Maternal Chronic Hypertension Elevates the Risk for Long-Term Selected Endocrine and Metabolic Morbidity in the Offspring,Particularly Childhood Obesity

Abstract

Background:

Maternal hypertensive disorders during pregnancy are known to be associated with high rates of perinatal complications for both mother and child. We aimed at determining whether maternal chronic hypertension impacts long-term pediatric endocrine and metabolic morbidity.

Methods:

A population-based, retrospective cohort study was performed. Exposure was defined as the presence of maternal chronic hypertension. Hospitalizations of the offspring up to the age of 18 years involving endocrine and metabolic morbidity were evaluated. A Kaplan–Meier survival curve was employed to compare the cumulative morbidity incidence between both groups (exposed and unexposed offspring). Cox proportional hazards models were used to control for confounders.

Results:

During the study period, 232,841 singleton deliveries met the inclusion criteria. Of them, 1.1% (n = 2655) were exposed to maternal chronic hypertension during pregnancy. Total hospitalization rate involving endocrine-metabolic morbidities was doubled in the hypertensive group (1% vs. 0.5% in the normotensive group, p < 0.001). Specifically, childhood obesity was significantly more common in offspring of mothers with chronic hypertension (0.7% vs. 0.2%, respectively, p < 0.001). The survival curve demonstrated significantly higher cumulative incidence of total endocrine and metabolic morbidity in the exposed group (log rank p = 0.002). In a Cox regression model, maternal chronic hypertension exhibited an independent association with long-term childhood endocrine or metabolic morbidity (adjusted hazard ratio = 1.5, 95% confidence interval 1.01–2.2, p = 0.045).

Conclusions:

Maternal chronic hypertension appears to be an independent and a significant risk factor for long-term pediatric endocrine and metabolic morbidity, and specifically for childhood obesity, in the offspring.

Introduction

Chronic maternal disorders during pregnancy, particularly hypertension, diabetes mellitus, and obesity, are known to be associated with higher incidence of perinatal complications,^1–3 with potentially long-term consequences for both mother and her offspring.^4–6 Chronic hypertension is complicated between 1 and 5 percent of pregnancies and may be an increasing clinical problem, contributed by higher rates of advanced maternal age due to delayed conception and by maternal obesity.^7,8 Adverse pregnancy outcomes associated with chronic hypertension include superimposed preeclampsia and eclampsia, preterm delivery, cesarean delivery, low birthweight, neonatal intensive care unit admission, and perinatal death.^1,9,10 Optimal management of pregnant women suffering from chronic hypertension enables early identification and treatment, thereby reducing rates of adverse perinatal outcomes. However, this requires increased awareness and employment of prenatal counseling as well as antenatal surveillance involving a multidisciplinary professional health care team, including family physicians, cardiologists, nephrologists, endocrinologists, ophthalmologists, pharmacologists, and high-risk obstetricians.

It is now well established that pregnancy-related hypertension and its complications, such as preeclampsia and other placental syndromes, adversely impact the offspring's health in the long term. A number of epidemiological studies and systematic reviews have demonstrated pregnancy-related hypertension to be a significant risk factor for offspring diseases later in life, including cardiovascular morbidity (chronic hypertension and stroke),^11,12 endo-metabolic morbidity (childhood type 2 diabetes and obesity),^13,14 immune disorders (allergic sensitization),¹⁵ and neurological, neuropsychiatric, and behavioral disorders (lower cognitive performance, autism, and attention deficit hyperactivity disorders).^16,17 A systematic review of cardio-metabolic sequelae in adult offspring exposed to any maternal hypertensive disorders during pregnancy, including chronic hypertension, has shown an increased risk of cardiovascular events, in particular hypertension and stroke, overweight, and obesity.¹⁸

Maternal impaired endothelial dysfunction is the hallmark pathology underlying pregnancy-related hypertensive disorders, which may explain, at least in part, the complications and morbidities observed in offspring mentioned earlier. However, the pure impact of maternal chronic hypertension, and the possible associated endothelial dysfunction, on offspring future health remains unclear. Although pregnancy complications related to hypertensive disorder, such as prematurity and low birthweight, have been inversely associated with later offspring health, it is difficult to distinguish between the different causes of the observed long-term negative impact.^19,20 Moreover, maternal chronic hypertension is often complicated by superimposed pregnancy-related hypertensive disorders, thus making the differentiation even more challenging.

We, therefore, opted to evaluate the impact of isolated maternal chronic hypertension on long-term pediatric endocrine and metabolic morbidity of the offspring, while excluding other hypertensive disorders of pregnancy and rigorously controlling for several other important and clinically relevant confounders.

Methods

We conducted a retrospective cohort study including all women who delivered at the Soroka University Medical Center (SUMC), the sole hospital of the Negev region (southern Israel), between the years 1991 and 2014. SUMC serves the entire population in the region, which occupies ∼1,272,100 inhabitants—14.5% of Israel's population and 65.5% of the country's land.²¹ Thus, our study is based on nonselective population data. The study protocol was approved by the SUMC institutional review board, and informed consent was exempt due to the nature of the study design.

The primary objective of the study was to investigate the impact of maternal chronic hypertension on the risk of childhood endocrine and metabolic morbidity in the offspring followed up to the age of 18 years, as compared with offspring born to mothers without chronic hypertension. A new diagnosis of chronic hypertension was defined as a systolic blood pressure value of 140 or higher, or a diastolic value of 90 or higher on at least two occasions, measured at least 4 hours apart. Measurements were documented either before pregnancy (but more than 12 weeks after a previous pregnancy) or during pregnancy but before 20 weeks' gestation. Of note, women with a documented history of chronic hypertension, regardless of the use of antihypertensive medication and regardless of their control status, were included in the chronic hypertensive (exposed) group.

The study population consisted of all singleton deliveries, from 24 0/7 gestational weeks and onward, occurring during the study period. Multiple gestations and fetuses with congenital malformations were excluded. In addition, all mothers diagnosed at any point during pregnancy with other pregnancy-related hypertensive disorders, including gestational hypertension, preeclampsia with or without severe features, or eclampsia, were excluded. Long-term endocrine and metabolic morbidity of the offspring was evaluated via any hospitalizations of the offspring (up to the age of 18 years) at SUMC, involving endocrine and metabolic morbidity. All endocrine and metabolic diagnoses obtained during hospitalizations of the offspring were predefined according to a set of ICD-9 codes detailed in the Supplementary Table S1. Endocrine morbidity included pathologies defined as specific entities within pediatric endocrinology (hypothyroidism and diabetes mellitus type I and II), whereas metabolic morbidity referred to entities characterized by out-of-range laboratory values, not necessarily a part of a specific or a well-defined disease (hypoglycemia and hyperlipidemia as an example). Overweight and obesity have both metabolic and endocrine impacts and were, thus, included in the long-term outcome.²² Follow-up time was defined as time to an event (endocrine- or metabolic-related hospitalization), or until censored. Offspring follow-up started on the date of birth (from January 1, 1991 and on) and ended if any of the following occurred (whichever came first): the first endo-metabolic diagnosis during hospitalization, death of the offspring (during hospitalization unrelated to an endo-metabolic event), and age 18 years (which was calculated for each child based on date of birth) or on January 1, 2014. Repeated events for the same offspring were not accounted for.

Data were collected from two databases that were cross-linked and merged: the computerized hospitalization database of the SUMC (“Demog-ICD9”), and on the computerized perinatal database of the Obstetrics and Gynecology department. The Demog-ICD9 database includes demographic information and ICD-9 codes for all medical diagnoses made during hospitalizations at the SUMC. The perinatal database consists of information recorded immediately after delivery by an obstetrician. Coding is performed after assessing medical prenatal care records as well as routine hospital documents. Experienced medical secretaries routinely review the information before entering it into the database to ensure maximal completeness and accuracy.

Statistical Analysis

Statistical analysis was performed by using STATA (version 12.0) and SPSS (version 23.0) software. Assumptions were two sided with α = 0.05 and β = 0.2. Initial analysis compared background, pregnancy, and perinatal characteristics between the two study groups (mothers with and without chronic hypertension), using the chi-square and t-test for continuous variables.

Incidence rates of maternal and fetal background and perinatal characteristics were calculated and compared. These included: mean maternal age, parity, maternal obesity, diabetes mellitus (pre- or gestational), mean gestational age on delivery and preterm delivery (<37 gestation weeks), offspring gender, mean birthweight, Apgar scores at 5 minutes, and mean follow-up time. In each study group, crude rates of endo-metabolic-related hospitalizations of offspring, as well as the rates per 1000 person-years, were calculated. Kaplan–Meier survival curves were constructed, and the cumulative endo-metabolic-related hospitalization incidences was compared between the two groups by using the Cox-Mantel log-rank test.

To adjust for length of follow-up, the multivariable Cox regression analysis was performed. This regression model was used to establish an independent association between maternal chronic hypertension and total endocrine- and metabolic-related hospitalization incidences in the offspring, while controlling for potential confounders including: gestational age on delivery, maternal obesity, and maternal diabetes mellitus. The final model was selected based on the best model fit and lowest −2 log likelihood.

Results

During the study period, 232,841 singleton deliveries met the inclusion criteria. Of them, 1.1% (n = 2655) occurred in patients diagnosed with chronic hypertension. Table 1 presents the baseline demographic characteristics, pregnancy course, and immediate perinatal outcomes in the two groups. Mean maternal age was higher in the hypertensive group (32.6 vs. 28.1 years, p < 0.001), and the likelihood of grand multiparity (more than five deliveries) was also higher (40.5% vs. 25.2% in the normotensive group, p < 0.001). Rates of pre- or gestational diabetes mellitus were 5 times higher in the hypertensive group (p < 0.001), and preterm delivery (<37 0/7 gestational weeks) was significantly more common (p < 0.001). There were no significant differences in the rates of low Apgar scores (at 5 minutes) or fetal gender between the groups.

Table 1.

Maternal Characteristics, Pregnancy Course, and Delivery Outcome in Parturient with and without Chronic Hypertension

	Chronic hypertension group 1.1% (n = 2655)	Normotensive group 98.9% (n = 230 186)	p
Maternal age (mean ± SD)	32.6 ± 6.3	28.1 ± 5.8	<0.001
Maternal obesity % (n)	2.7 (73)	1.0 (2247)	<0.001
Parity: % (n)			<0.001
1	15.6 (414)	23.0 (52 934)
2–4	43.9 (1165)	51.8 (119 217)
≥5	40.5 (1075)	25.2 (57 985)
Diabetes mellitus^a % (n)	24.0 (636)	4.6 (10 590)	<0.001
Gestational age in weeks (mean ± SD)	38.5 ± 1.9	39.2 ± 1.8	<0.001
Preterm delivery: % (n), weeks
<37	12.4 (329)	6.0 (13 821)	<0.001
<34	1.5 (41)	0.9 (2171)	0.002
Gender: % (n)
Female	49.1 (1303)	49.2 (113 176)	0.927
Male	50.9 (1352)	50.8 (117 010)
Mean birthweight in grams (mean ± SD)	3210 ± 683	3223 ± 483	<0.001
Low birth weight (≤2500 g) % (n)	10.1 (269)	5.8 (13 399)	<0.001
Low Apgar score at 5 minutes (<7) % (n)	1.4 (36)	1.8 (4212)	0.070
Follow-up time, years (mean ± SD)	12.0 ± 5.3	10.3 ± 5.9	<0.001

Data are presented as % (n) or mean ± SD; significance was measured by using chi-squared and Mann–Whitney tests.

Including pre-gestational and gestational diabetes.

SD, standard deviation.

Hospitalizations of the offspring involving endocrine and metabolic morbidity up to 18 years of age were recorded, with a total of 1085 events during the follow-up period. Rates of different morbidity entities, including rates per 1000-person year and hazard ratio (HR) adjusted for follow-up time, in the two groups are presented in Table 2; detailed diagnoses of each category are detailed in Supplementary Table S1. In the chronic hypertensive mother's group, total pediatric endo-metabolic-related hospitalizations were doubled as compared with the normotensive group (1% vs. 0.5%, p < 0.001, Table 2). In addition, rates of childhood obesity were significantly higher in the offspring of chronic hypertensive mothers (0.7% vs. 0.2%, p < 0.001).

Table 2.

Comparison of Selected Long-Term Endocrine and Metabolic Morbidity in Offspring (up to the Age of 18 Years) According to the Presence or Absence of Maternal Chronic Hypertension during Pregnancy

Endocrine and metabolic hospitalizations	Chronic hypertension group N = 2655		Normotensive group N = 230,186		p	Adjusted hazards ratio^a (95% CI)
Endocrine and metabolic hospitalizations	% (n)	Rates per 1000-person year	% (n)	Rates per 1000-person year	p	Adjusted hazards ratio^a (95% CI)
Total	1.0 (26)	0.82	0.50 (1059)	0.45	<0.001	1.82 (1.23–2.68)
Obesity	0.7 (18)	0.57	0.20 (384)	0.16	<0.001	3.31 (2.06–5.31)
Thyroid diseases	0.04 (1)	0.03	0.05 (104)	0.04	0.856	0.73 (0.10–5.25)
Diabetes mellitus	0.2 (4)	0.13	0.10 (204)	0.09	0.287	1.39 (0.52–3.73)
Hypoglycemia	0.2 (4)	0.13	0.10 (272)	0.12	0.629	1.19 (0.44–3.19)
Other^b	0	—	0.30 (4)	0.002	0.830	—

Bold indicates significant p value.

Not all endocrine and metabolic morbidity types and cases are shown, but all are included in the total (first row). Significance for differences was measured by using chi-squared test.

Adjusted for follow-up time.

Including other specified and unspecified endocrine disorders.

CI, confidence interval.

The Kaplan–Meier survival analysis is presented in Figure 1. The figure demonstrates a significantly higher cumulative incidence of endocrine and metabolic morbidity in the hypertensive group, log rank, p = 0.002.

Figure 1.

Kaplan–Meier survival curve demonstrating the cumulative incidence of endocrine- and metabolic-related hospitalizations of children in both groups (log-rank p-value = 0.002).

Several Cox proportional hazards models were performed to establish an independent association between maternal chronic hypertension and childhood endocrine and metabolic morbidity in the offspring.

A Cox model was employed for the association with total endocrine- and metabolic-related hospitalizations while controlling for gestational age at birth, maternal diabetes mellitus (both pre-gestational and gestational), and maternal obesity (shown in Table 3). Exposure to maternal chronic hypertension was found to be a significant and independent risk factor for endocrine and metabolic morbidity of the offspring, with an adjusted HR of 1.5 [95% confidence interval (CI) 1.01–2.22, p = 0.045]. This observation remained true (i.e., significant and independent association) in further multivariable analyses, controlled separately for other optional clinically relevant variables such as ethnicity (adjusted HR = 1.8, 95% CI 1.2–2.7; p = 0.003), calendar year (adjusted HR = 1.9, 95% CI 1.3–2.8; p = 0.001), cesarean delivery (adjusted HR = 1.8, 95% CI 1.2–2.6; p = 0.004), and neonatal birthweight (adjusted HR = 1.8, 95% CI 1.2–2.7; p = 0.003; models not shown in a table).

Table 3.

Cox Multivariable Analysis Evaluating the Independent Association between Maternal Chronic Hypertension and Long-Term Endocrine and Metabolic Morbidity in Offspring

Covariates	Adjusted hazard ratio (95% CI)	p
Chronic hypertension	1.50 (1.01–2.22)	0.045
Gestational age at birth	0.93 (0.91–0.96)	<0.001
Maternal obesity	2.58 (1.84–3.64)	<0.001
Maternal diabetes^a	1.82 (1.49–2.23)	<0.001

Including pre-gestational and gestational diabetes.

Next, in a sub-analysis (not shown in tables), specific for childhood obesity, the Cox model revealed a significant and independent association with maternal chronic hypertension (adjusted HR = 3.45, 95% CI 2.2–5.5, p < 0.001) while controlling for maternal obesity.

Discussion

According to our data, which include a large cohort of offspring with an extended follow-up period, a significant and independent association was demonstrated between maternal chronic hypertension and later endocrine and metabolic childhood and adolescence morbidity in the offspring up to the age of 18 years. This association was found to be independent of several important background and perinatal characteristics such as maternal diabetes disorders, maternal obesity, and gestational age. An independent association was also demonstrated specifically with childhood obesity, independent of maternal obesity.

The impact of maternal hypertensive disorders during pregnancy (including gestational hypertension and preeclampsia) on later endo-metabolic health of the offspring was previously studied with conflicting results.^23–27 Some authors could not prove an association on several anthropometric measurements,^23,24 whereas others^25,26 have found an association between gestational hypertension and higher body mass index in the offspring. Regarding bone mineral contents, Miettola et al. found greater bone mineral density in offspring exposed to hypertensive mothers.²⁷ As for blood biomarkers, including cholesterol, triglycerides, glucose, insulin, C-reactive protein, interleukins, and apolipoprotein, most studies were consistent in showing no evidence of association with maternal hypertension during pregnancy.^28,29

The idea that maternal and perinatal factors play a role in the development of later childhood morbidity in general is not new. This association may be explained by several underlying pathophysiologic mechanisms. First, according to Barker's “fetal programming” theory, an abnormal in utero environment may negatively impact fetal organogenesis, thereby increasing the risk for later several chronic diseases.³⁰ This may result from an abnormal functional expression of the hormonal axis and metabolites aimed at aiding in the physiological adaptation to the postnatal life.³⁰ For instance, exposure to maternal hypertension or diabetes during pregnancy was shown to be associated with childhood obesity, glucose intolerance, and adult type 2 diabetes mellitus in the offspring.^14,31,32 In addition, oxidative stress associated with higher blood pressure may alter the developing fetal vasculature alongside epigenetic changes, which may potentially result in endocrine and metabolic disorders later in life.

Second, previous studies have shown that maternal hypertensive disorders in pregnancy may cause inadequate fetal nutrition and hypoxia due to abnormal placentation, systemic inflammatory reaction, and glucocorticoids overexposure (maternal or exogenous), all of which could affect later offspring health.^33–35

The association between isolated maternal chronic hypertension and offspring endo-metabolic morbidity, highlighted in our study, may be explained by the mechanisms mentioned earlier or, alternatively, by a simple hereditary predisposition. The increased rates of maternal diabetes and obesity, as a part of an underlying metabolic syndrome, may cause endocrine and metabolic dysfunction in the next generation.^36,37 Nevertheless, the association remained independent of these overt maternal morbidities (controlled for in the regression model), thus suggesting an additional, yet undefined, mechanism.

It is well established that preterm delivery and low birthweight occur more often in offspring born to women with hypertensive disorders of pregnancy.³⁸ These outcomes are, in turn, associated with several metabolic disorders later in life, including impaired glucose tolerance, obesity, and abnormal cholesterol metabolism.^39,40 Thus, higher rates of prematurity and low birthweight in newborns of hypertensive mothers must always be kept in mind when interpreting long-term outcomes. To address this potential bias, and to reduce the possibility that maternal characteristics and/or pregnancy complications were responsible for the increased risk for future endocrine and metabolic morbidity, we adjusted in the multivariable regression model for maternal morbidity including diabetes (pre-gestational and gestational), maternal obesity, as well as for gestational age at delivery (Table 3). In addition, we further performed several additional multivariable analyses, controlled separately for neonatal birthweight, ethnicity, calendar year of delivery, and mode of delivery. All regression models resulted in the same independent association between maternal chronic hypertension and future endocrine and metabolic morbidity of the offspring.

Our study has several notable strengths. Unique to our study population, SUMC is the only tertiary medical center treating and providing comprehensive care for the entire population of the Negev region. This setting allows minimal loss of follow-up, thus providing true long-term follow-up of offspring health. The long-term follow-up allowed us to closely examine any hospitalizations that occurred during childhood. In addition, our dataset combines maternal, neonatal, and long-term childhood data, enabling us the opportunity to examine the long-term outcomes of offspring with the ability to control for many parameters and potential confounders surrounding pregnancy and delivery. The large number of participants (n = 232,841) retrieved from the hospital database contributes to the strength of this study.

Nevertheless, the study possesses some limitations that need to be noted, mainly due to its retrospective design. The results suggest an association only, rather than causation or underlying pathogenesis. In addition, we focused on hospitalizations only, given the nature of our database. Thus, any encounter occurring at an ambulatory setting or at a different hospital, for any reason, could not be accounted for. However, this is true for both the hypertensive and the normotensive groups; thus, the specific impact of this limitation is probably minor. Finally, several potentially covariates were not available for the analysis, including different childhood exposures, breastfeeding, and socioeconomic status (other than proxies of ethnicity).

As maternal comorbidity rises in prevalence, due to increased rates of elderly gravidas and obesity, the impact on future offspring health must be considered. To the best of our knowledge, this is the first study to evaluate the impact of maternal chronic hypertensive disorders during pregnancy on the incidence of endocrine and metabolic morbidity of the offspring. Although intuitive, it is yet to be determined whether optimal treatment and surveillance in pregnancies involving chronic hypertension will positively impact not only perinatal outcome but also later offspring health.

We conclude that maternal chronic hypertension appears to be an independent and a significant risk factor for long-term pediatric endocrine and metabolic morbidities, specifically for childhood obesity in offspring.

Footnotes

Acknowledgment

Presented in part at the 40th Annual Meeting of the Society of Maternal-Fetal Medicine, February 3–8, 2020 (abstract #732).

Authors' Contributions

M.I. wrote the first draft of the article. No honorarium, grant, or other form of payment was given to anyone to produce the article.

Funding Information

No funding was received for this article.

Author Disclosure Statement

No competing financial interests exist.

Supplementary Material

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