Pregnancy Complications and Later Development of Hypertension

Abstract

Pregnancy complications such as preeclampsia and diabetes affect approximately 5 to 10 % of all pregnancies and compromise maternal and fetal health during gestation. Complications during pregnancy may also contribute to the development of hypertension and future cardiovascular risk in the mother. Moreover, fetal exposure to hypertension and diabetes during pregnancy can program hypertension and cardiovascular disease in the offspring. Transgenerational transmission of programmed cardiovascular risk highlights the importance of understanding the mechanisms that link complications during pregnancy with later hypertension in her offspring and subsequent generations. However, experimental studies are needed to investigate the cause and effect of increased blood pressure in the mother following a complicated pregnancy and provide insight into the development of preventative measures that may improve the long-term cardiovascular health of women and their offspring.

Introduction

Pregnancy is associated with profound physiological and anatomical changes in the mother that occur in order to meet the growing metabolic needs of the developing fetus and placenta [1]. However, complications such as hypertension and diabetes that occur during pregnancy compromise the health of the mother and the fetus [2, 3] (Fig. 1). Recent epidemiological studies suggest that adverse consequences of complications during pregnancy can persist well beyond the gestational period in the mother and child [4, 5] (Fig. 1). Experimental studies providing mechanistic insight into the causative factors linked to future risk of hypertension in the mother are limited. However, experimental studies investigating the mechanisms that contribute to the development of hypertension in the offspring of mothers with complications during pregnancy are providing significant insight into the etiology of fetal programming of chronic disease. This review highlights the impact of complications during pregnancy on future hypertension and cardiovascular (CV) in both the mother and child with a particular emphasis on potential mechanism.

Fig. 1.

This figure highlights the impact of complications during pregnancy on future hypertension and cardiovascular risk in the mother and the fetal programming of hypertension and adverse gestational health in the offspring

Pregnancy Complications and Maternal Hypertension and Cardiovascular Health

Preeclampsia is a pregnancy-specific disorder that is a leading cause of maternal and fetal mortality and morbidity [3]. Preeclampsia is defined as new onset of an elevated blood pressure of 140/90 mmHg or more in the presence of at least 0.3 grams of protein in a 24 hour urine sample [6]. Risk factors for the development of preeclampsia include extreme ages, history of diabetes, hypertension, and obesity [7.]. Obesity is also a risk factor for the development of diabetes during pregnancy [8]. Gestational diabetes mellitus (GDM), defined as any degree of glucose intolerance with onset or first recognition during pregnancy [9], is also a common complication during pregnancy [2].

Epidemiologic Studies

Recent studies indicate that women with preeclampsia exhibit an increased risk for hypertension and CV disease after pregnancy [4, 10-12], preterm delivery and/or intrauterine growth restriction (IUGR) magnify this risk [13, 14]. Moreover, the risk of death from CV disease is higher in women that develop early-onset (< 32 weeks gestation) preeclampsia compared to women with late-onset (>32 weeks gestation) preeclampsia [10]. The association of hypertension in pregnancy and future CV risk is significantly enhanced in women that experience hypertension in more than one pregnancy [12]. Moreover, IUGR, similar to preeclampsia, is a condition related to placental health, and a pregnancy complicated by IUGR can serve as a risk factor for future CV disease in the mother [15]. GDM is also associated with higher blood pressure [16] and increased CV risk following delivery [4, 17]. However, the exact mechanisms linking complications during pregnancy with later CV risk in the mother including hypertension remain unclear. Moreover, whether complications during pregnancy associated with future hypertension and increased CV disease in the mother share a common genetic or environmental cause or whether postpartum hypertension and increased CV risk originate as a consequence of the adverse events that occur during a complicated pregnancy is not clear.

Potential Mechanisms

Preeclampsia and CV disease share many pathophysiological mechanisms including high blood pressure, increased body mass index (BMI) and endothelial dysfunction [18]. These CV risk factors may be present prior to pregnancy [19], and thus, not only predispose a woman to hypertension during pregnancy [12], but may also be a more important determinant in the development of hypertension in later life than the existence of increased blood pressure during pregnancy [18]. Although within the normotensive range, blood pressure is higher following a pregnancy complicated by new-onset hypertension [20] relative to women with a history of a normotensive pregnancy. Furthermore, elevations in blood pressure are reported as early as 12 weeks [21] and up to 10 [22, 23] to 20 years postpartum [24, 25]. Often, hypertension in women with a history of a preeclamptic pregnancy is associated with a higher BMI [12, 22]. Postpartum increases in blood pressure are also associated with impaired flow-mediated vasodilation [26]. Yet, whether endothelial dysfunction persists following a preeclamptic pregnancy is controversial. Evans et al. reported that stress-induced endothelial function is impaired in conjunction with an increase in MAP at 16 months post-partum in women with prior preeclampsia [27]. However, mediators of endothelial dysfunction such as cellular fibronectin or E-selectin were not altered in this study [27]. Yinon et al. reported that impaired flow-mediated vasodilation is noted only in women with early-onset preeclampsia or delivery of an IUGR infant [28]. However, this impairment was not associated with a change in expression of angiogenic factors such as sFlt-1 [28], a critical mediator of preeclampsia [3]. Yet, other studies noted that flow-mediated dilatation is normalized by 12 weeks postpartum [21], or that despite a marked increase in SBP, endothelial function does not differ at 5 to 8 years postpartum in women with prior preeclampsia unless complicated by delivery of an SGA infant [29]. Thus preeclampsia is associated with risk factors linked to CV disease. However, whether preeclampsia serves as an independent risk factor for later hypertension and CV disease due to the development of factors that develop as a consequence of a preeclamptic pregnancy is not yet defined.

The etiology of preeclampsia involves activation of several pathways that contribute to the development of hypertension in this pregnancy-specific disorder [3]. Increases in anti-angiogenic factors such as soluble fms-like Tyrosine Kinase 1 (sFlt-1) and soluble Endoglin (sEng) are observed during preeclampsia and the relevance for an increase in these angiogenic factors in the etiology of preeclampsia is supported by experimental studies [30]. Abnormal activation of maternal inflammatory responses and the formation of reactive oxygen species are also thought to contribute to the pathogenesis of the hypertension in preeclampsia [3]. Increased risk for hypertension and CV disease in women with a prior history of preeclampsia is proposed to involve sustained activation of these pathways. However, whether alterations in angiogenic factors persist after a preeclamptic pregnancy is not clear. Kvehaugen et al. noted that a marked elevation in s-Flt-1 in women 5 to 8 years post-partum of a preeclamptic pregnancy is associated with a marked increase in blood pressure [29]. However, in other studies an increase in blood pressure is not associated with an increase in sFlt-1 levels [20] regardless of the length of follow-up; 12 weeks [21] or 10 years postpartum [31]. Investigation into the importance of oxidative stress in the development of hypertension in women with a history of preeclampsia is very limited but one study reports a marked elevation in mean arterial pressure at 16 months postpartum in women with prior preeclampsia is not associated with an increase in markers of oxidative stress [27]. Evidence from different experimental models of hypertension implicates a role for oxidative stress in mediating increased blood pressure in males, but not females [32]. Thus, oxidative stress may not be a contributory factor in the development of hypertension in women following a preeclamptic pregnancy. Inflammatory cytokines such as tumor necrosis factor (TNF)-alpha are elevated in the maternal serum of pregnancies complicated by preeclampsia [33] and experimental studies demonstrate a direct causative role for TNF-alpha in the etiology of hypertension during pregnancy [34]. TNF-alpha levels remain elevated in women following a preeclamptic pregnancy [35]. However, experimental studies indicate that placental factors associated with the hormonal environment of a pregnancy are required for cytokine-induced hypertension in females [34, 36] indicating that an increase in an inflammatory cytokine such as TNF-alpha may not be sufficient to induce hypertension in the absence of other confounding factors.

Increased sympathetic nervous system (SNS) [37] and/or renin angiotensin system (RAS) [38] activation contribute to the etiology of hypertension in many experimental models of hypertension. Yet, the exact contribution of these regulatory systems to the development of hypertension and increased CV risk following a hypertensive disorder during pregnancy has not been fully elucidated. Two studies suggest that chronic activation of the SNS does not contribute to the increase in blood pressure observed in later life in women with a history of a hypertensive pregnancy [12, 39]. However, alterations in sensitivity to the RAS may be a key mediator. Enhanced sensitivity to angiotensin II (Ang II), a hallmark of preeclampsia, is present at 8 months postpartum following a pregnancy complicated by preeclampsia [20]. Circulating agnostic angiotensin II type 1 autoantibodies (AAT-AAS) that bind to the angiotensin type 1 receptor (AT₁R) develop in women with preeclampsia [40] and are reported to remain elevated in a subset of women 18 months after a preeclamptic pregnancy [41]. Thus, the mechanism involved in mediating enhanced sensitivity to Ang II in women with a history of preeclampsia is not yet apparent, but the etiology may entail a sustained increase in the AAT-AAS which may also serve as a component of the increased risk for hypertension and CV disease in women following preeclampsia.

Recent studies indicate that epigenetic mechanisms may contribute to complications during pregnancy [42]. Epigenetic processes alter heritable changes in gene function without changing the nucleotide sequence [43]. Only a few studies have directly tested the importance of epigenetics in the pathophysiology of preeclampsia [44, 45] and the exact physiological relevance of these findings is unclear. However, epigenetic modifications that contribute to preeclampsia may also underlie the development of hypertension and increased CV risk in women with a history of preeclampsia.

Diabetes in Pregnancy and Vascular Dysfunction

Although glucose tolerance returns to normal in most women with GDM, GDM is a known risk factor for the development of later CV disease [46]. Only a few studies have investigated potential mechanisms related to later hypertension and increased CV risk following a pregnancy complicated by diabetes; however, endothelial dysfunction, a marker of CV risk [47], may be a contributing factor. Endothelial dysfunction is observed in women with prior GDM despite current normal glucose tolerance and regardless of current BMI [48]. Impaired small artery function is observed as early as 2 years postpartum after GDM in women with normal glycemic control [49] suggesting that risk for later CV disease may have its origins long before adverse CV events transpire. The mechanisms mediating impaired vascular function following GDM may involve alterations in angiogenic factors. Pro-atherogenic markers such as plasminogen activator inhibitor-1 (PAI-1) are elevated in women with GDM relative to age-matched controls in late gestation [50]. Vascular dysfunction in women with prior GDM is associated with sustained increases in PAI-1 [51] suggesting that events initiated during GDM, may persist into later life and contribute to later CV risk.

To summarize, complications during pregnancy that alter the health of the mother can also lead to the development of hypertension and thus, increased CV risk in later life (Fig. 1). Additional studies are needed to identify the exact mechanisms involved. Moreover, use of experimental models will allow investigation into cause and effect and provide insight into preventative measures that may improve the long-term CV health of women that experience complications such as hypertension or diabetes during pregnancy.

Pregnancy Complications and Offspring Cardiovascular Health

The maternal-fetal interface ensures an environment during pregnancy that is able to maintain and nurture the development of the fetus [52]. Alterations in the formation of the maternal-fetal interface can occur during pregnancy-specific disorders such as preeclampsia and lead to IUGR [53] or preterm delivery [54]. IUGR can also be a consequence of a diabetic pregnancy [2]. Numerous studies now implicate the impact of a pregnancy complicated by hypertension or diabetes on the development of hypertension and CV risk in the offspring (Fig. 1). Importantly, experimental studies are providing significant insight into the mechanisms that link adverse influences during fetal life and the etiology of fetal programming of hypertension [55].

Epidemiological Studies

In addition to an increased CV risk in the mother, children of preeclamptic pregnancies are at an increased risk to develop hypertension and CV complications in later life [5, 56, 57]. CV risk factors such as increased blood pressure [5, 56] and BMI are observed in children of preeclamptic pregnancies [5]. In addition, hypertension during pregnancy is a risk factor for intrauterine growth restriction (IUGR) or preterm delivery [58]. Higher blood pressure in adult life is observed in individuals born with IUGR relative to normal birth weight for gestation [57]. Preterm birth (<37 weeks gestation) is also associated with higher systolic blood pressure [59]. Low birth weight is not only a risk factor for increased blood pressure [60], but is also associated with an increased risk for diabetes, stroke, heart attack or heart disease in offspring of complicated pregnancies [61]. Children exposed to diabetes during fetal life also exhibit an increase in blood pressure associated with an increase in BMI [62, 63], an association that remains after adjustment for current body weight [64]. Thus, fetal exposure to complications during pregnancy programs hypertension and increased CV risk in the offspring. Experimental studies substantiate the associations noted by epidemiological reports and are providing insight into the mechanisms linking complications during pregnancy and hypertension and increased CV risk in the offspring.

Potenial Mechanisms

Numerous experimental models are utilized to study the impact of an abnormal intrauterine milieu on later CV health [55]. These include models induced via placental insufficiency, under-nutrition, diabetes, or obesity [65]. Insight into the mechanisms leading to the fetal programming of hypertension and later CV risk are provided by these diverse experimental models and despite the experimental model utilized, implicate an important role for the RAS [66, 67], the SNS [68, 69], oxidative stress [70-72] and impaired vascular function [70] (Extensive reviews are provided by [5, 55, 73-75].). Recent studies indicate that alterations in blood pressure and vascular dysfunction are transmitted to the F2 generation in the absence of a maternal insult in the programmed F1 generation [76, 77]. In addition to serving as a mediator of later maternal health in response to complications during pregnancy, recent studies indicate that epigenetics may also contribute to programmed hypertension and increased CV risk in the offspring of complicated pregnancies [78, 79] (review [80]). Moreover, epigenetic mechanisms may also be responsible for the transgenerational passage of hypertension and vascular dysfunction from the F1 to the F2 generation [81]. Several studies indicate that the fetal response to complications during pregnancy results in sex differences in adult blood pressure (for extensive reviews see: [82, 83]). Aging also impacts CV risk programmed by in utero insults [84]. Thus, these findings highlight the need for additional experimental studies to elucidate the mechanisms and additional physiological influences that mediate programming of hypertension and CV risk in offspring of a complicated pregnancy.

Risk for a Complicated Pregnancy in Women Born with low Birth Weight

The risk of preeclampsia is increased in women born preterm or in low birth weight women [85, 86], obesity amplifies this risk [87]. Women with low birth weight are also at risk for glucose intolerance and diabetes during gestation [85, 88]. Moreover, women born with low birth weight exhibit a greater risk of preterm delivery [89], an observation enhanced by obesity [90]. Experimental studies are limited but Gallo et al. report that rats born small exhibit glucose intolerance during late pregnancy [91] that may be linked to enhanced basal hepatic insulin sensitivity [92]. Thus, exposure to complications during pregnancy in one generation has far reaching consequences on the gestational health of future generations. When the additive effect of developmental programming of later CV risk is considered, the impact of a complicated pregnancy in one generation is a significant event that transcends the effect on maternal health to include the gestational and CV health of future generations (Fig. 1).

Conclusions

Despite the significant number of studies that implicate increased blood pressure and CV risk in women following a pregnancy complicated by hypertension or diabetes, little is known regarding the mechanisms that link this association. Insight into the mechanisms that mediate the development of hypertension and increased CV risk as it accumulates across the lifespan following a complicated pregnancy will provide a basis for the development of future preventative strategies to alleviate the adverse influence of a complicated pregnancy on later maternal health. The adverse effect of a complicated pregnancy on the CV health of the offspring is well documented and significant insight into the potential mechanisms that link insults during fetal life with the development of hypertension in offspring are being elucidated by experimental studies. However, evidence indicating the transgenerational transmission of hypertension highlights the importance of understanding how risk transmits to the next generation. Insight into the mechanisms that mediate the development of hypertension in offspring programmed in response to a complicated pregnancy may alleviate the transmission of increased CV disease risk to subsequent generations.