Long-term risk of diabetes following hypertensive disorders of pregnancy: A retrospective cohort study

Abstract

BACKGROUND

The impact of varying degrees of pregnancy-induced hypertension (PIH) on the risk of developing diabetes later in life is currently unknown.

AIM

To assess the long-term risks of type 2 diabetes mellitus (T2DM), prediabetes, and mortality that are associated with hypertensive disorders of pregnancy.

METHODS

This retrospective cohort study used the TriNetX United States Collaborative Network to examine outcomes, especially T2DM, prediabetes and mortality, related to hypertensive disorders of pregnancy in females aged 21-45. Participants had no history of hypertension or diabetes before pregnancy or before 20 weeks of gestation. Propensity score matching was applied to balance covariates such as gestational diabetes, polycystic ovarian syndrome, chronic kidney disease, hyperlipidemia, overweight/obesity, nicotine dependence, alcohol abuse, and healthcare utilization. This ensured comparability between groups and reduced potential confounding in outcome evaluation.

RESULTS

This study included 318544 females aged 21-45 with and without PIH. Females with PIH had higher risks of T2DM [hazard ratio (HR): 1.907, 95% confidence interval (CI): 1.821-1.998), prediabetes (HR: 1.610, 95%CI: 1.537-1.687), and mortality (HR: 1.501, 95%CI: 1.361-1.655) over a follow-up of up to 18 years. Incidence rates for T2DM, prediabetes, and mortality were 3.2%, 2.7%, and 0.6%, respectively. Subgroup analyses showed that the presence of gestational hypertension, preeclampsia, and eclampsia increased risks across all outcomes. Persistent hypertension beyond 12 weeks postpartum was linked to more than a 3-fold increase in mortality. Preventative aspirin use during pregnancy did not reduce the risks of T2DM, prediabetes, or mortality among those with PIH.

CONCLUSION

PIH significantly increases the long-term risks of T2DM, prediabetes, and mortality, highlighting the urgent need for improved long-term management strategies to enhance overall health in such individuals.

Key Words: Hypertensive disorders of pregnancy; Gestational hypertension; Preeclampsia; Eclampsia; Type 2 diabetes mellitus; Prediabetes; Mortality

Core Tip: This study highlighted the increased risks of type 2 diabetes mellitus (T2DM), prediabetes, and mortality in females with a history of pregnancy-induced hypertension (PIH). These risks were further amplified in cases of persistent postpartum hypertension. Gestational hypertension, preeclampsia, and eclampsia were associated with elevated risks, particularly for mortality and T2DM. Preventative aspirin use during pregnancy did not appear to mitigate these long-term risks. Our findings underscored the importance of enhanced monitoring and preventive strategies for females who experienced PIH and especially in those who had persistent hypertension during the postpartum period.

INTRODUCTION

Hypertensive disorders of pregnancy impact 10% of pregnancies globally and include chronic hypertension, gestational hypertension, preeclampsia/eclampsia, and chronic hypertension with superimposed preeclampsia[1]. Gestational hypertension and preeclampsia/eclampsia often develop after 20 weeks of gestation[1]. Preeclampsia, in addition to hypertension, is also accompanied by signs of maternal organ or uteroplacental dysfunction or proteinuria. It is a significant contributor to maternal morbidity and is linked to several adverse fetal outcomes including intrauterine growth restriction, preterm birth, placental abruption, fetal distress, and fetal death in utero[1].

Females with preeclampsia often experience insulin resistance during pregnancy that is independent of obesity and glucose intolerance[2]. Research suggests that insulin resistance may precede the onset of preeclampsia, indicating that it may contribute to preeclampsia development[2,3]. Therefore, the presence of insulin resistance with preeclampsia may serve as a marker for future diabetes risk, even in the absence of gestational diabetes mellitus.

Previous research have suggested that females with a history of preeclampsia or eclampsia are at an increased risk of developing type 2 diabetes[1,4-6]. A population-based cohort study found that the incidence rate of diabetes is higher in females with preeclampsia than in those with gestational hypertension[4]. However, the risk of developing diabetes later in life in females who experienced pregnancy-induced hypertension (PIH), including gestational hypertension, preeclampsia, preeclampsia with severe features, eclampsia, and preeclampsia with persistent hypertension lasting more than 12 weeks, has not been determined.

The present study addressed this research gap by conducting a retrospective analysis using extensive data from the TriNetX database. We specifically focused on examining patients who developed hypertensive disorders after 20 weeks of gestation and their association with the subsequent development of type 2 diabetes mellitus (T2DM) over a follow-up period of up to 18 years.

MATERIALS AND METHODS

Data source

We performed a retrospective analysis using data from the United States Collaborative Network, which includes information from 80 healthcare organizations within the TriNetX Research Network. TriNetX primarily collects data from structured electronic health record systems and encompasses demographics, diagnoses, procedures, and medications and employs natural language processing to extract information from clinical documents. The TriNetX database consists of de-identified electronic health records that undergo extensive preprocessing to address missing values. The platform has standardized data across healthcare organizations, ensuring consistency and allowing uniform querying. Additionally, natural language processing is used to extract relevant clinical information from unstructured records.

While TriNetX applies data harmonization techniques to improve data completeness, missing data were managed through the inherent standardization process of the platform. This ensures a robust and comprehensive dataset for analysis[7]. The utilization of TriNetX data in scholarly research has demonstrated consistent growth since 2015. Between 2018 and 2021, the annual publication output more than doubled, culminating in 248 peer-reviewed publications and abstracts by 2022. This sustained expansion as well as the established role of the network in facilitating clinical trial partnerships and supporting published research underscore its viability as a robust, secure, and sustainable framework for maintaining research-oriented data networks across academic and industry sectors[7].

Ethics statement

Ethical considerations were thoroughly addressed including obtaining an informed consent waiver due to the anonymous nature of the data. The study complied with regulatory guidelines such as the Health Insurance Portability and Accountability Act and the General Data Protection Regulation. Approval was granted by the Institutional Review Board of Taichung Veterans General Hospital (CE24431B).

Cohort description

The study utilized data from the TriNetX database from January 1, 2006 to December 31, 2020. Two cohorts were established: The PIH cohort that included females aged 21-45 years with PIH (defined as gestational hypertension, preeclampsia with or without severe features, and eclampsia) and no history of hypertension or diabetes before pregnancy or before 20 weeks of gestation; and the non-PIH cohort that consisted of females aged 21-45 who delivered without complications and had no prior hypertension or diabetes.

The age range of 21-45 was selected to focus on individuals in their reproductive years while minimizing confounding factors associated with younger or older age groups. Females younger than 21 were excluded due to potential differences in risk profiles and healthcare access in adolescent pregnancies. Females older than 45 were excluded to reduce the influence of perimenopausal changes and age-related comorbidities, which could confound associations between PIH and long-term metabolic risks.

Blood pressure records in the database are based on the measurements taken during patient medical visits. Propensity score matching (PSM) was used to balance covariates such as gestational diabetes mellitus, polycystic ovarian syndrome, chronic kidney disease, hyperlipidemia, overweight/obesity, nicotine dependence, alcohol abuse, and healthcare utilization. The risk of T2DM, prediabetes, and mortality was evaluated for an 18-year follow-up period. Figure 1 illustrates the study flowchart. Supplementary Table 1 lists the diseases discussed in this article along with their corresponding codes.

Figure 1 Study flowchart. DM: Diabetes mellitus.

Statistical analysis

In this investigation, we utilized PSM through the integrated TriNetX tool to establish 1: 1 matched groups characterized by similar baseline traits. PSM was applied selectively to covariates without missing values, and distinct matching procedures were employed for subsequent stratified analyses involving a constrained set of covariates. The PSM process seamlessly integrated with the TriNetX system and employed a greedy nearest neighbor algorithm with a 0.1 caliper of pooled standard deviations. The assessment of balance relied on the standardized mean difference and utilized proprietary technology safeguarded by trade secrets.

For time-to-event outcomes, Cox proportional hazards regression models were employed to estimate hazard ratios (HR) and 95% confidence intervals (CI). These models were used to assess the association between PIH and the risk of developing T2DM, prediabetes, and mortality over the follow-up period. Subsequent to PSM HR were computed using χ² tests for measures of association. Cumulative probability was evaluated through Kaplan-Meier curves, incorporating log-rank tests and HR for cohort comparisons. A two-sided P value < 0.05 was considered statistically significant. All statistical analyses were executed on the TriNetX online platform.

RESULTS

The initial dataset included 662464 patients, with 159301 in the PIH cohort and 503163 in the non-PIH cohort. After applying PSM, each cohort was balanced to include 159272 patients. The average age at index was 27.5 years, with the cohort comprising 57.2% White, 18.5% Black or African American, and 2.6% Asian individuals (Table 1).

Table 1 Baseline characteristics of study population, n (%).

	Before PSM				After PSM
	Pregnancy-induced hypertension (n = 159301)	Non-pregnancy hypertension (n = 503163)	SMD	P value	Pregnancy-induced hypertension (n = 159272)	Non-pregnancy hypertension (n = 159272)	SMD	P value
Age at index (mean ± SD)	27.7 ± 5.6	26.9 ± 5.5	0.147	< 0.001	27.7 ± 5.6	27.7 ± 5.6	0.001	0.898
Race
White	91079 (57.2)	261926 (52.1)	0.103	< 0.001	91061 (57.2)	91025 (57.2)	0.001	0.897
Black or African American	29538 (18.5)	74161 (14.7)	0.102	< 0.001	29527 (18.5)	29673 (18.6)	0.002	0.506
Asian	4128 (2.6)	20490 (4.1)	0.083	< 0.001	4128 (2.6)	4112 (2.6)	0.003	0.858
Lifestyle
Personal history of nicotine dependence	5366 (3.4)	11826 (2.4)	0.061	< 0.001	5361 (3.4)	5344 (3.4)	0.001	0.867
Alcohol abuse	94 (0.1)	259 (0.1)	0.003	0.256	94 (0.1)	72 (0.1)	0.006	0.088
Persons encountering health services for examinations	64133 (40.3)	199470 (39.6)	0.013	< 0.001	64120 (40.3)	64196 (40.3)	0.001	0.784
Comorbidities
Gestational Diabetes mellitus	12509 (7.9)	25732 (5.1)	0.111	< 0.001	12486 (7.8)	12450 (7.8)	0.001	0.812
Polycystic ovarian syndrome	3870 (2.4)	6079 (1.2)	0.091	< 0.001	3845 (2.4)	3796 (2.4)	0.002	0.57
Chronic kidney disease	298 (0.2)	460 (0.1)	0.026	< 0.001	295 (0.2)	276 (0.2)	0.003	0.426
Hyperlipidemia	1368 (0.9)	3777 (0.5)	0.048	< 0.001	1362 (0.9)	1314 (0.8)	0.003	0.351
Overweight and obesity	26168 (16.4)	44970 (8.9)	0.226	< 0.001	26139 (16.4)	26169 (16.4)	0.001	0.886

SMD: Standardized mean difference.

Risk of T2DM, prediabetes, and mortality

We observed a maximum follow-up of 18 years and an average follow-up of 8.3 years. Our analysis revealed that individuals with PIH had a significantly elevated risk of T2DM compared to those without PIH. The HR was 1.907 (95%CI: 1.821-1.998), indicating almost a 2-fold increase in risk (Figure 2). The risk of prediabetes (HR: 1.601, 95%CI: 1.537-1.687) and overall mortality (HR: 1.501, 95%CI: 1.361-1.655) was also significantly higher. The incidence rates of T2DM, prediabetes, and mortality among individuals with a history of PIH were 3.2%, 2.7%, and 0.6%, respectively (Table 2).

Figure 2 Kaplan-Meier curves of cumulative probability (%) of diabetes, comparing pregnancy-induced hypertension cohort and non-pregnancy-induced hypertension cohort.

Table 2 Hazard ratio and 95% confidence intervals for the risk of diabetes, prediabetes and deceased according to the status of pregnancy-induced hypertension.

	DM	Pre DM	Deceased
Pregnancy-induced hypertension status (n = 159272)1
Yes	5050 (3.2%)	4457 (2.7%)	981 (0.6%)
No	2797 (1.8%)	2932 (1.8%)	681 (0.4%)
HR (95%CI)	1.907 (1.821, 1.998)	1.610 (1.537, 1.687)	1.501 (1.361, 1.655)

¹Pregnancy-induced hypertension includes gestational hypertension, preeclampsia with or without severe features, eclampsia group.

DM: Diabetes mellitus; Pre DM: Prediabetes; HR: Hazard ratio; CI: Confidence interval.

Subgroup analysis of gestational hypertension

Subgroup analyses comparing the gestational hypertension cohort with the non-PIH cohort revealed that gestational hypertension was associated with a significantly increased risk of developing T2DM (HR: 1.936, 95%CI: 1.844-2.033), prediabetes (HR: 1.658, 95%CI: 1.579-1.742), and mortality (HR: 1.315, 95%CI: 1.185-1.459) (Table 3).

Table 3 Hazard ratio and 95% confidence intervals for the risk of diabetes, prediabetes and deceased according to the status of gestational hypertension, preeclampsia with or without severe features, eclampsia.

	DM	Pre DM	Deceased
Gestational hypertension status (n = 145012)
Yes	4539	4001	797
No	2527	2624	647
HR (95%CI)	1.936 (1.844, 0.033)	1.658 (1.579, 1.742)	1.315 (1.185, 1.459)
Preeclampsia without severe features (n = 11660)
Yes	540	405	123
No	226	228	47
HR (95%CI)	1.971 (1.687, 2.303)	1.429 (1.214, 1.681)	2.133 (1.523, 2.988)
Preeclampsia with severe features (n = 12546)
Yes	483	419	98
No	258	281	44
HR (95%CI)	1.837 (1.579, 2.137)	1.465 (1.260, 1.705)	2.160 (1.513, 3.083)
Eclampsia (n = 6628)
Yes	258	199	87
No	137	154	26
HR (95%CI)	1.772 (1.440, 2.180)	1.181 (0.957, 1.458)	3.118 (2.011, 4.834)

DM: Diabetes mellitus; Pre DM: Prediabetes; HR: Hazard ratio; CI: Confidence interval.

Impact of preeclampsia and eclampsia

All forms of preeclampsia, including that without severe features, with severe features, or eclampsia, were linked to higher risks of T2DM, prediabetes, and mortality. The only exception was eclampsia, which did not show a statistically significant increased risk for prediabetes (HR: 1.181; 95%CI: 0.957-1.458) (Table 3).

Persistent postpartum hypertension and long-term risks

We also explored a cohort of patients with PIH during pregnancy that persisted for up to 12 weeks postpartum. This group was defined as having chronic hypertension[8]. These individuals had a significantly increased likelihood of developing T2DM (HR: 2.543, 95%CI: 2.144-3.016) and prediabetes (HR: 2.073, 95%CI: 1.756-2.448) compared with those in the non-PIH cohort. Additionally, these patients had more than a 3-fold increased risk of mortality with HR of 3.143 (95%CI: 1.983-4.982) (Table 4).

Table 4 Hazard ratio and 95% confidence intervals for the risk of diabetes, prediabetes and deceased according to the status of pregnancy hypertension status with postpartum hypertension > 12 weeks or with aspirin prevention.

	DM	Pre DM	Deceased
Pregnancy hypertension status with postpartum hypertension > 12 weeks (n = 5910)
Yes	457	419	74
No	186	209	24
HR (95%CI)	2.543 (2.144, 3.016)	2.073 (1.756, 2.448)	3.143 (1.983, 4.982)
Pregnancy hypertension status with aspirin prevention (n = 4374)
Yes	170	195	21
No	126	145	14
HR (95%CI)	1.736 (1.369, 2.201)	1.783 (1.429, 2.225)	2.133 (1.056, 4.311)

DM: Diabetes mellitus; Pre DM: Prediabetes; HR: Hazard ratio; CI: Confidence interval.

Preventative aspirin use and risk for PIH

Our study found that the risks of T2DM, prediabetes, and overall mortality remained high even with preventative aspirin use. Among patients with PIH who used aspirin (50-150 mg) during pregnancy, the risk of developing T2DM (HR: 1.736, 95%CI: 1.369-2.201), prediabetes (HR: 1.783, 95%CI: 1.429-2.225), and overall mortality (HR: 2.133, 95%CI: 1.056-4.311) was increased (Table 4).

Additionally, we examined the impact of preventative aspirin use on these risks among patients with PIH. The results showed no significant differences in the risk of T2DM (HR: 1.075, 95%CI: 0.844-1.369) or mortality (HR: 0.950, 95%CI: 0.479-1.884) between those who used aspirin and those who did not. However, aspirin use was associated with an increased risk of developing prediabetes (HR: 1.344, 95%CI: 1.106-1.634).

When stratified by the PIH subtypes, gestational hypertension, preeclampsia (with or without severe features), and eclampsia, aspirin use did not reduce the risk of T2DM or mortality. However, an increased risk of prediabetes was observed in patients with gestational hypertension who used aspirin (HR: 1.599) and in patients with eclampsia who used aspirin (HR: 3.820) (Supplementary Table 2).

DISCUSSION

Our study, with a follow-up period of up to 18 years, highlighted the significant long-term health risks associated with PIH. Individuals with a history of PIH were at a significantly higher risk of T2DM (HR: 1.907), prediabetes (HR: 1.610), and mortality (HR: 1.501) compared with those without PIH. Subgroup analyses further revealed that gestational hypertension was linked to increased risks of T2DM, prediabetes, and mortality. Preeclampsia in various forms also elevated these risks, although eclampsia did not appear to significantly impact the risk of prediabetes. Specifically, individuals with chronic postpartum hypertension had even greater risks, including a more than 3-fold increase in mortality (HR: 3.143) and significantly higher likelihood of developing T2DM (HR: 2.543) and prediabetes (HR: 2.073). Notably, preventative aspirin use during pregnancy did not decrease the risk of T2DM, prediabetes, and mortality in patients with PIH compared with patients without PIH.

Gestational hypertension and preeclampsia are significant contributors to maternal, fetal, and neonatal mortality and morbidity[9]. Preeclampsia primarily results from abnormal placentation and is marked by defective cytotrophoblast invasion of spiral arteries and an impaired differentiation process[10]. This dysfunction disrupts the nitric oxide pathway, leading to increased uterine arterial resistance and chronic placental ischemia[10]. Concurrently, oxidative stress releases harmful substances into the maternal circulation, resulting in endothelial dysfunction, vascular hyperpermeability, and hypertension[11]. Insulin resistance is also hypothesized to play a role in the pathophysiology of preeclampsia. Those who develop preeclampsia exhibit higher levels of insulin resistance prior to pregnancy, during the first and second trimesters, and even years after pregnancy than patients who do not experience preeclampsia. This association is linked to the many overlapping risk factors for preeclampsia and insulin resistance, such as obesity, advanced maternal age, non-White race, chronic hypertension, diabetes, and gestational diabetes[12].

A cohort study in Scotland found that 10.4% of mothers who had preeclampsia subsequently developed T2DM. Logistic regression analysis revealed an adjusted odds ratio of 1.40 (95%CI: 1.12-1.75) for future T2DM in the cohort[5]. Similarly, a retrospective cohort study in Canada reported that females who experienced preeclampsia during pregnancy had twice the risk of developing diabetes in the 16.5 years following delivery compared with females without preeclampsia, with an HR of 2.08 (95%CI: 1.97-2.19)[4]. However, not all studies have found a consistent link between preeclampsia and an increased risk of diabetes. For instance, a cohort study in Finland compared females with preeclampsia or eclampsia to normotensive females. They reported an HR of 1.42 (95%CI: 0.92-2.19) for developing T2DM over a 40-year follow-up period, indicating no statistically significant difference in risk between the two groups[6]. In our study, we found that females who experienced PIH had a nearly 2-fold increased risk of developing T2DM, which aligns with the findings of the aforementioned Canadian retrospective study.

Although varying degrees of PIH may impact the risk of developing diabetes later in life, there is currently no comprehensive research addressing this issue. A previous study from Finland found that gestational hypertension significantly increased the risk of T2DM, with an HR of 1.52 (95%CI: 1.21-1.89). In contrast, the HR for preeclampsia/eclampsia did not show a statistically significant difference, a finding that may seem counterintuitive[6]. Another cohort study reported that both gestational hypertension and preeclampsia approximately doubled the risk of developing T2DM. The HR for gestational hypertension was 1.95 (95%CI: 1.83-2.07), while the HR for preeclampsia/eclampsia was 2.08 (95%CI: 1.97-2.19)[4].

Our findings indicated that the risk of developing T2DM or prediabetes was consistently elevated across different levels of PIH, including gestational hypertension, preeclampsia with or without severe features, and eclampsia. However, an exception was observed in eclampsia, which did not significantly increase the risk of prediabetes (HR: 1.181, 95%CI: 0.957-1.458). This seemingly contradictory result may be explained by several factors. Females with a history of eclampsia may bypass the intermediate stage of prediabetes and progress more rapidly to T2DM. Additionally, the database may not accurately capture prediabetes diagnoses because prediabetes is often undiagnosed or not formally coded for management, leading to potential underrepresentation in the data. In contrast, T2DM is more likely to be formally recorded once diagnosed. Furthermore, the HR for prediabetes suggests that there may be a trend toward increased risk, but the study may not have had sufficient power to detect a significant association. Future research should incorporate more detailed metabolic analyses and long-term follow-up to further explore the underlying mechanisms.

Most females who experience PIH will see their blood pressure return to normal within 12 weeks postpartum[13]. The American College of Obstetricians and Gynecologists recommends that all females affected by PIH have an initial contact with an obstetric care provider within 3 weeks postpartum, followed by a comprehensive postpartum visit by 12 weeks postpartum[14]. This is to ensure that the patient’s blood pressure has returned to normal and to recommend further treatment if needed. No previous study has focused on the risk of T2DM in females with preeclampsia and persistent postpartum hypertension beyond 12 weeks. Our findings indicate that if a patient experiences PIH and hypertension beyond 12 weeks postpartum, her risk of developing T2DM is 2.5 times higher compared with females without PIH. This risk is significantly higher than the 1.9-fold increase associated with PIH alone.

A meta-analysis suggested that aspirin is highly effective in preventing preterm preeclampsia when administered to high-risk females and started before 16 weeks of gestation, reducing its incidence by more than 60%[15]. The American College of Obstetricians and Gynecologists also recommends aspirin prophylaxis for females at high risk of preeclampsia to prevent the condition[16]. However, the current literature has not explored the impact of aspirin use in patients who develop preeclampsia on the subsequent risk of T2DM. One double-blind, placebo-controlled trial found that daily oral low-dose aspirin can reduce the incidence of T2DM, but this study focused on individuals who were at least 65 years of age and free of cardiovascular disease, physical disabilities, or dementia[17]. Our findings suggest that aspirin use during pregnancy does not reduce the risk of T2DM or mortality in patients with PIH. Surprisingly, it may even be associated with an increased risk of developing prediabetes, particularly among those with gestational hypertension and eclampsia. These results highlighted the need for further research to assess the long-term metabolic impacts of aspirin use in PIH patients.

While the previously discussed studies focused solely on the risk of T2DM, they did not specifically analyze the risks of prediabetes or mortality. Our findings indicated that both prediabetes and mortality risks are almost universally increased. Specifically, different degrees of PIH appear to have a similar impact on the risk of prediabetes. However, the risk of mortality is notably higher with more severe forms of PIH. The increased mortality risk associated with severe PIH may be influenced by several factors. For instance, preeclampsia is known to significantly increase the risk of cardiovascular disease death, with a 2-fold increase noted within 1-10 years postpartum according to one meta-analysis[18]. T2DM and cardiovascular disease share many common risk factors, such as hypertension, obesity, and dyslipidemia. Therefore, the interrelationships between preeclampsia, T2DM, and mortality are complex and likely interconnected, with each condition potentially exacerbating the risks associated with the others.

While our study was robust, certain limitations should be acknowledged. The absence of specific coding in the dataset restricted detailed reporting of key metrics, including the gestational age at preeclampsia diagnosis, week of delivery, time to blood pressure normalization postpartum, and aspirin dose, duration, and adherence. Additionally, unmeasured confounders such as socioeconomic status, lifestyle behaviors, and medication adherence may have influenced the observed associations. Future research should investigate the mechanisms linking preeclampsia to diabetes risk and explore potential confounding factors.

CONCLUSION

Our retrospective cohort study using the TriNetX database provided robust evidence of an increased long-term risk of T2DM in patients who developed hypertension after 20 weeks of gestation. The severity of preeclampsia appeared to have a similar impact on diabetes risk. PIH with chronic postpartum hypertension lasting more than 12 weeks further amplified these risks. Additionally, preventative aspirin use during pregnancy did not mitigate the risks of T2DM, prediabetes, nor mortality in patients with preeclampsia.