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Hypertensive Pregnancy Disorders and Subsequent Cardiovascular Morbidity and Type 2 Diabetes Mellitus in the Mother

Originally publishedhttps://doi.org/10.1161/HYPERTENSIONAHA.109.130765Hypertension. 2009;53:944–951

Abstract

Minimal data exist concerning the relationship between hypertensive pregnancy disorders and various subsequent cardiovascular events and the effect of type 2 diabetes mellitus on these. In a registry-based cohort study, we identified women delivering in Denmark from 1978 to 2007 with a first singleton (n=782 287) and 2 first consecutive singleton deliveries (n=536 419). The exposures were gestational hypertension and mild and severe preeclampsia. We adjusted for preterm delivery, small for gestational age, placental abruption, and stillbirth and, in a second model, we also adjusted for the development of type 2 diabetes mellitus. The end points were subsequent hypertension, ischemic heart disease, congestive heart failure, thromboembolic event, stroke, and type 2 diabetes mellitus. The risk of subsequent hypertension was increased 5.31-fold (range: 4.90 to 5.75) after gestational hypertension, 3.61-fold (range: 3.43 to 3.80) after mild preeclampsia, and 6.07-fold (range: 5.45 to 6.77) after severe preeclampsia. The risk of subsequent type 2 diabetes mellitus was increased 3.12-fold (range: 2.63 to 3.70) after gestational hypertension and 3.68-fold (range: 3.04 to 4.46) after severe preeclampsia. Women having 2 pregnancies both complicated by preeclampsia had a 6.00-fold (range: 5.40 to 6.67) increased risk of subsequent hypertension compared with 2.70-fold (range: 2.51 to 2.90) for women having preeclampsia in their first pregnancy only and 4.34-fold (range: 3.98 to 4.74) for women having preeclampsia in their second pregnancy only. The risk of subsequent thromboembolism was 1.03-fold (range: 0.73 to 1.45), 1.53-fold (range: 1.32 to 1.77), and 1.91-fold (range: 1.35 to 2.70) increased after gestational hypertension and mild and severe preeclampsia, respectively. Thus, hypertensive pregnancy disorders are strongly associated with subsequent type 2 diabetes mellitus and hypertension, the latter independent of subsequent type 2 diabetes mellitus. The severity, parity, and recurrence of these hypertensive pregnancy disorders increase the risk of subsequent cardiovascular events.

Hypertensive pregnancy disorders complicate ≈5% to 7% of all pregnancies, the incidence being higher in nulliparous compared with parous women.1 These frequently interrelate with other complications, eg, preterm delivery and fetal growth restriction, as well as placental abruption and stillbirth; a “placenta-associated syndrome” has been proposed composed of these pregnancy complications.2 In this aspect, the severity of the preeclampsia may be reflected in the coexisting of other pregnancy complications.

Despite vigorous investigation in the pathophysiology of these disorders, a clear etiology remains elusive. Contributing factors that have been proposed include immunology3 and nulliparity,1 as well as thrombophilia,4 and endothelial dysfunction,5 including an antiangiogenic state,6 obesity, 7 and factors of the metabolic syndrome.8,9 These latter factors are also intimately related to the development of cardiovascular disease; indeed, several epidemiological studies have linked preeclampsia with later cardiovascular events.10,11

The principal end points in previous follow-up studies of preeclampsia, other than death death,12 have been ischemic heart disease13 and stroke.14 Other specific cardiovascular end points have been less well studied,15,16 and only 1 study has focused on later diabetes mellitus.17 In addition, only 2 studies have investigated the effect of the recurrence of hypertensive pregnancy disorders on the risk of subsequent ischemic heart disease but not other end points.18,19

We have designed a study using the Danish National Registries investigating the association among the following: (1) hypertensive pregnancy disorders in a first pregnancy and later cardiovascular morbidity and type 2 diabetes mellitus; (2) combinations of (mild and severe) preeclampsia, preterm delivery, and small for gestational age (SGA) offspring in a first pregnancy and later cardiovascular morbidity and type 2 diabetes mellitus; (3) the parity and recurrence of preeclampsia (mild and severe) in the second pregnancy and later cardiovascular morbidity and type 2 diabetes mellitus; and (4) the contribution of type 2 diabetes mellitus to the above associations.

Methods

The National Patient Registry (NPR) collects information on all of the discharge diagnoses from hospitals and deliveries in Denmark. Since 1978, the registry has had complete coverage, and since 1994 it has included diagnoses from outpatient clinics as well.20 The discharging physicians code each medical diagnosis (≥1 per visit) by the International Classification of Diseases. We linked information in NPR with the Central Person Registry and Cause of Death Registry retrieving status on emigration and death on March 1, 2008.

We extracted information on all of the singleton deliveries in Denmark from January 1, 1978, to October 1, 2007, which accrued 1 795 806 deliveries of 965 475 women. From this population, we defined 2 cohorts: cohort 1 was defined as women aged 15 to 50 years with a first delivery (n=796 915), excluding those with a preceding cardiovascular diagnosis (n=11 605 [1.5%]) or type 1 and 2 diabetes mellitus (n=2387 [0.3%]) and women who died or emigrated within 3 months of delivery (n=65 and n=571, respectively). Thus, cohort 1 consisted of 782 287 women. Cohort 2, being a subpopulation of cohort 1, was defined as women who had a first delivery after the age of 15 years and a second delivery before the age of 50 years (n=550 809), excluding those with a cardiovascular diagnosis (n=11 969 [2.2%]) or type 1 and 2 diabetes mellitus (n=2179 [0.5%]) preceding the second delivery and women who died or emigrated within 3 months of the second delivery (n=46 and n=196, respectively). Thus, cohort 2 consisted of 536 419 women.

The primary exposure was hypertensive pregnancy disorders; the secondary exposures, used as effect modifiers, were preterm delivery, SGA offspring, placental abruption, and stillbirth after 20 weeks of gestation. The end points were defined as the first diagnosis of hypertension, ischemic heart disease, congestive heart failure, thromboembolism, stroke, and type 2 diabetes mellitus.

The hypertensive pregnancy disorders were stratified into gestational hypertension, mild preeclampsia, and severe preeclampsia (including eclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome); the definitions of these have changed in accordance with the change in American College of Obstetricians and Gynecologists criteria during the 30 study years,21 but the overall frequency in the NPR has remained stable. The accuracy of the hypertensive diagnoses in the NPR has been manually validated several times, accruing specificities >99% for all types but sensitivities at 10% for gestational hypertension and 69% for preeclampsia (mild and severe combined)21; when combined with preterm delivery, the sensitivity of preeclampsia was 75%.22

Preterm delivery was defined as a delivery before 37 weeks of pregnancy. In earlier years, the gestational age has been assessed by the last menstrual period; gradually, in later years, it has been verified and/or corrected by early second-trimester sonography. Fetal growth was measured by the birth weight standardized for sex and gestational age23; SGA was defined as fetal growth 2 SD below the mean. Implausible values of birth weight, gestational age, fetal growth, and the combination of these were reassigned as missing values. Missing values occurred more frequently in the earlier years; these were analyzed as separate groups.

Hypertensive pregnancy disorders, placental abruption, stillbirth, and all of the end points were ascertained by the specific International Classification of Diseases 8 and 10 codes for these diagnoses (please see the online data supplement available at http://hyper.ahajournals.org). When investigating combinations of preeclampsia, preterm delivery, and SGA offspring in cohort 1 and combinations of preeclampsia in 2 pregnancies in cohort 2, we dichotomized hypertensive pregnancy disorders into 2 groups of preeclampsia and no preeclampsia (the latter being the reference group). We did so because of the low sensitivity of gestational hypertension, the relatively large size of the normotensive group, and because we wanted to differentiate preeclampsia from gestational hypertension.

We used Cox proportional-hazard models, including years from index delivery to censoring as a time-dependent variable, and included maternal age at delivery and year of delivery in all of the models. We calculated 2 adjusted models: in model 1, we additionally controlled for preterm delivery, SGA, placental abruption, and stillbirth; in model 2, we further controlled for type 2 diabetes mellitus subsequent to the index pregnancy.

After initial stratification in the Cox models, we included interaction links in a stepwise forward procedure using likelihood ratio statistics with an entry criterion of P<0.05. All of the hazard ratios (HRs) are presented with 95% CIs. SPSS (v 16.0 for Macintosh, SPSS Inc) was used for all of the calculations. The study was approved by the Danish Data Protection Agency.

Results

The baseline characteristics of cohorts 1 and 2 are shown in Table 1. In cohort 1, the median follow-up time from delivery to time of censoring was 14.60 years (range: 0.25 to 30.20 years; interquartile range: 7.61 to 21.8 years) corresponding with 11 600 945 person-years of observation. During this follow-up period, 15 902 (2.0%) emigrated and 8876 (1.1%) died. In cohort 2, the median follow-up time from second delivery to time of censoring was 12.90 years (range: 0.25 to 29.40 years; interquartile range: 6.86 to 18.90 years) corresponding with 6 990 836 person-years of observation. During this follow-up period, 7109 (1.3%) women emigrated and 4888 (0.9%) died.

Table 1. Baseline Characteristics and Outcomes of Cohorts 1 and 2

Characteristics and OutcomesCohort 1Cohort 2
First DeliverySecond Delivery
Unless stated otherwise, the numbers refer to the numbers of women and the percentage of the total population.
Maternal age at delivery, mean (SD), y26.8 (4.6)25.9 (4.0)29.5 (4.2)
Birth weight, mean (SD), g3394 (566)3401 (554)3558 (555)
Gestational age, mean (SD), d279.8 (13.6)280.3 (13.0)280.0 (11.9)
    ≥37 wk, n (%)713 739 (91.2)490 245 (91.4)510 805 (95.2)
    32 to 36 wk, n (%)35 255 (4.5)21 945 (4.1)16 454 (3.1)
    28 to 31 wk, n (%)4698 (0.6)2845 (0.5)2121 (0.4)
    20 to 27 wk, n (%)1706 (0.2)928 (0.2)728 (0.1)
    Missing values, n (%)26 889 (3.4)20 456 (3.8)6311 (1.2)
Size
    SGA, n (%)43 109 (5.5)28 671 (5.3)15 448 (2.9)
    Appropriate for gestational age, n (%)691 267 (88.4)473 213 (88.2)491 694 (91.7)
    Large for gestational age, n (%)11 646 (1.5)7208 (1.3)18 220 (3.4)
    Missing values, n (%)36 265 (4.6)27 327 (5.1)11 057 (2.1)
Hypertensive pregnancy disorders, n (%)41 275 (5.3)26 939 (5.0)13 511 (2.5)
    Gestational hypertension7449 (1.0)4741 (0.9)3352 (0.6)
    Preeclampsia33 826 (4.3)22 198 (4.1)10 159 (1.9)
    Mild preeclampsia26 810 (3.4)18 010 (3.4)8435 (1.6)
    Severe preeclampsia7016 (0.9)4188 (0.8)1724 (0.3)
Placental abruption7684 (1.0)5193 (1.0)4613 (0.9)
Stillbirth4039 (0.5)3161 (0.6)1938 (0.4)
Censoring
    Emigrated15 902 (2.0)7109 (1.3)
    Deceased8876 (1.1)4888 (0.9)
Follow-up time, median (range), y14.63 (0.25 to 30.2)12.88 (0.25 to 29.4)
Person-years, n11 600 9456 990 836
Maternal age at censoring, mean (SD), y41.6 (8.3)42.6 (7.3)
Outcomes, n (%)
    Hypertension18 551 (2.4)12 324 (2.3)
    Ischemic heart disease8516 (1.1)5810 (1.1)
    Congestive heart failure2271 (0.3)1339 (0.2)
    Stroke8987 (1.1)5836 (1.1)
    Thromboembolism3881 (0.5)2304 (0.4)
    Type 2 diabetes mellitus6720 (0.9)4040 (0.8)

Women having severe preeclampsia in a first pregnancy had 7.58-fold (range: 7.05 to 8.14) increased risk of subsequent hypertension compared with women with no hypertensive disorders. After controlling for other pregnancy complications (model 1), this risk increase was attenuated to 6.73-fold (range: 6.04 to 7.49), and when further controlling for later type 2 diabetes mellitus (model 2), it was attenuated to 6.07-fold (range: 5.45 to 6.77). The same effect of adjusting was present in all of the other outcomes, albeit not at as-large attenuations.

Women experiencing mild or severe preeclampsia had a significantly increased risk of developing congestive heart failure by 1.67-fold (range: 1.41 to 1.97) and 1.71-fold (range: 1.22 to 2.40), respectively, after adjustment for other pregnancy complications and type 2 diabetes mellitus (model 2). Women experiencing gestational hypertension did not, however, have this risk increase after adjustment (adjusted HR: 1.37 [range: 0.98 to 1.93]).

There was a risk gradient of subsequent thromboembolism. Women experiencing gestational hypertension had the same risk as normotensive women (adjusted HR: 1.03 [range: 0.73 to 1.45]). Mild preeclampsia increased the risk 1.53-fold (range: 1.32 to 1.77), and severe preeclampsia increased the risk 1.91-fold (range: 1.35 to 2.70).

Hypertensive pregnancy disorders increased the risk of subsequent type 2 diabetes mellitus between 3.41-fold and 4.09-fold (P<0.001) for gestational hypertension and severe preeclampsia, respectively (Table 2). Controlling for other pregnancy complications altered the estimates minimally (model 1).

Table 2. Hypertensive Pregnancy Disorders in the First Pregnancy and the Risk of Subsequent Cardiovascular Events and Type 2 Diabetes Mellitus

Hypertensive Disordern%NumbersCrudeModel 1Model 2
n%RateHRCIPHRCIPHRCIP
HR indicates hazard ratio; NA, not applicable. Rate is number of events per 10 000 years of observation. Maternal age and year of delivery were included in all of the models. In model 1, preterm delivery, SGA offspring, placental abruption, and stillbirth were included. In model 2, later type 2 diabetes mellitus was included, as well as the variables in model 1.
Hypertension
    No hypertensive disorder741 01294.714 7622.013.51 (reference)1 (reference)1 (reference)
    Gestational hypertension74491.087011.782.75.94(5.55 to 6.36)<0.0015.72(5.28 to 6.20)<0.0015.31(4.90 to 5.75)<0.001
    Mild preeclampsia26 8103.421267.952.23.87(3.70 to 4.05)<0.0014.00(3.80 to 4.21)<0.0013.61(3.43 to 3.80)<0.001
    Severe preeclampsia70160.979311.392.47.58(7.05 to 8.14)<0.0016.73(6.04 to 7.49)<0.0016.07(5.45 to 6.77)<0.001
Ischemic heart disease
    No hypertensive disorder741 01294.777271.07.11 (reference)1 (reference)1 (reference)
    Gestational hypertension74491.01381.912.51.67(1.41 to 1.97)<0.0011.64(1.38 to 1.94)<0.0011.48(1.25 to 1.76)<0.001
    Mild preeclampsia26 8103.45302.012.71.76(1.61 to 1.92)<0.0011.73(1.58 to 1.88)<0.0011.57(1.44 to 1.72)<0.001
    Severe preeclampsia70160.91211.713.32.11(1.76 to 2.52)<0.0011.75(1.46 to 2.11)<0.0011.61(1.34 to 1.94)<0.001
Congestive heart failure
    No hypertensive disorder741 01294.720500.31.91 (reference)1 (reference)1 (reference)
    Gestational hypertension74491.0340.53.11.57(1.12 to 2.20)0.0101.54(1.10 to 2.16)0.0131.37(0.98 to 1.93)0.068
    Mild preeclampsia26 8103.41510.63.61.90(1.61 to 2.24)<0.0011.86(1.58 to 2.20)<0.0011.67(1.41 to 1.97)<0.001
    Severe preeclampsia70160.9360.53.92.24(1.61 to 3.12)<0.0011.89(1.35 to 2.65)<0.0011.71(1.22 to 2.40)0.002
Stroke
    No hypertensive disorder741 01294.782401.17.51 (reference)1 (reference)1 (reference)
    Gestational hypertension74491.01472.013.31.68(1.42 to 1.97)<0.0011.58(1.32 to 1.89)<0.0011.51(1.26 to 1.81)<0.001
    Mild preeclampsia26 8103.44711.811.31.44(1.32 to 1.59)<0.0011.50(1.36 to 1.66)<0.0011.43(1.30 to 1.58)<0.001
    Severe preeclampsia70160.91291.814.21.61(1.35 to 1.93)<0.0011.66(1.29 to 2.14)<0.0011.58(1.23 to 2.03)<0.001
Thromboembolism
    No hypertensive disorder741 01294.735700.53.31 (reference)1 (reference)1 (reference)
    Gestational hypertension74491.0360.53.21.01(0.72 to 1.40)0.981.06(0.75 to 1.49)0.741.03(0.73 to 1.45)0.88
    Mild preeclampsia26 8103.42120.85.11.54(1.34 to 1.77)<0.0011.58(1.36 to 1.83)<0.0011.53(1.32 to 1.77)<0.001
    Severe preeclampsia70160.9630.96.92.18(1.70 to 2.80)<0.0011.98(1.40 to 2.81)<0.0011.91(1.35 to 2.70)<0.001
Type 2 diabetes mellitus
    No hypertensive disorder741 01294.756040.85.11 (reference)1 (reference)NA
    Gestational hypertension74491.01972.618.03.41(2.96 to 3.93)<0.0013.12(2.63 to 3.70)<0.001NA
    Mild preeclampsia26 8103.47422.817.93.45(3.20 to 3.73)<0.0013.53(3.23 to 3.85)<0.001NA
    Severe preeclampsia70160.91772.519.64.09(3.52 to 4.76)<0.0013.68(3.04 to 4.46)<0.001NA

Compared with women without preeclampsia or any other complications in the first pregnancy, women experiencing preeclampsia only had a 4.07-fold (range: 3.88 to 4.27) increased risk of developing subsequent hypertension (Table 3). Women experiencing preeclampsia and preterm delivery had a 8.72-fold (range: 7.77 to 9.77) increased risk; however, women experiencing preeclampsia and SGA offspring had a 4.17-fold (range: 3.63 to 4.79) increased risk. Women having all 3 of the complications had a 7.68-fold (range: 6.80 to 8.67) increase in risk.

Table 3. Combinations of Preeclampsia, Preterm Delivery, and SGA Offspring in the First Pregnancy and the Hazard Ratios of Subsequent Cardiovascular Events and Type 2 Diabetes Mellitus

Combinationn%Variable
n%RateHRCIP
HR indicates hazard ratio; PE, preeclampsia (mild or severe); PTD, preterm delivery; Rate is the number of events per 10 000 years of observation. Maternal age, year of delivery, placental abruption, and stillbirth were included in all of the models.
Hypertension
    No complications643 93582.312 2341.913.31 (reference)
    PE25 1843.219587.853.54.07(3.88 to 4.27)<0.001
    PE+PTD26620.330911.6100.68.72(7.77 to 9.77)<0.001
    PE+SGA23740.32058.655.84.17(3.63 to 4.79)<0.001
    PE+PTD+SGA22180.327912.697.67.68(6.80 to 8.67)<0.001
Ischemic heart disease
    No complications643 93582.360860.96.61 (reference)
    PE25 1843.24581.812.21.82(1.65 to 2.00)<0.001
    PE+PTD26620.3491.815.02.51(1.90 to 3.33)<0.001
    PE+SGA23740.3431.811.41.64(1.21 to 2.21)<0.001
    PE+PTD+SGA22180.3452.014.82.26(1.69 to 3.04)<0.001
Stroke
    No complications643 93582.365551.07.11 (reference)
    PE25 1843.24121.611.01.53(1.38 to 1.69)<0.001
    PE+PTD26620.3411.512.61.83(1.35 to 2.49)<0.001
    PE+SGA23740.3602.515.92.18(1.69 to 2.81)<0.001
    PE+PTD+SGA22180.3532.417.42.44(1.86 to 3.20)<0.001
Congestive heart failure
    No complications643 93582.316600.31.81 (reference)
    PE25 1843.21230.53.31.79(1.49 to 2.16)<0.001
    PE+PTD26620.3130.54.02.29(1.33 to 3.96)0.003
    PE+SGA23740.3210.95.52.97(1.93 to 4.57)<0.001
    PE+PTD+SGA22180.3180.85.93.29(2.06 to 5.24)<0.001
Type 2 diabetes mellitus
    No complications643 93582.345310.74.91 (reference)
    PE25 1843.26702.718.03.63(3.34 to 3.93)<0.001
    PE+PTD26620.3953.629.56.59(5.34 to 8.13)<0.001
    PE+SGA23740.3472.012.52.58(1.93 to 3.44)<0.001
    PE+PTD+SGA22180.3431.914.23.25(2.40 to 4.40)<0.001
Thromboembolism
    No complications643 93582.328180.43.11 (reference)
    PE25 1843.21870.75.01.61(1.39 to 1.87)<0.001
    PE+PTD26620.3160.64.91.62(0.99 to 2.65)0.054
    PE+SGA23740.3321.38.52.74(1.93 to 3.88)<0.001
    PE+PTD+SGA22180.3241.17.92.57(1.72 to 3.84)<0.001

A similar significant effect was noted with respect to the subsequent development of both ischemic heart disease and type 2 diabetes mellitus. In contrast, delivering an SGA offspring in a preeclamptic pregnancy significantly added to the risk of subsequent thromboembolism. The risk of developing congestive heart failure and stroke was also increased when adding SGA and preterm delivery to a pregnancy complicated by preeclampsia; however, these increases were nonsignificant compared with women having preeclampsia only.

Compared with women with 2 nonpreeclamptic pregnancies (cohort 2), women having preeclampsia in the first pregnancy only had an adjusted 2.70-fold (range: 2.51 to 2.90) higher risk of subsequent hypertension (Table 4, model 2); women with preeclampsia in the second pregnancy only were at even higher risk by a 4.34-fold (range: 3.98 to 4.74) increase. Women with preeclampsia in both pregnancies were in the highest risk, with a 6.00-fold (range: 5.40 to 6.67) increase. This risk gradient was also present in all of the other outcomes, except in subsequent stroke.

Table 4. Women in Cohort 2 Experiencing Combinations of Preeclampsia in Either Pregnancies and Risk of Subsequent Cardiovascular Events and Type 2 Diabetes Mellitus

Combinationn%NumbersCrudeModel 1Model 2
n%RateHRCIPHRCIPHRCIP
HR indicates hazard ratio; NA, not applicable; PE, preeclampsia (mild or severe). Maternal age and year of delivery were included in all of the models. In model 1, preterm delivery, SGA offspring, placental abruption, and stillbirth were included. In model 2, later type 2 diabetes mellitus was included.
Hypertension
    No PE in either pregnancy507 58194.610 1302.015.41 (reference)1 (reference)NA
    PE in first pregnancy18 6793.510125.441.92.79(2.61 to 2.97)<0.0012.90(2.70 to 3.12)<0.0012.70(2.51 to 2.90)<0.001
    PE in second pregnancy66401.268910.478.84.86(4.49 to 5.25)<0.0014.80(4.40 to 5.24)<0.0014.34(3.98 to 4.74)<0.001
    PE in both pregnancies35190.749314.0109.87.36(6.72 to 8.06)<0.0017.31(6.58 to 8.12)<0.0016.00(5.40 to 6.67)<0.001
Ischemic heart disease
    No PE in either pregnancy507 58194.652631.08.01 (reference)1 (reference)1 (reference)
    PE in first pregnancy18 6793.52621.410.71.35(1.19 to 1.53)<0.0011.38(1.20 to 1.59)<0.0011.30(1.13 to 1.49)<0.001
    PE in second pregnancy66401.21652.518.22.10(1.80 to 2.45)<0.0012.20(1.86 to 2.61)<0.0012.01(1.70 to 2.38)<0.001
    PE in both pregnancies35190.71203.425.43.17(2.64 to 3.80)<0.0013.32(2.70 to 4.08)<0.0012.79(2.27 to 3.43)<0.001
Congestive heart failure
    No PE in either pregnancy507 58194.612100.21.81 (reference)1 (reference)1 (reference)
    PE in first pregnancy18 6793.5640.32.61.42(1.11 to 1.83)0.0061.39(1.08 to 1.78)0.0111.29(1.00 to 1.66)0.048
    PE in second pregnancy66401.2370.64.12.11(1.52 to 2.92)<0.0011.90(1.37 to 2.65)<0.0011.71(1.23 to 2.38)0.002
    PE in both pregnancies35190.7280.85.93.18(2.18 to 4.62)<0.0012.86(1.96 to 4.17)<0.0012.39(1.63 to 3.50)<0.001
Stroke
    No PE in either pregnancy507 58194.653561.18.11 (reference)1 (reference)1 (reference)
    PE in first pregnancy18 6793.52641.410.71.32(1.17 to 1.50)<0.0011.28(1.13 to 1.45)<0.0011.24(1.10 to 1.40)0.001
    PE in second pregnancy66401.21462.216.11.86(1.58 to 2.19)<0.0011.72(1.46 to 2.03)<0.0011.65(1.40 to 1.95)<0.001
    PE in both pregnancies35190.7702.014.81.80(1.42 to 2.27)<0.0011.60(1.26 to 2.03)<0.0011.48(1.16 to 1.87)0.001
Thromboembolism
    No PE in either pregnancy507 58194.621080.43.21 (reference)1 (reference)1 (reference)
    PE in first pregnancy18 6793.51100.64.51.38(1.14 to 1.67)0.0011.32(1.09 to 1.60)0.0041.29(1.07 to 1.57)0.009
    PE in second pregnancy66401.2520.85.71.70(1.29 to 2.24)<0.0011.56(1.18 to 2.06)0.0021.50(1.14 to 1.98)0.004
    PE in both pregnancies35190.7341.07.22.20(1.57 to 3.09)<0.0011.93(1.37 to 2.71)<0.0011.80(1.28 to 2.54)0.001
Type 2 diabetes mellitus
    No PE in either pregnancy507 58194.633370.75.11 (reference)1 (reference)1 (reference)
    PE in first pregnancy18 6793.53752.015.33.09(2.77 to 3.44)<0.0013.10(2.75 to 3.50)<0.001NA
    PE in second pregnancy66401.21812.720.03.86(3.31 to 4.50)<0.0013.55(2.96 to 4.26)<0.001NA
    PE in both pregnancies35190.71474.231.36.43(5.44 to 7.60)<0.0015.69(4.66 to 6.93)<0.001NA

Discussion

We found a robust association between hypertensive pregnancy disorders and subsequent type 2 diabetes mellitus and a risk gradient in hypertensive pregnancy disorders with subsequent cardiovascular events independent of overt type 2 diabetes mellitus.

The former association with type 2 diabetes is in accordance with the study by Callaway et al,17 who found a 2-fold increase in self-reported diabetes mellitus 21 years after a hypertensive pregnancy disorder; controlling for important factors, eg, family income, smoking, and body mass index attenuated the estimate of the association by 18%. Smaller studies have also found increased frequencies of subclinical features of a metabolic syndrome later in life associated with preeclampsia.24–26

A recent systematic review demonstrated a 2.2-fold higher risk of ischemic heart disease after preeclampsia.10 Hannaford et al15 reported a 1.6-fold higher risk of venous thromboembolism after preeclampsia; Kestenbaum et al16 found a 3.0-fold greater risk of subsequent cardiovascular events after any type of hypertensive pregnancy disorders and 2.3-fold higher risk of venous thromboembolism after a pregnancy complicated by severe preeclampsia. van Walraven et al27 found the risk of subsequent venous thromboembolism to be 2.2-fold higher after a pregnancy complicated by preeclampsia. However, a significant limitation of these studies is the lack of control for other pregnancy complications.

The metabolic syndrome has previously been associated with thromboembolism,28,29 a finding also present in our data, ie, type 2 diabetes mellitus (data not shown). Importantly, controlling for type 2 diabetes mellitus in the risk of subsequent thromboembolism did not substantially alter the estimates. Previous studies have shown that thromboembolism preceding a pregnancy is associated with a higher risk of preeclampsia,30 and preeclampsia, likewise, is a strong risk factor for postpartum thromboembolism.31,32 Our study adds epidemiological evidence of the association between preeclampsia and a thrombophilic tendency; whether this is because of underlying genetic thrombophilia33 or other mechanisms34,35 cannot be ascertained from this study.

Women having preeclampsia and delivering preterm had a higher risk of subsequent hypertension, ischemic heart disease, congestive heart failure, and type 2 diabetes mellitus compared with women having preeclampsia and delivering at term. These findings indicate that early onset preeclampsia is different from late-onset preeclampsia and may represent a distinct and more severe clinical disease entity.36

Women delivering an SGA offspring had an additionally increased risk of stroke and thromboembolism compared with women experiencing preeclampsia only; however, SGA did not add further to the risk of subsequent hypertension, ischemic heart disease, or type 2 diabetes mellitus. Thus, a unifying “placenta-associated syndrome” involving preeclampsia and fetal growth restriction only partially explains the shared etiology; disparate factors are likely involved in the pathophysiology of these disorders.

Wikstrom et al19 investigated ischemic heart disease after hypertensive disorders in 2 pregnancies in Swedes and found a nonsignificant risk gradient comparable to our findings. Funai et al18 investigated cardiovascular related mortality in a small, well-described population in Jerusalem, Israel, and found a nonsignificant risk gradient rising with an increasing number of preeclamptic pregnancies. These results imply that the underlying factors leading to subsequent cardiovascular disease in nulliparous and parous women are not identical.37

The strengths and limitations of the study are based in the registry used. We were able to investigate rare exposures and outcomes in a homogeneous, nonselected, relatively young, low-risk population. However, the hypertensive diagnoses in the NPR are encumbered with low sensitivities but high specificities.21 The low sensitivity for gestational hypertension at 10% and a prevalence of only 1% in the NPR make this diagnosis less reliable. We speculate that this underreporting is likely to be associated with a more severe type and an underlying and more imminent essential hypertension. The diagnoses of mild and severe preeclampsia were, however, acceptable for use of etiologic studies in that the specificities were >99% with sensitivities >43% separately and 69% combined.21

The accuracy of the end points is a limitation: ischemic heart disease, stroke, and other serious cardiovascular events usually require hospitalization and are, thus, obligated to be registered in the NPR38; in contrast, hypertension and type 2 diabetes mellitus are usually diagnosed primarily by the general practitioner and are, thus, not included in the NPR. Thus, we suspect that these latter diagnoses are largely underreported and represent severe cases that required hospitalization.39 In addition, we may also have missed nonreported dyslipidemia and other factors of a metabolic syndrome.9 This is a limitation in controlling for subsequent type 2 diabetes mellitus as a surrogate for the metabolic syndrome. Thus, we acknowledge that considerable residual confounding may remain.

We were not able to control for body mass index, smoking, or socioeconomic status, a frequent limitation also seen in other registry-based studies11,12; other studies controlling for these confounders have resulted only in small changes in estimates.17,40 Thus, the associations found in our data should be interpreted with caution.

Perspectives

Physicians and other health care professionals should be encouraged to include the history of a woman’s pregnancy outcomes when estimating the risk of cardiovascular disease. Because hypertensive pregnancy disorders are strongly linked with subsequent cardiovascular morbidity, especially hypertension and type 2 diabetes mellitus, both being essential components of the metabolic syndrome, a possible direct link may exist between these disorders.41 Also, the severity of the hypertensive disorders seems to predispose to thromboembolic events; this also merits caution when prescribing oral contraceptives for these women.42 Identifying these women early will allow for prompt intervention, either primarily as modification of other classical cardiovascular risk factors or secondarily as medical prophylaxis.

Disclosures

B.M.S. has been an expert witness to review medical records related to preeclampsia and has served on the advisory boards of Ortho Clinical Diagnostics and Beckman Coulter. The remaining authors report no conflicts.

Footnotes

Correspondence to Jacob A. Lykke, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar St, LLCI 8, New Haven, CT 06510. E-mail

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