the publication process, and a statement of “no permission to send data outside the national borders.” Eventually, the IPD of 22 articles were included in this IPD metaanalysis ( Figure 1 ). The combined database comprised a total of 99,415 women.

Inclusion of articles

van Oostwaard. Individual participant data metaanalysis on the recurrence of HDP. Am J Obstet Gynecol 2015 .

An overview of the study characteristics of the included studies can be seen in Table 1 . Most of the women were included from 3 registry-based studies that lack demographic and clinical detail. Two authors of included registry-based studies were unable to provide the original data but offered to perform a new data-extraction. They used the criteria from the initial study to create an extended and more recent database. Eight prospective trials were included that investigated the effects of aspirin, low-molecular-weight (LMW) heparin, vitamins, and close surveillance on the recurrence of hypertensive disease and maternal and fetal outcome. Quality characteristics of all included studies that used the Newcastle Ottawa Scale are shown in Figure 2 .

Risk of bias graph

Quality characteristics of all included studies that were evaluated with the Newcastle Ottawa Scale for cohort studies. The item “selection of the nonexposed cohort” was not relevant in this individual participant data analysis and therefore was indicated as “low risk” in all studies.

van Oostwaard. Individual participant data metaanalysis on the recurrence of HDP. Am J Obstet Gynecol 2015 .

To test for selection bias in the process of inclusion of IPD, a metaanalysis of recurrence rates in literature was performed. We used the originally included 88 articles (leaving out the overlapping datasets). Where available we used IPD (22 articles). Another 24 articles had to be excluded because applicable recurrence rates were not published. Of these articles, only IPD that did not reach publication would have been useful, for example in specific subgroups. Regarding gestational hypertensive disorders, 64 articles that encompassed a total of 152,213 women with an HDP reported on 27,558 recurrences, which resulted in a recurrence rate of 18.1% (95% CI, 17.9–18.3). The range of recurrence rates in the cohorts was 6-83%. Recurrence rates of individual syndromes of HDP were not reported very consistently over studies. References of the 64 articles in this metaanalysis are available in the Appendix ( Supplementary Table ).

The baseline characteristics of the 99,415 women who were included in the IPD are shown in Table 2 . The occurrence of major maternal complications (such as pulmonary edema or maternal death) was recorded too sporadically to be reported.

An HDP (any type) recurred in 20,545 of 99,415 women (20.7%; 95% CI, 20.4–20.9). The odds ratio (OR) between this recurrence risk and the recurrence risk that was calculated with the 64 included articles was 1.18 (95% CI, 1.15–1.20; P < .001). Recurrence manifested as preeclampsia in 13,725 women (n = 99,208; 13.8%; 95% CI, 13.6–14.1) and GH in 6797 women (n = 79,169; 8.6%; 95% CI, 8.4–8.8). HELLP complicated the HDP in 79 women (n = 39,301; 0.2%; 95% CI, 0.16–0.25). The delivery of an SGA child accompanied a hypertensive disorder in 1156 women (n = 34.359; 3.4%; 95% CI, 3.2–3.6). If we include nonhypertensive SGA as recurrence, SGA occurred in 4183 subsequent pregnancies (n = 34.359; 12%; 95% CI, 11.8–12.5). The different numbers of women in which the specific hypertensive syndrome was recorded (N) cause these percentages not to add up to the 20.7% overall recurrence. Premature delivery that accompanied the recurrent hypertensive disorder occurred at <37 weeks’ gestation in 3316 women (n = 99,415; 3.3%; 95% CI, 3.2–3.5), at <34 weeks’ gestation in 1224 women (n = 99,415; 1.2%; 95% CI, 1.2–1.3), and at <28 weeks’ gestation in 179 women (n = 99,415; 0.18%; 95% CI, 0.16–0.22). Figure 3 gives a more detailed overview of recurrence of the separate syndromes of hypertensive disorders and the effects of prematurity on recurrence according to hypertensive syndrome and gestational age at onset at the index pregnancy.

Recurrence rates

Recurrence rates of the individual hypertensive syndromes of the 99,415 patients, according to the hypertensive syndrome at the index pregnancy: A, index pregnancy; B, GA at onset (or diagnosis).

PE , preeclampsia; GA , gestational age; GH , gestational hypertension; HELLP , hemolysis, elevated liver enzymes and low platelets syndrome; SGA , small for gestational age.

van Oostwaard. Individual participant data metaanalysis on the recurrence of HDP. Am J Obstet Gynecol 2015 .

Sensitivity analyses showed comparable recurrence rates when studies with unclear or high risk of bias were excluded from analysis and showed the same range of recurrence rates when discriminating studies by size and study design (data not shown).

Subgroup analysis

We compared recurrence among multiple and singleton pregnancies. Of the index pregnancies, 516 were multiple and 98.553 were singleton pregnancies. Recurrence occurred in 56 (10.9%) and 20.408 (20.7%), respectively (OR, 0.53; 95% CI, 0.40–0.70; P < .001). Furthermore, we performed a subgroup analysis based on the presence of thrombophilia and the association between LMW-heparin use and recurrence. The combined database included 206 women with and 296 women without thrombophilia. A statistically significant interaction was present between thrombophilia and LMW-heparin use ( P = .005). Stratified analysis in those women with thrombophilia showed that 26 of 56 women (46%) who used prophylactic LMW-heparin experienced recurrence of a HDP, compared with 56 of 141 women (39.7%) who did not use LMW-heparin (OR, 0.95; 95% CI, 0.46–2.0; P = .89). In those women without thrombophilia, 8 of 52 (15.4%) who used prophylactic LMW-heparin experienced recurrence, compared with 104 of 244 (42.6%) who did not use LMW-heparin (OR, 0.44; 95% CI, 0.13–1.5; P = .20).

The clinical syndrome in the index and subsequent pregnancy

To assess differences between the clinical hypertensive syndrome in the index and subsequent pregnancy in women with recurrence, we compared the variables as shown in Table 3 . Heterogeneity was high for intravenous anticonvulsive medication, cesarean delivery, and premature delivery at <34 and <37 weeks’ gestation; was moderate for oral antihypertensive medication and premature delivery at <28 weeks’ gestation; was low for maximum diastolic blood pressure, SGA < p10, and was absent for the other outcomes. The maximum diastolic blood pressure was, on average, lower in the subsequent pregnancy; proteinuria >300 mg/24 hours occurred less often, and oral antihypertensive or intravenous anticonvulsive medication was necessary less frequently. The subsequent pregnancy was complicated less often by a cesarean delivery, delivery of an SGA child, premature delivery, and perinatal death.

Table 3

Differences in the clinical hypertensive syndrome between the index and subsequent pregnancy in recurrent disease

Variable	n a	Index pregnancy	Subsequent pregnancy	P value	I 2 , %	References
Maximum systolic blood pressure, mm Hg b	194	165 (19)	153 (17)	.055	0
Maximum diastolic blood pressure, mm Hg b	331 c	107 c (11)	100 c (8.9)	< .001 c	25
Proteinuria >300 mg/24 h	119 c	82 c (69%)	58 c (49%)	.011 c	0
Thrombocytopenia <100 × 10 9 /L	162	37 (23%)	18 (11%)	.24	0
Use of medication
Oral antihypertensive	504 c	295 c (59%)	237 c (47%)	.002 c	71
Intravenous antihypertensive	263	67 (26%)	27 (10%)	.12	0
Intravenous anticonvulsive	508 c	82 c (16%)	31 c (6%)	< .001 c	72
Hospital days d	154	5 (2–11)	3 (1–5)	.17	0
Cesarean delivery	18,488 c	6195 c (34%)	6423 (35%)	< .001 c	99
Small for gestational age < p10	6542 c	996 c (15%)	841 c (13%)	< .001 c	45
Perinatal deaths	20,111 c	466 c (2.3%)	256 c (1.3%)	< .001 c	0
Premature delivery
<28 wk	18,638 c	267 (1.4%) c	155 (0.8%) c	< .001 c	54
<34 wk	18,735 c	1868 (10%) c	1106 (5.9%) c	< .001 c	76
<37 wk	18,925 c	4312 (23%) c	3125 (17%) c	< .001 c	93

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