Maternal hypertensive disorders during pregnancy and the risk of offspring diabetes mellitus in childhood, adolescence, and early adulthood: a nationwide population-based cohort study

Maternal hypertensive disorders during pregnancy (HDP), including chronic hypertension, gestational hypertension, and preeclampsia, are common complications during pregnancy [1]. HDP affects approximately 10% of pregnancies [2, 3] and remains one of the most critical issues in public health and perinatal medicine. Given the serious epidemic situation of HDP, it is urgent to determine any short- and long-term adverse effects of maternal HDP on the health of the offspring.

Substantial evidence has reported that women with HDP were at an increased long-term risk of cardiovascular disease, diabetes mellitus, and premature mortality [4‐6]. Exposure to maternal HDP abnormal in utero environment may negatively impact the fetal functional expression of the hormonal axis and metabolites, increasing the risk of childhood obesity, endocrine disorders, and glucose metabolism abnormity, in offspring [7‐9]. Although the association between specific maternal HDP and the development of diabetes in offspring has been reported [8, 10‐14], most of the study has stemmed from case-control [12‐14] or retrospective cohort studies [8], except for two prospective cohort with a relative small number of events (n<400) [10, 11]. Comprehensive studies assessing the effects of overall maternal HDP and its different subtypes on offspring diabetes within the same study population are still lacking. Regarding type-specific offspring diabetes, current evidence mainly focuses on type 2 diabetes [8, 10, 11]. Research on type 1 diabetes is limited to preeclampsia only [12‐14]. Furthermore, evidence on the association of maternal HDP with offspring gestational diabetes remains scarce.

Our study aimed to comprehensively assess the effects of maternal overall HDP and its different subtypes (chronic hypertension, gestational hypertension, and preeclampsia) on diabetes mellitus and diabetes subtypes (including type 1, type 2, and gestational diabetes) in offspring from birth to young adulthood (age of up to 41 years) based on the Danish nationwide population-based cohort study. We further evaluated the combined effect of maternal HDP and maternal history of diabetes on the onset of offspring diabetes.

Among all 2,448,753 individuals born during 1978 to 2018, 102,698 (4.19%) were exposed to mothers with HDP (chronic hypertension: 0.63%, gestational hypertension: 0.76%, and preeclampsia: 2.81%, respectively). A total of 90,165 offspring (3.68%) were censored through follow-up, of which 66,818 (2.73%) were owing to emigration and 23,347 (0.95%) were owing to non-diabetes deaths. Compared with mothers without HDP, those with HDP were more likely to be older, primiparous, and overweight or obese, to smoke less during pregnancy, and to have a history of diabetes, and no singleton birth. Offspring exposed to maternal HDP tended to have a higher proportion of paternal history of diabetes and hypertension (Table 1).

During the follow-up period of up to 41 years (median: 19.3 years, IQR: 9.6 to 28.5 years), 1247 offspring born to mothers with HDP and 23,645 offspring born to mothers without HDP were diagnosed with diabetes. Adjusted cumulative incidence of offspring diabetes among offspring born to mothers with or without HDP at 40 years of age were 4.59% (4.25 to 4.95%) and 3.62% (3.55 to 3.69%), respectively (Fig. 1). Compared with offspring unexposed to maternal HDP, those exposed to maternal HDP had a 27% higher risk of developing diabetes in their first 41 years of life (HR=1.27, 95%CI=1.20–1.34). We observed increased risks of type 2 diabetes (HR=1.57, 95%CI=1.38–1.78) and gestational diabetes (HR=1.37, 95%CI=1.25–1.49) for offspring exposed to maternal HDP, while there was no obvious increased risk for type 1 diabetes (HR=1.08, 95%CI=0.98–1.18). The risk of type 2 diabetes was higher among offspring exposed to gestational hypertension (HR=1.37, 95%CI=1.00–1.88) and preeclampsia (HR=1.62, 95%CI=1.41–1.87), particularly for severe preeclampsia (HR=2.00, 95%CI=1.42–2.82). We only found offspring born to mothers with gestational hypertension had a higher risk of type 1 diabetes (HR=1.41, 95%CI=1.17–1.71), compared with mothers without maternal HDP. In addition, the risks for gestational diabetes were also increased among offspring exposed to any type-specific HDP, with higher HRs seen in chronic hypertension (HR=1.60, 95%CI=1.06–2.41), gestational hypertension (HR=1.29, 95%CI=1.04–1.59), and preeclampsia (HR=1.38, 95%CI=1.24–1.53), respectively (Table 2). Besides, an increased risk of developing diabetes was seen in offspring born to mothers who had HDP and comorbid diabetes (HR=4.64, 95%CI=3.85–5.60), compared with those born to mothers with either only, or with neither HDP nor diabetes history (Table 3).

An increased risk of type 2 diabetes was observed for offspring exposed to maternal HDP in early adolescence (10 to 14 years: HR=1.74, 95%CI=1.02–2.97), late adolescence (15–19 years: HR=1.48, 95%CI=1.08–2.02), and early adulthood (20–24 years: HR=1.51, 95%CI=1.11–2.04, 25 to 41 years: HR=1.65, 95%CI=1.38–1.96) (Fig. 2). We also observed an increased risk of gestational diabetes for offspring exposed to maternal HDP and the association was attenuated (but still significant) with the increased age (15–19 years: HR=2.06, 95%CI=1.13–3.75; 20–24 years: HR=1.84, 95%CI=1.51–2.25; and 25 to 41 years: HR=1.26, 95%CI=1.13–1.39) (Fig. 2). In terms of diagnostic time of maternal HDP, compared with mothers without HDP, an increased risk was found only when maternal HDP was diagnosed before birth (HR=1.21, 95%CI=1.14–1.28) (Fig. 3).

Subgroup analyses showed that the positive association between maternal HDP and offspring diabetes was largely similar in each subgroup by baseline characteristics (Additional file 1: Table S4). Sensitivity analyses restricted to offspring born after 1991 for maternal smoking adjustment, excluded offspring of mothers who diagnosed multiple types of HDP in one pregnancy, additionally adjusted for paternal hypertension, or adjusted for maternal obesity before childbirth, restricted analysis to offspring born after 1994 for the capture of diabetes diagnoses in same period in different registers, to offspring born before 2014 for the redefined preeclampsia concept, additionally adjusting for low birth weight, and excluded those diabetic patients identified through age from the main analysis, yielded similar results to the primary analyses (Additional file 1: Tables S5-9).

Using this large population-based cohort study, we found that offspring exposure to maternal HDP had higher risk of diabetes, and was associated with 56% and 37% increased risks of offspring type 2 diabetes and gestational diabetes, respectively. However, we uncovered no association between maternal HDP and type 1 diabetes in offspring. The occurrence of maternal HDP, either gestational hypertension or preeclampsia, was associated with an increased risk of offspring type 2 diabetes. An increased risk of type 1 diabetes was solely observed in offspring exposed to gestational hypertension. In addition, offspring exposed to any subtypes of maternal HDP would have increased risks of gestational diabetes. We also observed stronger associations among offspring born to mothers with HDP and comorbid diabetes.

To our knowledge, limited studies comprehensively evaluated the effect of maternal HDP on offspring diabetes [8, 23]. A meta-analysis including 11,050,451 offspring of 13 studies reported that preeclampsia was associated with a weak increased risk of offspring diabetes (rate ratio=1.12, 95%CI=0.98–1.27) [23]. However, the significant heterogeneity between studies (I²: 48.2%, P=0.02) limited the reliability of results. Another population-based retrospective study of 232,841 singleton deliveries between 1991 to 2014 in Israel showed that compared with young offspring (≤18 years) born to normotensive women, offspring born to women with chronic hypertension had 1.39-fold increased risk of diabetes with a relative wide confidence interval (95%CI=0.52–3.73) due to a small number of events (n=4) [8]. In addition, the abovementioned studies only assessed the effect of maternal type-specific HDP on offspring overall diabetes. In our study, we comprehensively assessed the association of maternal HDP and its subtypes (preeclampsia, chronic hypertension, and gestational hypertension) with diabetes in offspring from birth to young adulthood (up to 41 years old) and found an increased risk of diabetes in offspring born to mothers with overall or type-specific HDP.

We also found that the offspring of mothers with either gestational hypertension or preeclampsia had an increased risk of offspring type 2 diabetes. Consistent with our findings, a study composed of 5335 older adults born in 1934–1944 from the Helsinki Birth Cohort Study reported that offspring exposed to maternal gestational hypertension in utero had a 1.14-fold risk of type 2 diabetes at 50–61 years [10]. But this study did not report obvious risk for type 2 diabetes among offspring of mothers with severe (HR=1.02, 95%CI=0.69–1.53) or non-severe preeclampsia (HR=0.94, 95%CI=0.58–1.53) [10]. However, a previous cohort study including 8648 offspring born between 1952 and 1958 based on the Walker Cohort reported an adverse effect of maternal preeclampsia on type 2 diabetes in offspring (odds ratio=1.38, 95%CI=0.89–2.13) [11]. The inconsistent findings abovementioned might be attributed to the baseline characteristics of the study populations, duration of follow-up, statistical power, adjusted covariates, and identification of diabetes. In the present study, based on data from several national registers of Denmark, we ascertained and verified diabetes with high reliability [24]. After comprehensively adjusting for several maternal and birth characteristics and socioeconomic factors, we assessed the effects of overall and type-specific maternal HDP on offspring type 2 diabetes using the large prospective cohort study (n=2,448,753). Type 2 diabetes, usually refers to as adult-onset disease, is partially determined by the accumulation of risk factors during early development [25]. We observed positive associations between maternal HDP and type 2 diabetes through adolescence and early adulthood (≥10 years), and this adverse effect seemed to enhance with increased age.

Earlier studies in 1990s have reported that preeclampsia was associated with offspring type 1 diabetes [12, 13]. However, a case-control designed register study including 14,949 type 1 diabetes cases onset at ages 0–14 years from the Swedish Childhood Diabetes Register and 55,712 matched controls from the Swedish Total Population Register born from 1973 to 2013 [14], as well as the present population-based register study, covered a contemporary considerable time span of birth cohorts, showed no association of maternal preeclampsia with offspring type 1 diabetes. The inconsistent findings might be explained by new and more active pregnancy treatments, which might eliminate some of the adverse effects of preeclampsia. Simultaneously, we observed obvious increased risk for type 1 diabetes in the offspring of mothers with gestational hypertension for the first time. The differences in the association between maternal HDP and type-specific diabetes in offspring may be owing to the effects of various future risk factors and differential pathogenesis for type 1 (organ-specific immune destruction of the pancreatic β-islets) [26] and type 2 diabetes (insulin resistance) [27]. Further studies on the underlying mechanisms and other potential risk factors throughout life for offspring type 1 diabetes are warranted.

We also observed an increased risk of gestational diabetes among offspring exposed to maternal overall and any subtypes of HDP, compared with those who were not exposed to maternal HDP. Evidence suggested that women with high blood pressure before or during pregnancy tended to have an increased risk of gestational diabetes [28], and several common pathogenic pathways might be underlying the association including insulin resistance [29, 30], endothelial dysfunction [31, 32], and inflammation markers [33, 34]. Offspring exposed to higher levels of glucose spectrum in utero are more likely to be insulin resistant and limited β-cell compensation [35, 36]. Such modulation in girls might increase the propensity to develop gestational diabetes.

The underlying mechanisms between maternal HDP and diabetes in offspring are not fully elucidated. Maternal HDP has been suggested to be associated with non-specific systemic inflammatory reaction and circulating cortisol levels overexposure, which further result in hypoxia and fetal malnutrition [37, 38]. Evidence showed that perturbed maternal-fetal environment was associated with the development of adult diabetes according to the modulation of epigenetic regulation of gene expression [25]. Methylation presence has been identified among women with preeclampsia [39], and in cord blood [40], which could decrease the numbers of stem cells involved in islet cell development, with an increased risk for abnormal insulin secretion, resistance to insulin, and type 2 diabetes in offspring [39]. Thus, epigenetic changes might have an essential role in the association between maternal HDP and diabetes in offspring.

We found that mothers with both HDP and diabetes history tended to have a higher risk of offspring diabetes, compared with offspring born to mothers without HDP and diabetes history. Further research on the added effects of coexisting maternal HDP and maternal diabetes history on offspring diabetes is required to evaluate the burden of multimorbidity through pregnancy.

This study has several strengths. First, we used the large population-based cohort study based on the Danish national registries, which covered all Danish residents with a long follow-up duration of up to 41 years, thus providing sufficient power and minimizing the possibility of selection and recall bias to obtain reliable statistical estimates. Second, we comprehensively assessed the association of maternal HDP and its different subtypes on diabetes in offspring from birth to young adulthood. Third, the availability of maternal and birth baseline characteristics and socioeconomic factors from the several Danish registration systems enables us to adjust for a wide range of important covariables. However, several limitations should be noted. First, although we have adjusted for a large number of important confounding factors, residual confounding caused by unmeasured confounders in childhood or adulthood, such as smoking status, alcohol intake, physical activity, sleep quality, and body mass index, may influence our findings. However, further adjustment for paternal hypertension in sensitivity analyses yielded similar results as the primary analyses, which suggested that the observed associations are unlikely to be completely attributable to unmeasured confounders. Second, there might be potential misclassification in the diagnosis of maternal HDP and offspring diabetes. In addition, due to the periods captured in the different registries and unavailable specific codes for type 1 and type 2 diabetes among offspring born from 1978 to 1986, potential misclassification might exist for subtypes of diabetes. However, we performed sensitivity analyses restricted to offspring born after 1994, excluded those diabetic patients identified through age from the main analysis, respectively, and found similar results to the primary analyses. Previous validation studies showed high reliability for ascertainment of maternal HDP (sensitivity: 69%, specificity: 99%) [18, 41] and offspring diabetes (sensitivity ≥95%) in Denmark [24]. Third, as our study was conducted in Denmark, the generality of our findings to other countries should be made cautiously. Fourth, the presentation of the mediation analysis of birthweight might have a potential limitation, as it is prone to residual confounding of the mediator/outcome relationship and collider bias.

In conclusion, our study provides evidence that offspring born to mothers with HDP, especially mothers with comorbid diabetes, had higher risk of diabetes later in life, especially for type 2 diabetes and gestational diabetes. Maternal HDP did not increase the risk of offspring type 1 diabetes, except for gestational hypertension. These findings emphasize the importance and necessity of screening HDP status in women of childbearing age to identify and control maternal HDP early, thereby reducing the risk of diabetes in their offspring.