- Email: [email protected]
Preeclampsia-eclampsia and future cardiovascular risk among women in Taiwan
Taiwanese Journal of Obstetrics & Gynecology 57 (2018) 364e369
Contents lists available at ScienceDirect
Taiwanese Journal of Obstetrics & Gynecology journal homepage: www.tjog-online.com
Original Article
Preeclampsia-eclampsia and future cardiovascular risk among women in Taiwan Yu-Ling Kuo a, Te-Fu Chan a, b, Chien-Yi Wu c, Chin-Ru Ker a, Hung-Pin Tu d, * a
Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan Department of Obstetrics and Gynecology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan c Department of Family Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan d Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan b
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 25 April 2018
Objective: This study aims to examine the long-term cardiovascular and cerebrovascular risks in a large cohort of women with past history of preeclampsia and/or eclampsia. Materials and methods: This is a retrospective longitudinal study using National Health Insurance Research Database from 1996 to 2010. We identified 1295 women with preeclampsia and eclampsia. The control group was 5180 pregnant women without preeclampsia/eclampsia, who were matched for age and date of delivery. The incidences of diabetes, dyslipidemia, hypertension and cardiovascular events after pregnancy were identified from medical records after the date of delivery to the date of an event or the end of the study. Results: The median follow-up duration was 9.8 years (interquartile 5.1e12.7 years). The incidences of diabetes, dyslipidemia, hypertension, congestive heart failure and cerebrovascular disease events were significantly greater in women with eclampsia or preeclampsia than those in controls. Eclampsia or preeclampsia increased the risk of diabetes, dyslipidemia, hypertension, congestive heart failure and cerebrovascular disease events (hazard ratio [HR] 3.84 and 5.42, P < 0.0001; HR 2.75 and 3.40, P < 0.0001; HR 6.52 and 7.31, P < 0.0001; HR 9.07, P ¼ 0.0060 and 7.39, P < 0.0001; HR 10.71, P < 0.0001 and 3.47, P ¼ 0.0048, respectively). The survival curves for the development of congestive heart failure and cerebrovascular disease in women with eclampsia/preeclampsia and in control differed significantly (Log-rank test P < 0.0001). From the curve, we can find dramatic increases of congestive heart failure and cerebrovascular disease incidences at roughly 3 years and 10 years since the diagnosis of eclampsia/ preeclampsia. Conclusions: Our study revealed that women with a history of preeclampsia/eclampsia were at increased risks for subsequent diagnoses of diabetes, dyslipidemia, hypertension, congestive heart failure and cerebrovascular disease. Preventive counseling, more vigilant screening and management for the modifiable risks should be provided to the affected women. Clinicians should closely monitor these patients in the first three years postpartum and continuously for up to at least a decade. © 2018 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Cardiovascular disease Cerebrovascular disorders Eclampsia Preeclampsia
Introduction Preeclampsia has an incidence rate of 2e8% in all pregnancy, posing as one of the leading causes of maternal and neonatal morbidity and mortality [1]. More and more evidence suggests that the harmful effects of preeclampsia/eclampsia might not be limited
* Corresponding author. Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, No.100, Shih-Chuan 1st Road, Kaohsiung, 807, Taiwan. E-mail address: [email protected] (H.-P. Tu).
to the gestation period only, but remained as an important risk for long-term cardiovascular sequelae in impacted women [2e6]. The meta-analysis done by Bellamy et al. found that women with preeclampsia history have four-fold increased risk of hypertension, two-fold risk of ischemic heart disease, stroke and venous thromboembolism later in their lives [7]. Similarly, McDonald et al. revealed a doubled risk of cardiac, cerebrovascular, peripheral arterial disease and cardiovascular mortality in women who had previous preeclampsia in their work, also a meta-analysis [8]. Dozens of other studies, mostly case controlled cohort series, reported agreeable results with associated risk ratio ranged from two
https://doi.org/10.1016/j.tjog.2018.04.035 1028-4559/© 2018 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
Y.-L. Kuo et al. / Taiwanese Journal of Obstetrics & Gynecology 57 (2018) 364e369
to four folds [9e16]. However, these reports were inconsistent in study designs, patient population, sample size and length of follow up, making it difficult to generalize the conclusion to all affected women or to delineate the long-term natural course of the etiology. In the current study, we extended the observation period to approximately 10 years, using data from birth registry linked to National Health Insurance claims to examine the long-term cardiovascular and cerebrovascular risks in a large cohort of women with past history of preeclampsia and/or eclampsia. Materials and methods Study population In Taiwan, the National Health Insurance is a single-payer program that has covered more than 98% of the population since 1995. National Health Insurance Research Database (NHIRD, www.nhri. org.tw/nhird) contains information regarding patients’ demographic descriptions, diagnoses, prescriptions, inpatient and outpatient claims. It is one of the largest nationwide and population-based data banks in the world. A double-scrambling protocol that encrypts original patient identification numbers is used to protect confidentiality while maintaining consistency. In this study, one million pregnant women were randomly selected from NHIRD and their medical records reviewed from January 1, 1996 to December 31, 2010. Study design A cohort of one million pregnant women with or without preeclampsia/eclampsia was sampled from NHIRD for analysis of their long-term cardiovascular or cerebrovascular risks. All diagnoses were made and coded according to the ninth edition of International Classification of Diseases, Clinically Modification (ICD-9-CM) system. We identified 1295 women with preeclampsia using ICD-9-CM codes 642.4e642.5 and eclampsia 642.6e642.7. We excluded those with previous history of myocardial infarction (ICD-9-CM codes 410.x-412.x), congestive heart failure (ICD-9-CM codes 398.91, 402.01, 402.11.402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93, 425.4e425.9, 428.x), peripheral vascular diseases (ICD-9-CM codes 093.0, 437.3, 440.x, 441.x, 443.1e443.9, 47.1, 557.1, 557.9, V43.4), cerebrovascular diseases (ICD-9-CM codes 362.34, 430.x-438.x), diabetes mellitus (ICD-9-CM code 250), dyslipidemia (ICD-9-CM code 272) and hypertension (ICD-9 code 401e405). Patients with medical data entry, as inpatient or outpatient, at least 12 months prior to delivery were included. The control group of 5180 pregnant women without preeclampsia/eclampsia diagnoses was matched for age and date of delivery. The follow up period was defined starting from the date of delivery to the date of an event or to the end of the study. Three or more inpatient and/or outpatient insurance claims submitted for diabetes mellitus, dyslipidemia, hypertension, congestive heart failure, and cerebrovascular diseases were considered confirmed diagnoses and thus used for analysis. Ethical concerns of this study protocol were approved by the institutional review board of Kaohsiung Medical University Hospital. Statistical analysis Parametric continuous data were compared across groups using t-test and categorical data were compared across groups using chisquire test or Fisher's exact test as appropriate. Survival time was calculated from the date of delivery with preeclampsia/eclampsia occurrence to the onset date of hypertension, congestive heart
365
failure, cerebrovascular diseases or the end of the study (December 31, 2010). The KaplaneMeier method was used to plot the survival curves for each group, and the log-rank test was used to test the homogeneity between survival curves. The hazard ratios (HRs) and 95% confidence interval were calculated for diabetes, dyslipidemia, hypertension, congestive heart failure and cerebrovascular disease events using Cox proportional hazards model. Study subjects were further classified into E/H-, Eþ/H-, E/Hþ, Eþ/Hþ (E: eclampsia/ preeclampsia, H: hypertension) groups to examine which factor might play a greater role in the disease pathophysiology. Relative risks (RR) were estimated by Cox proportional hazards model. Adjusted RRs were calculated after standardizing age, diabetes mellitus and dyslipidemia using Cox proportional hazards regression model. All statistical analyses were performed using SAS statistical software, version 9.4 (SAS Institute, Carry, NC), and the significant level was set at p < 0.05. Results The median follow up period last 9.8 years (interquartile 5.1e12.7 years). A total number of 1295 women with preeclampsia or eclampsia history was properly matched by age to 5180 controls (p ¼ 0.4541; Table 1). The majority them aged between 26 and 35 years old (63.3%), averaged at 29.7 years old. Eighty-six percent of the women were having their first pregnancies. Patients with preeclampsia or eclampsia had significantly higher rates of receiving surgical delivery, acquiring diabetes mellitus, dyslipidemia, hypertension, congestive heart failure, and cerebrovascular diseases than those in the control group (75.1% v.s. 37.3%, 8.4% v.s. 2.1%, 12.1% v.s 3.9%, 28.3% v.s. 4%, 1.0% v.s. 0.1%, 1.0% v.s. 0.2%, respectively; p < 0.0001).When these figures were converted to incidence per 1000 person-years, the results remained significant (Table 2). The incidences of eclamptic/pre-eclamptic women suffering from diabetes, dyslipidemia, hypertension, congestive heart failure and cerebrovascular disease per 1000 person-years were higher than those in the controls: 7.30/11.27 v.s. 2.45, 12.18/ 15.05 v.s. 4.44, 42.39/40.31 v.s. 4.62, 1.40/1.12 v.s. 0.15, 2.81/0.92 v.s. 0.26, respectively). Hazard ratio can then be derived from the above findings, attributing the risks of acquiring subsequent diabetes mellitus, dyslipidemia, hypertension, congestive heart failure and cerebrovascular disease from eclampsia/preeclampsia by factor of 3.84/5.42, 2.75/3.40, 6.52/7.31, 9.07/7.39, and 10.71/3.47, respectively; p < 0.0060.When cerebrovascular diseases were further classified into subtypes, it was found that eclampsia was associated with hemorrhagic stroke (HR 19.74, p < 0.0001) and preeclampsia was associated with ischemic stroke (HR 4.76, p ¼ 0.0274). In order to capture the temporal changes of the disease courses, KaplaneMeier curves were adopted to examine the incidence of developing hypertension, congestive heart failure and cerebrovascular diseases over the years since the diagnosis of eclampsia/ preeclampsia, with the follow up period lasting 16 years. As illustrated by the divergent lines in Fig. 1, the cumulative incidences of hypertension, congestive heart failure and cerebrovascular diseases were significantly higher than those in age-matched controls (Logrank test p < 0.0001). For the cumulative incidence of hypertension, steady increases over the years with constant slops were observed for both eclampsia and preeclampsia groups. On the contrary, dramatic increases of congestive heart failure incidence at roughly 3 years and 10 years since the diagnosis of eclampsia/preeclampsia were noted. Similar patterns were also seen in the cumulative incidence rates for cerebrovascular diseases. To further test the validity of the figures despite of its small sample sizes, actual incidence rates were grouped into follow up periods less than 2 years, 2e9 years and longer than 9 years (Table 3). Statistical significances were found at time periods less than 2 years and at more
366
Y.-L. Kuo et al. / Taiwanese Journal of Obstetrics & Gynecology 57 (2018) 364e369
Table 1 Characteristics of the study population.
Occurrence, n (%) First delivery Second delivery Third delivery or beyond Frequency of occurrence, n (%) Once More than once Pregnant first delivery age (SD), y's Age group, n (%) 14e20 21e25 26e30 31e35 36e40 >40 First delivery, n (%) Surgical delivery Vaginal delivery Cumulative incidence number, n (%) Diabetes Dyslipidemia Hypertension Myocardial infarction Peripheral vascular disease Congestive heart failure Cerebrovascular disease* Hemorrhagic Cerebral infarction Other
Eclampsia (n ¼ 151)
Preeclampsia (n ¼ 1144)
P value
Total patients (n ¼ 1295)
130 (86.1) 13 (8.6) 8 (5.3)
Age-matched controls (n ¼ 5180)
P value
986 (86.2) 105 (9.2) 53 (4.6)
0.9172
1116 (86.2) 118 (9.1) 61 (4.8)
136 (90.1) 15 (9.9) 29.3 (6.3)
1080 (94.4) 64 (5.6) 29.8 (5.5)
0.0363 0.2922
1216 (93.9) 79 (6.1) 29.7 (5.6)
29.6 (5.4)
0.4886
9 (6.0) 30 (19.9) 48 (31.8) 35 (23.2) 22 (14.6) 7 (4.6)
41 (3.6) 183 (16.0) 359 (31.4) 378 (33.0) 145 (12.7) 38 (3.3)
0.1416
50 (3.9) 213 (16.5) 407 (31.4) 413 (31.9) 167 (12.9) 45 (3.5)
222 (4.3) 811 (15.7) 1761 (34.0) 1551 (29.9) 675 (13.0) 160 (3.1)
0.4541
118 (78.2) 33 (21.9)
854 (74.7) 290 (25.4)
0.3508
972 (75.1) 323 (24.9)
1930 (37.3) 3250 (62.7)
<0.0001
10 (6.6) 17 (11.3) 47 (31.1) 0 (0.0) 1 (0.7) 2 (1.3) 4 (2.7) 3 (1.99) 1 (0.66) 0 (0.0)
99 (8.7) 139 (12.2) 320 (28.0) 2 (0.2) 3 (0.3) 11 (1.0) 9 (0.8) 1 (0.09) 4 (0.35) 4 (0.35)
109 (8.4) 156 (12.1) 367 (28.3) 2 (0.2) 4 (0.3) 13 (1.0) 13 (1.0) 4 (0.31) 5 (0.39) 4 (0.31)
107 (2.1) 200 (3.9) 208 (4.0) 2 (0.0) 6 (0.1) 7 (0.1) 12 (0.2) 5 (0.10) 4 (0.08) 3 (0.06)
0.3981 0.7516 0.4289 1.0000 0.3914 0.6567 0.0547
0.0103
<0.0001 <0.0001 <0.0001 0.1335 0.1207 <0.0001 <0.0001
0.0013
SD:standard deviation. Cerebrovascular disease (Stroke): Subarachnoid hemorrhage, Intracerebral hemorrhage, and unspecified intracranial hemorrhage (ICD-9-CM 430.x, 431.x, 432.x); Cerebral infarction (ICD-9-CM 433.x, 434.x); Other (ICD-9-CM 435.x, 436.x, 437.x, 438.x). Data of continuous and categorical variables were analyzed by t-test and chi-square test/Fisher's exact test to make comparisons between preeclampsia/eclampsia cases and matched controls and to make comparisons between preeclampsia and eclampsia, as appropriate. *Cerebrovascular disease (stroke).....other (ICD-9 CM 435.x, 436.x, 437.x, 438.x). Table 2 Association of (pre-)eclampsia to diabetes, dyslipidemia, hypertension, congestive heart failure and cerebrovascular diseases. The date of delivery to the date of an event
Eclampsia cases
Preeclampsia
Age-Matched controls
Diabetes events, n(%) Incidence per 1000 person-years (95% CI) HR (95% CI), p-value Dyslipidemia, events, n(%) Incidence per 1000 person-years (95% CI) HR (95% CI), p-value Hypertension events, n(%) Incidence per 1000 person-years (95% CI) HR (95% CI), p-value Congestive heart failure, events, n(%) Incidence per 1000 person-years (95% CI) HR (95% CI), p-value Cerebrovascular disease, events, n(%) Incidence per 1000 person-years (95% CI) HR (95% CI), p-value Hemorrhagic Incidence per 1000 person-years (95% CI) HR (95% CI), p-value Cerebral infarction Incidence per 1000 person-years (95% CI) HR (95% CI), p-value
10 7.30 (6.92e7.69) 3.84(1.99e7.40), <0.0001 17 12.18 (11.55e12.83) 2.75(1.68e4.51), <0.0001 47 42.39 (39.97e44.96) 6.52(4.49e9.47), <0.0001 2 1.40 (1.32e1.47) 9.07(1.88e43.68), 0.0060 4 2.81 (2.67e2.96) 10.71(3.45e33.24), <0.0001 3 2.11 (2.00e2.21) 19.74 (4.71e82.68), <0.0001 1 0.70 (0.67e0.74) 7.84 (0.88e70.14), 0.0656
99 11.27 (11.04e11.51) 5.42(4.01e7.32), <0.0001 139 15.05 (14.75e15.36) 3.40(2.73e4.24), <0.0001 320 40.31 (39.43e41.20) 7.31(6.07e8.80), <0.0001 11 1.12 (1.10e1.14) 7.39(2.86e19.06), <0.0001 9 0.92 (0.90e0.94) 3.47(1.46e8.23), 0.0048 1 0.10 (0.10e0.10) 0.93 (0.11e7.97), 0.9472 4 0.41 (0.40e0.42) 4.76(1.19e19.03), 0.0274
107 2.45 1.00 200 4.44 1.00 208 4.62 1.00 7 0.15 1.00 12 0.26 1.00 5 0.11 1.00 4 0.09 1.00
(2.43e2.47)
(4.40e4.48)
(4.58e4.67)
(0.15e0.15)
(0.26e0.26)
(0.11e0.11)
(0.09e0.09)
Bold signifies findings that reach statistical significance. Hazard Ratios (HR) with 95% and their P values were calculated using a Cox proportional-hazards regression model.
than 9 years in eclamptic/preeclamptic patients developing subsequent cerebrovascular diseases (36.27, p ¼ 0.0016; 6.72, p ¼ 0.0092, respectively) and congestive heart failure (36.31, p ¼ 0.0016; 6.05, p ¼ 0.048, respectively). To pursue further the influences of preeclampsia/eclampsia and/or hypertension to cerebrovascular diseases and to congestive heart failure development, we divided the study population into E/H, Eþ/H, E/Hþ, Eþ/Hþ groups (E: preeclampsia/eclampsia,
H:hypertension). As shown in Table 4, significantly more patients with preeclampsia/eclampsia history acquired subsequent congestive heart failure, whether she had hypertension (adjusted RR 7.43, p ¼ 0.0005) or not (adjusted RR 6.52, p ¼ 0.0096). On the other hand, it was observed that more patients with hypertension history suffered from cerebrovascular diseases, whether she had preeclampsia/eclampsia (adjusted RR 8.76, p < 0.0001) or not (RR 4.80, p ¼ 0.0427; adjusted RR 2.87, p ¼ 0.1942).
Y.-L. Kuo et al. / Taiwanese Journal of Obstetrics & Gynecology 57 (2018) 364e369
Age-matched controls
Preeclampsia cases
367
Eclampsia cases
ProporƟon of Hypertension (%)
45.0 40.0
38.9
35.0 28.8
30.0 25.0 20.0
15.6 10.6
15.0 10.0
0.0 1
2
3
25.9 24.2
26.7
3.2
4.0
4.4
28.3
28.3 28.3
6.5
7.6
15.2
10.5
4
5
6
7
2.6
2.1
1.8
1.3
0.9
0.5
0.2
0.1
0.0
20.2 20.1
19.2 17.8
23.9 24.2
33.3
12.2
8.2 7.6
6.0 5.3
5.0
18.3
23.1 21.8
31.9 28.3
34.9
8
9
10
11
12
5.5 13
14
15
8.3
16
Years
Age-matched controls
ProporƟon of congesƟve heart failure (%)
B
Preeclampsia cases
Eclampsia cases
2.5 2.2
2.2
2.2
2.2
2.0 1.5
1.6
1.0 0.8 0.5 0.0
1.2
1.0
0.0 0
0.0
0.0 1
0.0
0.0 2
0.5
0.5
0.4
0.4
3
0.8
5
0.7
6
0.8
1.6
1.6
1.2
0.8
0.8
0.8
0.8
0.1
0.1
0.2
0.2
0.7 0.1
0.1
0.0
0.0 4
0.8 0.7
0.6
1.2
7
8
9
10
11
0.2 12
0.3
0.2
0.3
13
14
15
4.5
4.5
4.5
Years
C
Age-matched controls
Preeclampsia cases
Eclampsia cases
ProporƟon of cerebrovascular disease(%)
5.0 4.5 4.0
3.5 3.0
2.6
2.6
0.9
0.9
0.9
0.9
0.9
0.3
0.3
0.3
12
13
14
2.4
2.5 2.0 1.4
1.5 1.0 0.5
0.7
0.7
0.0
0.1 0.0
0.3 0.0
0
1
2
1.4
1.4
1.4
1.4
1.4
1.4
1.4
0.5 0.2
0.5 0.2
0.6
0.6
0.6
0.6
0.6
0.2
0.2
0.2
0.2
0.2
0.2
0.3
3
4
5
6
7
8
9
10
11
0.6
0.0 15
Years
Fig. 1. Cumulative incidences of (A) hypertension (B) congestive heart failure and (C) cerebrovascular disease for pregnant women patients with (pre-)eclampsia and the agematched pregnant women controls control cohorts.
368
Y.-L. Kuo et al. / Taiwanese Journal of Obstetrics & Gynecology 57 (2018) 364e369
Table 3 Odds ratios for associations of cerebrovascular disease and congestive heart failure with follow-up period <2 years and >9 years. <2 vs No eventa
Follow-up period, events No event Cerebrovascular disease Controls 5168 (99.77) Eclampsia/Preeclampsia cases 1282 (99.00) Congestive heart failure Controls 5173 (99.86) Eclampsia/Preeclampsia cases 1282 (99.00)
Pa
<2 years 2e9 years >9 years OR (95% CI)
2e9 vs No event
P
OR (95% CI)
>9 vs No event
P
OR (95% CI)
0 (0.00) 4 (0.31)
9 (0.17) 4 (0.31)
3 (0.06) 5 (0.39)
1.00 1.00 36.27 (1.95e674.10) 0.0016 1.79 (0.55e5.83)
1.00 0.3325 6.72 (1.60e28.15) 0.0092
0 (0.00) 4 (0.31)
5 (0.10) 6 (0.46)
2 (0.04) 3 (0.23)
1.00 1.00 36.31 (1.95e674.75) 0.0016 4.84 (1.48e15.89) 0.0093 6.05 (1.01e36.26) 0.0487
Odds ratios (OR) with 95% and their P values were calculated using a multinomial logistic regression model. Bold signifies findings that reach statistical significance. a These logit estimators use a correction of 0.5 in every cell of those tables that contain a zero; P value was analyzed by Fisher's exact test. Table 4 Preeclampsia/eclampsia associated with increased congestive heart failure and cerebrovascular disease occurrence.
Congestive heart failure disease Preeclampsia/Eclampsia cases e þ e þ Cerebrovascular disease Preeclampsia/Eclampsia cases e þ e þ
Event, n (%)
Total subjects
RR (95% CI)
P
Adjusted RR (95% CI)
P
Hypertension e e þ þ
5 8 2 5
(0.10) (0.86) (0.97) (1.38)
4973 932 207 363
1.00 8.54 (2.79e26.1) 9.61 (1.86e49.53) 13.7 (3.97e47.32)
0.0002 0.0068 <0.0001
1.00 7.43 (2.41e22.89) 5.73 (0.98e33.5) 6.52 (1.58e26.95)
0.0005 0.0528 0.0096
Hypertension e e þ þ
10 (0.20) 2 (0.21) 2 (0.97) 11 (3.03)
4973 932 207 363
1.00 1.07 (0.23e4.87) 4.80 (1.05e21.93) 15.07 (6.4e35.48)
0.9331 0.0427 <0.0001
1.00 1.02 (0.22e4.67) 2.87 (0.58e14.06) 8.76 (3.21e23.88)
0.9789 0.1942 <0.0001
Relative risk (RR) was calculated using a Cox proportional-hazards regression model. Adjusted RR was calculated after adjusted for age, diabetes and dyslipidemia using a Cox proportional-hazards regression model.
Discussion Decades of researches and efforts are devoted to learn about the pathophysiology, diagnosis and management of preeclampsia and eclampsia. They are such important issues in high-risk pregnancies in terms of their high prevalence with potentially disabling, if not deadly, complications that are potentially preventable and treatable. The impact of the disease is not limited to the gestation period or immediately postpartum, but remained as an important risk factor for numerous medical conditions in the long term. A number of case-controlled cohort studies asserted two to four fold risks of subsequent diabetes mellitus for those with hypertensive pregnancy disorder [11,12,17e22]. It has been postulated that women with preeclampsia have increased insulin resistance during pregnancy and the effect could persist after delivery. Therefore, these high-risk women are predisposed to the development of diabetes mellitus. Our findings were consistent with these previous studies that eclampsia and preeclampsia increased risks for subsequent diabetes mellitus by hazard ratio of 3.84 and 5.42 respectively. Similarly, previous studies have demonstrated a less favorable lipid profile in women with preeclampsia or eclampsia history [18,22,23]. Although normal pregnancy is characterized by elevated plasma triglyceride and cholesterol concentrations, women with preeclampsia or eclampsia experience more drastic changes in their lipid profile during their pregnancy. Magnussen et al. and Van Rijn et al. found these women tended to have higher levels of total cholesterol, low-density lipoprotein cholesterol and triglycerides [22,23]. Our findings were consistent with these previous studies that eclampsia and preeclampsia increased risks for subsequent dyslipidemia by hazard ratio of 2.75 and 3.40 respectively. Likewise, Bellamy et al. conducted a meta-analysis examining available prospective and retrospective cohort studies between 1996 and 2006 to find women with preeclampsia history had an increased risk of developing hypertension after an average follow up period of 14.1 years with a risk ratio of 3.70, 95% confidence interval 2.70e5.02
[7]. In this current study, we conducted similar analysis, except with an age-matched, population-based sample size and extended follow up period that lasted 15 years. More intriguing findings were disclosed in our KaplaneMeier curves that delineate the cumulative incidence rates of hypertension, congestive heart failure and cerebrovascular diseases over the period of 15 years. For hypertension, a steady increase with constant slope is observed, signaling a persistent risk for developing hypertension as long as 15 years after experiencing preeclampsia or eclampsia. This might be of clinical importance to the practitioners who should follow up preeclampsia/eclampsia patients’ blood pressure status for over a decade. As for congestive heart failure, a significantly increased risk with hazard ratios of 9.07, p ¼ 0.0060 and 7.39, p < 0.001 were noted for eclampsia and preeclampsia women, respectively. Its cumulative incidence rates in preeclampsia or eclampsia women have distinctively abrupt increases at time periods of less than 2 years and more than 9 years postpartum, signifying important timing of follow ups and patient education. The finding echoed the work done by Melchiorre et al. that asserted preeclampsia was associated with asymptomatic global left ventricular abnormal function, and that the impact of preeclampsia on cardiovascular function did not end with the birth of infant or placenta [24,25]. Likewise, significantly increased risks are observed in eclamptic/preeclamptic women to develop cerebrovascular diseases with hazard ratios of 10.71, P < 0.0001 and 3.47, p ¼ 0.0048, respectively, with a median follow-up period of 9.8 years. Time periods at less than 2 years and more than 9 years after delivery have noticeable increases of cumulative incidence rates for cerebrovascular diseases on the KaplaneMeier curves, similar to the pattern observed for congestive heart failure. Equally interesting is the finding that eclampsia is significantly associated with more hemorrhagic cerebrovascular events compared to those in controls and preeclampsia (2.11, 0.11 or 0.10 per 1000 person-years, HR 19.74, p < 0.0001 and 21.22, p ¼ 0.0082, respectively). Preeclampsia, on the other hand, is associated with significantly more
Y.-L. Kuo et al. / Taiwanese Journal of Obstetrics & Gynecology 57 (2018) 364e369
ischemic strokes (HR 4.76, p ¼ 0.0274). Whether or not these findings suggest fundamental differences in the pathophysiology of pre-eclampsia and eclampsia requires further investigations. To examine the roles played by hypertension and preeclampsia/ eclampsia in developing subsequent congestive heart failure and cerebrovascular diseases, we further divided our study subjects to E/H, Eþ/H, E/Hþ, Eþ/Hþ (E: eclampsia/preeclampsia, H: hypertension) groups. As shown in Table 4, preeclampsia and eclampsia might play a more important role than hypertension in leading to congestive heart failure, for both Eþ/H- and Eþ/Hþ groups have reached statistically significant relative risk of 7.43, p ¼ 0005 and 6.52, p ¼ 0.0096, respectively. On the contrary, patients with hypertension tend to have more sequent cerebrovascular diseases with relative risk of 8.76, p < 0.0001 in the Eþ/Hþ group, while those with only preeclampsia/eclampsia did not significantly increase the risk of cerebrovascular diseases (adjust RR 1.02, p ¼ 0.9789). These findings may again suggest preeclampsia and eclampsia as fundamentally different entities in terms of disease pathophysiology, of which further researches are needed. These findings may also have implications in explaining diseases’ prognosis and also in patient education. Several limitations were identified in our study. First, case number for cardiovascular diseases was limited. Despite that this was a population-based study and that the National Health Insurance covered more than 98% of the population, some cardiovascular disease cases could still be missed due to difficulties in case identifications. A larger number of cohorts are needed to signify meaningful associations. Secondly, some essential clinical parameters were not included in the NHIRD, such as body mass index and smoking. Thirdly, there were no data about the severity of the preeclampsia/eclampsia, prenatal care and whether these women received treatment during the follow up periods. Forth, diagnosis misclassification and under-reporting of diseases existed for ICD-9. This current study have found that women with history of preeclampsia/eclampsia were at increased risks for subsequent diagnosis of diabetes mellitus, dyslipidemia, hypertension, congestive heart failure and cerebrovascular diseases. Although the underlying explanations for the relationship among preeclampsia/ eclampsia, congestive heart failure and cerebrovascular diseases were mostly just hypotheses, our findings raise the awareness of these associations. Thus, more care and patient education in terms of disease prospective, natural course and prognosis could be informed of the patients. Preventive counseling, more vigilant screening and management for the modifiable risks should be provided to the affected women. Clinicians should closely monitor these patients in the first three years postpartum and continuously for up to at least a decade. Conflict of interest The authors declare no conflict of interest. References [1] Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol 2009;33(3):130e7.
369
[2] Chen CW, Jaffe IZ, Karumanchi SA. Pre-eclampsia and cardiovascular disease. Cardiovasc Res 2014;101(4):579e86. [3] Maynard SE. Preeclampsia and subsequent cardiovascular disease: villain or innocent bystander? Clin J Am Soc Nephrol 2013;8(7):1061e3. [4] Seely EW, Tsigas E, Rich-Edwards JW. Preeclampsia and future cardiovascular disease in women: how good are the data and how can we manage our patients? Semin Perinatol 2015;39(4):276e83. [5] Ahmed R, Dunford J, Mehran R, Robson S, Kunadian V. Pre-eclampsia and future cardiovascular risk among women: a review. J Am Coll Cardiol 2014;63(18):1815e22. [6] Lee G, Tubby J. Preeclampsia and the risk of cardiovascular disease later in lifeeA review of the evidence. Midwifery 2015;31(12):1127e34. [7] Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and metaanalysis. BMJ 2007;335(7627):974. [8] McDonald SD, Malinowski A, Zhou Q, Yusuf S, Devereaux PJ. Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses. Am Heart J 2008;156(5):918e30. [9] Yeh JS, Cheng HM, Hsu PF, Sung SH, Liu WL, Fang HL, et al. Synergistic effect of gestational hypertension and postpartum incident hypertension on cardiovascular health: a nationwide population study. J Am Heart Assoc 2014;3(6): e001008. [10] Garovic VD, Bailey KR, Boerwinkle E, Hunt SC, Weder AB, Curb D, et al. Hypertension in pregnancy as a risk factor for cardiovascular disease later in life. J Hypertens 2010;28(4):826e33. [11] Lykke JA, Langhoff-Roos J, Sibai BM, Funai EF, Triche EW, Paidas MJ. Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and type 2 diabetes mellitus in the mother. Hypertension 2009;53(6):944e51. [12] Mannisto T, Mendola P, Vaarasmaki M, Jarvelin MR, Hartikainen AL, Pouta A, et al. Elevated blood pressure in pregnancy and subsequent chronic disease risk. Circulation 2013;127(6):681e90. [13] Lin YS, Tang CH, Yang CY, Wu LS, Hung ST, Hwa HL, et al. Effect of preeclampsia-eclampsia on major cardiovascular events among peripartum women in Taiwan. Am J Cardiol 2011;107(2):325e30. [14] Savitz DA, Danilack VA, Elston B, Lipkind HS. Pregnancy-induced hypertension and diabetes and the risk of cardiovascular disease, stroke, and diabetes hospitalization in the year following delivery. Am J Epidemiol 2014;180(1): 41e4. [15] Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA. Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet 2005;366(9499):1797e803. [16] Kestenbaum B, Seliger SL, Easterling TR, Gillen DL, Critchlow CW, StehmanBreen CO, et al. Cardiovascular and thromboembolic events following hypertensive pregnancy. Am J Kidney Dis e Offi J Natl Kidney Found 2003;42(5): 982e9. [17] Feig DS, Shah BR, Lipscombe LL, Wu CF, Ray JG, Lowe J, et al. Preeclampsia as a risk factor for diabetes: a population-based cohort study. PLoS Med 2013;10(4):e1001425. [18] Hashemi S, Ramezani Tehrani F, Mehrabi Y, Azizi F. Hypertensive pregnancy disorders as a risk factor for future cardiovascular and metabolic disorders (Tehran Lipid and Glucose Study). J Obstet Gynaecol Res 2013;39(5):891e7. [19] Wang IK, Tsai IJ, Chen PC, Liang CC, Chou CY, Chang CT, et al. Hypertensive disorders in pregnancy and subsequent diabetes mellitus: a retrospective cohort study. Am J Med 2012;125(3):251e7. [20] Callaway LK, Lawlor DA, O'Callaghan M, Williams GM, Najman JM, McIntyre HD. Diabetes mellitus in the 21 years after a pregnancy that was complicated by hypertension: findings from a prospective cohort study. Am J Obstet Gynecol 2007;197(5):492 e1e7. [21] Carr DB, Newton KM, Utzschneider KM, Tong J, Gerchman F, Kahn SE, et al. Preeclampsia and risk of developing subsequent diabetes. Hypertens Pregnancy 2009;28(4):435e47. [22] Magnussen EB, Vatten LJ, Smith GD, Romundstad PR. Hypertensive disorders in pregnancy and subsequently measured cardiovascular risk factors. Obstet Gynecol 2009;114(5):961e70. [23] van Rijn BB, Nijdam ME, Bruinse HW, Roest M, Uiterwaal CS, Grobbee DE, et al. Cardiovascular disease risk factors in women with a history of early-onset preeclampsia. Obstet Gynecol 2013;121(5):1040e8. [24] Melchiorre K, Sutherland GR, Liberati M, Thilaganathan B. Preeclampsia is associated with persistent postpartum cardiovascular impairment. Hypertension 2011;58(4):709e15. [25] Melchiorre K, Thilaganathan B. Maternal cardiac function in preeclampsia. Curr Opin Obstet Gynecol 2011;23(6):440e7.
Contents lists available at ScienceDirect
Taiwanese Journal of Obstetrics & Gynecology journal homepage: www.tjog-online.com
Original Article
Preeclampsia-eclampsia and future cardiovascular risk among women in Taiwan Yu-Ling Kuo a, Te-Fu Chan a, b, Chien-Yi Wu c, Chin-Ru Ker a, Hung-Pin Tu d, * a
Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan Department of Obstetrics and Gynecology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan c Department of Family Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan d Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan b
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 25 April 2018
Objective: This study aims to examine the long-term cardiovascular and cerebrovascular risks in a large cohort of women with past history of preeclampsia and/or eclampsia. Materials and methods: This is a retrospective longitudinal study using National Health Insurance Research Database from 1996 to 2010. We identified 1295 women with preeclampsia and eclampsia. The control group was 5180 pregnant women without preeclampsia/eclampsia, who were matched for age and date of delivery. The incidences of diabetes, dyslipidemia, hypertension and cardiovascular events after pregnancy were identified from medical records after the date of delivery to the date of an event or the end of the study. Results: The median follow-up duration was 9.8 years (interquartile 5.1e12.7 years). The incidences of diabetes, dyslipidemia, hypertension, congestive heart failure and cerebrovascular disease events were significantly greater in women with eclampsia or preeclampsia than those in controls. Eclampsia or preeclampsia increased the risk of diabetes, dyslipidemia, hypertension, congestive heart failure and cerebrovascular disease events (hazard ratio [HR] 3.84 and 5.42, P < 0.0001; HR 2.75 and 3.40, P < 0.0001; HR 6.52 and 7.31, P < 0.0001; HR 9.07, P ¼ 0.0060 and 7.39, P < 0.0001; HR 10.71, P < 0.0001 and 3.47, P ¼ 0.0048, respectively). The survival curves for the development of congestive heart failure and cerebrovascular disease in women with eclampsia/preeclampsia and in control differed significantly (Log-rank test P < 0.0001). From the curve, we can find dramatic increases of congestive heart failure and cerebrovascular disease incidences at roughly 3 years and 10 years since the diagnosis of eclampsia/ preeclampsia. Conclusions: Our study revealed that women with a history of preeclampsia/eclampsia were at increased risks for subsequent diagnoses of diabetes, dyslipidemia, hypertension, congestive heart failure and cerebrovascular disease. Preventive counseling, more vigilant screening and management for the modifiable risks should be provided to the affected women. Clinicians should closely monitor these patients in the first three years postpartum and continuously for up to at least a decade. © 2018 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Cardiovascular disease Cerebrovascular disorders Eclampsia Preeclampsia
Introduction Preeclampsia has an incidence rate of 2e8% in all pregnancy, posing as one of the leading causes of maternal and neonatal morbidity and mortality [1]. More and more evidence suggests that the harmful effects of preeclampsia/eclampsia might not be limited
* Corresponding author. Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, No.100, Shih-Chuan 1st Road, Kaohsiung, 807, Taiwan. E-mail address: [email protected] (H.-P. Tu).
to the gestation period only, but remained as an important risk for long-term cardiovascular sequelae in impacted women [2e6]. The meta-analysis done by Bellamy et al. found that women with preeclampsia history have four-fold increased risk of hypertension, two-fold risk of ischemic heart disease, stroke and venous thromboembolism later in their lives [7]. Similarly, McDonald et al. revealed a doubled risk of cardiac, cerebrovascular, peripheral arterial disease and cardiovascular mortality in women who had previous preeclampsia in their work, also a meta-analysis [8]. Dozens of other studies, mostly case controlled cohort series, reported agreeable results with associated risk ratio ranged from two
https://doi.org/10.1016/j.tjog.2018.04.035 1028-4559/© 2018 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
Y.-L. Kuo et al. / Taiwanese Journal of Obstetrics & Gynecology 57 (2018) 364e369
to four folds [9e16]. However, these reports were inconsistent in study designs, patient population, sample size and length of follow up, making it difficult to generalize the conclusion to all affected women or to delineate the long-term natural course of the etiology. In the current study, we extended the observation period to approximately 10 years, using data from birth registry linked to National Health Insurance claims to examine the long-term cardiovascular and cerebrovascular risks in a large cohort of women with past history of preeclampsia and/or eclampsia. Materials and methods Study population In Taiwan, the National Health Insurance is a single-payer program that has covered more than 98% of the population since 1995. National Health Insurance Research Database (NHIRD, www.nhri. org.tw/nhird) contains information regarding patients’ demographic descriptions, diagnoses, prescriptions, inpatient and outpatient claims. It is one of the largest nationwide and population-based data banks in the world. A double-scrambling protocol that encrypts original patient identification numbers is used to protect confidentiality while maintaining consistency. In this study, one million pregnant women were randomly selected from NHIRD and their medical records reviewed from January 1, 1996 to December 31, 2010. Study design A cohort of one million pregnant women with or without preeclampsia/eclampsia was sampled from NHIRD for analysis of their long-term cardiovascular or cerebrovascular risks. All diagnoses were made and coded according to the ninth edition of International Classification of Diseases, Clinically Modification (ICD-9-CM) system. We identified 1295 women with preeclampsia using ICD-9-CM codes 642.4e642.5 and eclampsia 642.6e642.7. We excluded those with previous history of myocardial infarction (ICD-9-CM codes 410.x-412.x), congestive heart failure (ICD-9-CM codes 398.91, 402.01, 402.11.402.91, 404.01, 404.03, 404.11, 404.13, 404.91, 404.93, 425.4e425.9, 428.x), peripheral vascular diseases (ICD-9-CM codes 093.0, 437.3, 440.x, 441.x, 443.1e443.9, 47.1, 557.1, 557.9, V43.4), cerebrovascular diseases (ICD-9-CM codes 362.34, 430.x-438.x), diabetes mellitus (ICD-9-CM code 250), dyslipidemia (ICD-9-CM code 272) and hypertension (ICD-9 code 401e405). Patients with medical data entry, as inpatient or outpatient, at least 12 months prior to delivery were included. The control group of 5180 pregnant women without preeclampsia/eclampsia diagnoses was matched for age and date of delivery. The follow up period was defined starting from the date of delivery to the date of an event or to the end of the study. Three or more inpatient and/or outpatient insurance claims submitted for diabetes mellitus, dyslipidemia, hypertension, congestive heart failure, and cerebrovascular diseases were considered confirmed diagnoses and thus used for analysis. Ethical concerns of this study protocol were approved by the institutional review board of Kaohsiung Medical University Hospital. Statistical analysis Parametric continuous data were compared across groups using t-test and categorical data were compared across groups using chisquire test or Fisher's exact test as appropriate. Survival time was calculated from the date of delivery with preeclampsia/eclampsia occurrence to the onset date of hypertension, congestive heart
365
failure, cerebrovascular diseases or the end of the study (December 31, 2010). The KaplaneMeier method was used to plot the survival curves for each group, and the log-rank test was used to test the homogeneity between survival curves. The hazard ratios (HRs) and 95% confidence interval were calculated for diabetes, dyslipidemia, hypertension, congestive heart failure and cerebrovascular disease events using Cox proportional hazards model. Study subjects were further classified into E/H-, Eþ/H-, E/Hþ, Eþ/Hþ (E: eclampsia/ preeclampsia, H: hypertension) groups to examine which factor might play a greater role in the disease pathophysiology. Relative risks (RR) were estimated by Cox proportional hazards model. Adjusted RRs were calculated after standardizing age, diabetes mellitus and dyslipidemia using Cox proportional hazards regression model. All statistical analyses were performed using SAS statistical software, version 9.4 (SAS Institute, Carry, NC), and the significant level was set at p < 0.05. Results The median follow up period last 9.8 years (interquartile 5.1e12.7 years). A total number of 1295 women with preeclampsia or eclampsia history was properly matched by age to 5180 controls (p ¼ 0.4541; Table 1). The majority them aged between 26 and 35 years old (63.3%), averaged at 29.7 years old. Eighty-six percent of the women were having their first pregnancies. Patients with preeclampsia or eclampsia had significantly higher rates of receiving surgical delivery, acquiring diabetes mellitus, dyslipidemia, hypertension, congestive heart failure, and cerebrovascular diseases than those in the control group (75.1% v.s. 37.3%, 8.4% v.s. 2.1%, 12.1% v.s 3.9%, 28.3% v.s. 4%, 1.0% v.s. 0.1%, 1.0% v.s. 0.2%, respectively; p < 0.0001).When these figures were converted to incidence per 1000 person-years, the results remained significant (Table 2). The incidences of eclamptic/pre-eclamptic women suffering from diabetes, dyslipidemia, hypertension, congestive heart failure and cerebrovascular disease per 1000 person-years were higher than those in the controls: 7.30/11.27 v.s. 2.45, 12.18/ 15.05 v.s. 4.44, 42.39/40.31 v.s. 4.62, 1.40/1.12 v.s. 0.15, 2.81/0.92 v.s. 0.26, respectively). Hazard ratio can then be derived from the above findings, attributing the risks of acquiring subsequent diabetes mellitus, dyslipidemia, hypertension, congestive heart failure and cerebrovascular disease from eclampsia/preeclampsia by factor of 3.84/5.42, 2.75/3.40, 6.52/7.31, 9.07/7.39, and 10.71/3.47, respectively; p < 0.0060.When cerebrovascular diseases were further classified into subtypes, it was found that eclampsia was associated with hemorrhagic stroke (HR 19.74, p < 0.0001) and preeclampsia was associated with ischemic stroke (HR 4.76, p ¼ 0.0274). In order to capture the temporal changes of the disease courses, KaplaneMeier curves were adopted to examine the incidence of developing hypertension, congestive heart failure and cerebrovascular diseases over the years since the diagnosis of eclampsia/ preeclampsia, with the follow up period lasting 16 years. As illustrated by the divergent lines in Fig. 1, the cumulative incidences of hypertension, congestive heart failure and cerebrovascular diseases were significantly higher than those in age-matched controls (Logrank test p < 0.0001). For the cumulative incidence of hypertension, steady increases over the years with constant slops were observed for both eclampsia and preeclampsia groups. On the contrary, dramatic increases of congestive heart failure incidence at roughly 3 years and 10 years since the diagnosis of eclampsia/preeclampsia were noted. Similar patterns were also seen in the cumulative incidence rates for cerebrovascular diseases. To further test the validity of the figures despite of its small sample sizes, actual incidence rates were grouped into follow up periods less than 2 years, 2e9 years and longer than 9 years (Table 3). Statistical significances were found at time periods less than 2 years and at more
366
Y.-L. Kuo et al. / Taiwanese Journal of Obstetrics & Gynecology 57 (2018) 364e369
Table 1 Characteristics of the study population.
Occurrence, n (%) First delivery Second delivery Third delivery or beyond Frequency of occurrence, n (%) Once More than once Pregnant first delivery age (SD), y's Age group, n (%) 14e20 21e25 26e30 31e35 36e40 >40 First delivery, n (%) Surgical delivery Vaginal delivery Cumulative incidence number, n (%) Diabetes Dyslipidemia Hypertension Myocardial infarction Peripheral vascular disease Congestive heart failure Cerebrovascular disease* Hemorrhagic Cerebral infarction Other
Eclampsia (n ¼ 151)
Preeclampsia (n ¼ 1144)
P value
Total patients (n ¼ 1295)
130 (86.1) 13 (8.6) 8 (5.3)
Age-matched controls (n ¼ 5180)
P value
986 (86.2) 105 (9.2) 53 (4.6)
0.9172
1116 (86.2) 118 (9.1) 61 (4.8)
136 (90.1) 15 (9.9) 29.3 (6.3)
1080 (94.4) 64 (5.6) 29.8 (5.5)
0.0363 0.2922
1216 (93.9) 79 (6.1) 29.7 (5.6)
29.6 (5.4)
0.4886
9 (6.0) 30 (19.9) 48 (31.8) 35 (23.2) 22 (14.6) 7 (4.6)
41 (3.6) 183 (16.0) 359 (31.4) 378 (33.0) 145 (12.7) 38 (3.3)
0.1416
50 (3.9) 213 (16.5) 407 (31.4) 413 (31.9) 167 (12.9) 45 (3.5)
222 (4.3) 811 (15.7) 1761 (34.0) 1551 (29.9) 675 (13.0) 160 (3.1)
0.4541
118 (78.2) 33 (21.9)
854 (74.7) 290 (25.4)
0.3508
972 (75.1) 323 (24.9)
1930 (37.3) 3250 (62.7)
<0.0001
10 (6.6) 17 (11.3) 47 (31.1) 0 (0.0) 1 (0.7) 2 (1.3) 4 (2.7) 3 (1.99) 1 (0.66) 0 (0.0)
99 (8.7) 139 (12.2) 320 (28.0) 2 (0.2) 3 (0.3) 11 (1.0) 9 (0.8) 1 (0.09) 4 (0.35) 4 (0.35)
109 (8.4) 156 (12.1) 367 (28.3) 2 (0.2) 4 (0.3) 13 (1.0) 13 (1.0) 4 (0.31) 5 (0.39) 4 (0.31)
107 (2.1) 200 (3.9) 208 (4.0) 2 (0.0) 6 (0.1) 7 (0.1) 12 (0.2) 5 (0.10) 4 (0.08) 3 (0.06)
0.3981 0.7516 0.4289 1.0000 0.3914 0.6567 0.0547
0.0103
<0.0001 <0.0001 <0.0001 0.1335 0.1207 <0.0001 <0.0001
0.0013
SD:standard deviation. Cerebrovascular disease (Stroke): Subarachnoid hemorrhage, Intracerebral hemorrhage, and unspecified intracranial hemorrhage (ICD-9-CM 430.x, 431.x, 432.x); Cerebral infarction (ICD-9-CM 433.x, 434.x); Other (ICD-9-CM 435.x, 436.x, 437.x, 438.x). Data of continuous and categorical variables were analyzed by t-test and chi-square test/Fisher's exact test to make comparisons between preeclampsia/eclampsia cases and matched controls and to make comparisons between preeclampsia and eclampsia, as appropriate. *Cerebrovascular disease (stroke).....other (ICD-9 CM 435.x, 436.x, 437.x, 438.x). Table 2 Association of (pre-)eclampsia to diabetes, dyslipidemia, hypertension, congestive heart failure and cerebrovascular diseases. The date of delivery to the date of an event
Eclampsia cases
Preeclampsia
Age-Matched controls
Diabetes events, n(%) Incidence per 1000 person-years (95% CI) HR (95% CI), p-value Dyslipidemia, events, n(%) Incidence per 1000 person-years (95% CI) HR (95% CI), p-value Hypertension events, n(%) Incidence per 1000 person-years (95% CI) HR (95% CI), p-value Congestive heart failure, events, n(%) Incidence per 1000 person-years (95% CI) HR (95% CI), p-value Cerebrovascular disease, events, n(%) Incidence per 1000 person-years (95% CI) HR (95% CI), p-value Hemorrhagic Incidence per 1000 person-years (95% CI) HR (95% CI), p-value Cerebral infarction Incidence per 1000 person-years (95% CI) HR (95% CI), p-value
10 7.30 (6.92e7.69) 3.84(1.99e7.40), <0.0001 17 12.18 (11.55e12.83) 2.75(1.68e4.51), <0.0001 47 42.39 (39.97e44.96) 6.52(4.49e9.47), <0.0001 2 1.40 (1.32e1.47) 9.07(1.88e43.68), 0.0060 4 2.81 (2.67e2.96) 10.71(3.45e33.24), <0.0001 3 2.11 (2.00e2.21) 19.74 (4.71e82.68), <0.0001 1 0.70 (0.67e0.74) 7.84 (0.88e70.14), 0.0656
99 11.27 (11.04e11.51) 5.42(4.01e7.32), <0.0001 139 15.05 (14.75e15.36) 3.40(2.73e4.24), <0.0001 320 40.31 (39.43e41.20) 7.31(6.07e8.80), <0.0001 11 1.12 (1.10e1.14) 7.39(2.86e19.06), <0.0001 9 0.92 (0.90e0.94) 3.47(1.46e8.23), 0.0048 1 0.10 (0.10e0.10) 0.93 (0.11e7.97), 0.9472 4 0.41 (0.40e0.42) 4.76(1.19e19.03), 0.0274
107 2.45 1.00 200 4.44 1.00 208 4.62 1.00 7 0.15 1.00 12 0.26 1.00 5 0.11 1.00 4 0.09 1.00
(2.43e2.47)
(4.40e4.48)
(4.58e4.67)
(0.15e0.15)
(0.26e0.26)
(0.11e0.11)
(0.09e0.09)
Bold signifies findings that reach statistical significance. Hazard Ratios (HR) with 95% and their P values were calculated using a Cox proportional-hazards regression model.
than 9 years in eclamptic/preeclamptic patients developing subsequent cerebrovascular diseases (36.27, p ¼ 0.0016; 6.72, p ¼ 0.0092, respectively) and congestive heart failure (36.31, p ¼ 0.0016; 6.05, p ¼ 0.048, respectively). To pursue further the influences of preeclampsia/eclampsia and/or hypertension to cerebrovascular diseases and to congestive heart failure development, we divided the study population into E/H, Eþ/H, E/Hþ, Eþ/Hþ groups (E: preeclampsia/eclampsia,
H:hypertension). As shown in Table 4, significantly more patients with preeclampsia/eclampsia history acquired subsequent congestive heart failure, whether she had hypertension (adjusted RR 7.43, p ¼ 0.0005) or not (adjusted RR 6.52, p ¼ 0.0096). On the other hand, it was observed that more patients with hypertension history suffered from cerebrovascular diseases, whether she had preeclampsia/eclampsia (adjusted RR 8.76, p < 0.0001) or not (RR 4.80, p ¼ 0.0427; adjusted RR 2.87, p ¼ 0.1942).
Y.-L. Kuo et al. / Taiwanese Journal of Obstetrics & Gynecology 57 (2018) 364e369
Age-matched controls
Preeclampsia cases
367
Eclampsia cases
ProporƟon of Hypertension (%)
45.0 40.0
38.9
35.0 28.8
30.0 25.0 20.0
15.6 10.6
15.0 10.0
0.0 1
2
3
25.9 24.2
26.7
3.2
4.0
4.4
28.3
28.3 28.3
6.5
7.6
15.2
10.5
4
5
6
7
2.6
2.1
1.8
1.3
0.9
0.5
0.2
0.1
0.0
20.2 20.1
19.2 17.8
23.9 24.2
33.3
12.2
8.2 7.6
6.0 5.3
5.0
18.3
23.1 21.8
31.9 28.3
34.9
8
9
10
11
12
5.5 13
14
15
8.3
16
Years
Age-matched controls
ProporƟon of congesƟve heart failure (%)
B
Preeclampsia cases
Eclampsia cases
2.5 2.2
2.2
2.2
2.2
2.0 1.5
1.6
1.0 0.8 0.5 0.0
1.2
1.0
0.0 0
0.0
0.0 1
0.0
0.0 2
0.5
0.5
0.4
0.4
3
0.8
5
0.7
6
0.8
1.6
1.6
1.2
0.8
0.8
0.8
0.8
0.1
0.1
0.2
0.2
0.7 0.1
0.1
0.0
0.0 4
0.8 0.7
0.6
1.2
7
8
9
10
11
0.2 12
0.3
0.2
0.3
13
14
15
4.5
4.5
4.5
Years
C
Age-matched controls
Preeclampsia cases
Eclampsia cases
ProporƟon of cerebrovascular disease(%)
5.0 4.5 4.0
3.5 3.0
2.6
2.6
0.9
0.9
0.9
0.9
0.9
0.3
0.3
0.3
12
13
14
2.4
2.5 2.0 1.4
1.5 1.0 0.5
0.7
0.7
0.0
0.1 0.0
0.3 0.0
0
1
2
1.4
1.4
1.4
1.4
1.4
1.4
1.4
0.5 0.2
0.5 0.2
0.6
0.6
0.6
0.6
0.6
0.2
0.2
0.2
0.2
0.2
0.2
0.3
3
4
5
6
7
8
9
10
11
0.6
0.0 15
Years
Fig. 1. Cumulative incidences of (A) hypertension (B) congestive heart failure and (C) cerebrovascular disease for pregnant women patients with (pre-)eclampsia and the agematched pregnant women controls control cohorts.
368
Y.-L. Kuo et al. / Taiwanese Journal of Obstetrics & Gynecology 57 (2018) 364e369
Table 3 Odds ratios for associations of cerebrovascular disease and congestive heart failure with follow-up period <2 years and >9 years. <2 vs No eventa
Follow-up period, events No event Cerebrovascular disease Controls 5168 (99.77) Eclampsia/Preeclampsia cases 1282 (99.00) Congestive heart failure Controls 5173 (99.86) Eclampsia/Preeclampsia cases 1282 (99.00)
Pa
<2 years 2e9 years >9 years OR (95% CI)
2e9 vs No event
P
OR (95% CI)
>9 vs No event
P
OR (95% CI)
0 (0.00) 4 (0.31)
9 (0.17) 4 (0.31)
3 (0.06) 5 (0.39)
1.00 1.00 36.27 (1.95e674.10) 0.0016 1.79 (0.55e5.83)
1.00 0.3325 6.72 (1.60e28.15) 0.0092
0 (0.00) 4 (0.31)
5 (0.10) 6 (0.46)
2 (0.04) 3 (0.23)
1.00 1.00 36.31 (1.95e674.75) 0.0016 4.84 (1.48e15.89) 0.0093 6.05 (1.01e36.26) 0.0487
Odds ratios (OR) with 95% and their P values were calculated using a multinomial logistic regression model. Bold signifies findings that reach statistical significance. a These logit estimators use a correction of 0.5 in every cell of those tables that contain a zero; P value was analyzed by Fisher's exact test. Table 4 Preeclampsia/eclampsia associated with increased congestive heart failure and cerebrovascular disease occurrence.
Congestive heart failure disease Preeclampsia/Eclampsia cases e þ e þ Cerebrovascular disease Preeclampsia/Eclampsia cases e þ e þ
Event, n (%)
Total subjects
RR (95% CI)
P
Adjusted RR (95% CI)
P
Hypertension e e þ þ
5 8 2 5
(0.10) (0.86) (0.97) (1.38)
4973 932 207 363
1.00 8.54 (2.79e26.1) 9.61 (1.86e49.53) 13.7 (3.97e47.32)
0.0002 0.0068 <0.0001
1.00 7.43 (2.41e22.89) 5.73 (0.98e33.5) 6.52 (1.58e26.95)
0.0005 0.0528 0.0096
Hypertension e e þ þ
10 (0.20) 2 (0.21) 2 (0.97) 11 (3.03)
4973 932 207 363
1.00 1.07 (0.23e4.87) 4.80 (1.05e21.93) 15.07 (6.4e35.48)
0.9331 0.0427 <0.0001
1.00 1.02 (0.22e4.67) 2.87 (0.58e14.06) 8.76 (3.21e23.88)
0.9789 0.1942 <0.0001
Relative risk (RR) was calculated using a Cox proportional-hazards regression model. Adjusted RR was calculated after adjusted for age, diabetes and dyslipidemia using a Cox proportional-hazards regression model.
Discussion Decades of researches and efforts are devoted to learn about the pathophysiology, diagnosis and management of preeclampsia and eclampsia. They are such important issues in high-risk pregnancies in terms of their high prevalence with potentially disabling, if not deadly, complications that are potentially preventable and treatable. The impact of the disease is not limited to the gestation period or immediately postpartum, but remained as an important risk factor for numerous medical conditions in the long term. A number of case-controlled cohort studies asserted two to four fold risks of subsequent diabetes mellitus for those with hypertensive pregnancy disorder [11,12,17e22]. It has been postulated that women with preeclampsia have increased insulin resistance during pregnancy and the effect could persist after delivery. Therefore, these high-risk women are predisposed to the development of diabetes mellitus. Our findings were consistent with these previous studies that eclampsia and preeclampsia increased risks for subsequent diabetes mellitus by hazard ratio of 3.84 and 5.42 respectively. Similarly, previous studies have demonstrated a less favorable lipid profile in women with preeclampsia or eclampsia history [18,22,23]. Although normal pregnancy is characterized by elevated plasma triglyceride and cholesterol concentrations, women with preeclampsia or eclampsia experience more drastic changes in their lipid profile during their pregnancy. Magnussen et al. and Van Rijn et al. found these women tended to have higher levels of total cholesterol, low-density lipoprotein cholesterol and triglycerides [22,23]. Our findings were consistent with these previous studies that eclampsia and preeclampsia increased risks for subsequent dyslipidemia by hazard ratio of 2.75 and 3.40 respectively. Likewise, Bellamy et al. conducted a meta-analysis examining available prospective and retrospective cohort studies between 1996 and 2006 to find women with preeclampsia history had an increased risk of developing hypertension after an average follow up period of 14.1 years with a risk ratio of 3.70, 95% confidence interval 2.70e5.02
[7]. In this current study, we conducted similar analysis, except with an age-matched, population-based sample size and extended follow up period that lasted 15 years. More intriguing findings were disclosed in our KaplaneMeier curves that delineate the cumulative incidence rates of hypertension, congestive heart failure and cerebrovascular diseases over the period of 15 years. For hypertension, a steady increase with constant slope is observed, signaling a persistent risk for developing hypertension as long as 15 years after experiencing preeclampsia or eclampsia. This might be of clinical importance to the practitioners who should follow up preeclampsia/eclampsia patients’ blood pressure status for over a decade. As for congestive heart failure, a significantly increased risk with hazard ratios of 9.07, p ¼ 0.0060 and 7.39, p < 0.001 were noted for eclampsia and preeclampsia women, respectively. Its cumulative incidence rates in preeclampsia or eclampsia women have distinctively abrupt increases at time periods of less than 2 years and more than 9 years postpartum, signifying important timing of follow ups and patient education. The finding echoed the work done by Melchiorre et al. that asserted preeclampsia was associated with asymptomatic global left ventricular abnormal function, and that the impact of preeclampsia on cardiovascular function did not end with the birth of infant or placenta [24,25]. Likewise, significantly increased risks are observed in eclamptic/preeclamptic women to develop cerebrovascular diseases with hazard ratios of 10.71, P < 0.0001 and 3.47, p ¼ 0.0048, respectively, with a median follow-up period of 9.8 years. Time periods at less than 2 years and more than 9 years after delivery have noticeable increases of cumulative incidence rates for cerebrovascular diseases on the KaplaneMeier curves, similar to the pattern observed for congestive heart failure. Equally interesting is the finding that eclampsia is significantly associated with more hemorrhagic cerebrovascular events compared to those in controls and preeclampsia (2.11, 0.11 or 0.10 per 1000 person-years, HR 19.74, p < 0.0001 and 21.22, p ¼ 0.0082, respectively). Preeclampsia, on the other hand, is associated with significantly more
Y.-L. Kuo et al. / Taiwanese Journal of Obstetrics & Gynecology 57 (2018) 364e369
ischemic strokes (HR 4.76, p ¼ 0.0274). Whether or not these findings suggest fundamental differences in the pathophysiology of pre-eclampsia and eclampsia requires further investigations. To examine the roles played by hypertension and preeclampsia/ eclampsia in developing subsequent congestive heart failure and cerebrovascular diseases, we further divided our study subjects to E/H, Eþ/H, E/Hþ, Eþ/Hþ (E: eclampsia/preeclampsia, H: hypertension) groups. As shown in Table 4, preeclampsia and eclampsia might play a more important role than hypertension in leading to congestive heart failure, for both Eþ/H- and Eþ/Hþ groups have reached statistically significant relative risk of 7.43, p ¼ 0005 and 6.52, p ¼ 0.0096, respectively. On the contrary, patients with hypertension tend to have more sequent cerebrovascular diseases with relative risk of 8.76, p < 0.0001 in the Eþ/Hþ group, while those with only preeclampsia/eclampsia did not significantly increase the risk of cerebrovascular diseases (adjust RR 1.02, p ¼ 0.9789). These findings may again suggest preeclampsia and eclampsia as fundamentally different entities in terms of disease pathophysiology, of which further researches are needed. These findings may also have implications in explaining diseases’ prognosis and also in patient education. Several limitations were identified in our study. First, case number for cardiovascular diseases was limited. Despite that this was a population-based study and that the National Health Insurance covered more than 98% of the population, some cardiovascular disease cases could still be missed due to difficulties in case identifications. A larger number of cohorts are needed to signify meaningful associations. Secondly, some essential clinical parameters were not included in the NHIRD, such as body mass index and smoking. Thirdly, there were no data about the severity of the preeclampsia/eclampsia, prenatal care and whether these women received treatment during the follow up periods. Forth, diagnosis misclassification and under-reporting of diseases existed for ICD-9. This current study have found that women with history of preeclampsia/eclampsia were at increased risks for subsequent diagnosis of diabetes mellitus, dyslipidemia, hypertension, congestive heart failure and cerebrovascular diseases. Although the underlying explanations for the relationship among preeclampsia/ eclampsia, congestive heart failure and cerebrovascular diseases were mostly just hypotheses, our findings raise the awareness of these associations. Thus, more care and patient education in terms of disease prospective, natural course and prognosis could be informed of the patients. Preventive counseling, more vigilant screening and management for the modifiable risks should be provided to the affected women. Clinicians should closely monitor these patients in the first three years postpartum and continuously for up to at least a decade. Conflict of interest The authors declare no conflict of interest. References [1] Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol 2009;33(3):130e7.
369
[2] Chen CW, Jaffe IZ, Karumanchi SA. Pre-eclampsia and cardiovascular disease. Cardiovasc Res 2014;101(4):579e86. [3] Maynard SE. Preeclampsia and subsequent cardiovascular disease: villain or innocent bystander? Clin J Am Soc Nephrol 2013;8(7):1061e3. [4] Seely EW, Tsigas E, Rich-Edwards JW. Preeclampsia and future cardiovascular disease in women: how good are the data and how can we manage our patients? Semin Perinatol 2015;39(4):276e83. [5] Ahmed R, Dunford J, Mehran R, Robson S, Kunadian V. Pre-eclampsia and future cardiovascular risk among women: a review. J Am Coll Cardiol 2014;63(18):1815e22. [6] Lee G, Tubby J. Preeclampsia and the risk of cardiovascular disease later in lifeeA review of the evidence. Midwifery 2015;31(12):1127e34. [7] Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and metaanalysis. BMJ 2007;335(7627):974. [8] McDonald SD, Malinowski A, Zhou Q, Yusuf S, Devereaux PJ. Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses. Am Heart J 2008;156(5):918e30. [9] Yeh JS, Cheng HM, Hsu PF, Sung SH, Liu WL, Fang HL, et al. Synergistic effect of gestational hypertension and postpartum incident hypertension on cardiovascular health: a nationwide population study. J Am Heart Assoc 2014;3(6): e001008. [10] Garovic VD, Bailey KR, Boerwinkle E, Hunt SC, Weder AB, Curb D, et al. Hypertension in pregnancy as a risk factor for cardiovascular disease later in life. J Hypertens 2010;28(4):826e33. [11] Lykke JA, Langhoff-Roos J, Sibai BM, Funai EF, Triche EW, Paidas MJ. Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and type 2 diabetes mellitus in the mother. Hypertension 2009;53(6):944e51. [12] Mannisto T, Mendola P, Vaarasmaki M, Jarvelin MR, Hartikainen AL, Pouta A, et al. Elevated blood pressure in pregnancy and subsequent chronic disease risk. Circulation 2013;127(6):681e90. [13] Lin YS, Tang CH, Yang CY, Wu LS, Hung ST, Hwa HL, et al. Effect of preeclampsia-eclampsia on major cardiovascular events among peripartum women in Taiwan. Am J Cardiol 2011;107(2):325e30. [14] Savitz DA, Danilack VA, Elston B, Lipkind HS. Pregnancy-induced hypertension and diabetes and the risk of cardiovascular disease, stroke, and diabetes hospitalization in the year following delivery. Am J Epidemiol 2014;180(1): 41e4. [15] Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA. Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet 2005;366(9499):1797e803. [16] Kestenbaum B, Seliger SL, Easterling TR, Gillen DL, Critchlow CW, StehmanBreen CO, et al. Cardiovascular and thromboembolic events following hypertensive pregnancy. Am J Kidney Dis e Offi J Natl Kidney Found 2003;42(5): 982e9. [17] Feig DS, Shah BR, Lipscombe LL, Wu CF, Ray JG, Lowe J, et al. Preeclampsia as a risk factor for diabetes: a population-based cohort study. PLoS Med 2013;10(4):e1001425. [18] Hashemi S, Ramezani Tehrani F, Mehrabi Y, Azizi F. Hypertensive pregnancy disorders as a risk factor for future cardiovascular and metabolic disorders (Tehran Lipid and Glucose Study). J Obstet Gynaecol Res 2013;39(5):891e7. [19] Wang IK, Tsai IJ, Chen PC, Liang CC, Chou CY, Chang CT, et al. Hypertensive disorders in pregnancy and subsequent diabetes mellitus: a retrospective cohort study. Am J Med 2012;125(3):251e7. [20] Callaway LK, Lawlor DA, O'Callaghan M, Williams GM, Najman JM, McIntyre HD. Diabetes mellitus in the 21 years after a pregnancy that was complicated by hypertension: findings from a prospective cohort study. Am J Obstet Gynecol 2007;197(5):492 e1e7. [21] Carr DB, Newton KM, Utzschneider KM, Tong J, Gerchman F, Kahn SE, et al. Preeclampsia and risk of developing subsequent diabetes. Hypertens Pregnancy 2009;28(4):435e47. [22] Magnussen EB, Vatten LJ, Smith GD, Romundstad PR. Hypertensive disorders in pregnancy and subsequently measured cardiovascular risk factors. Obstet Gynecol 2009;114(5):961e70. [23] van Rijn BB, Nijdam ME, Bruinse HW, Roest M, Uiterwaal CS, Grobbee DE, et al. Cardiovascular disease risk factors in women with a history of early-onset preeclampsia. Obstet Gynecol 2013;121(5):1040e8. [24] Melchiorre K, Sutherland GR, Liberati M, Thilaganathan B. Preeclampsia is associated with persistent postpartum cardiovascular impairment. Hypertension 2011;58(4):709e15. [25] Melchiorre K, Thilaganathan B. Maternal cardiac function in preeclampsia. Curr Opin Obstet Gynecol 2011;23(6):440e7.