During normal pregnancy, blood pressure usually falls in the late first to early second trimester and rises again to prepregnancy levels in the third trimester (115). PIH complicates 5-10% of pregnancies in the USA, including 3-5% of pregnancies in previously normotensive women (115). Gestational hypertension is defined as elevated blood pressure on two occasions that develops after the twentieth week of pregnancy, without systemic symptoms, in previously normotensive women (171). Preeclampsia is the development of gestational hypertension plus proteinuria of greater than 300 mg protein in 24 h. Complications of preeclampsia include hepatic dysfunction, hemolysis, disseminated intravascular coagulation and seizures (115).
While many factors influence a woman's likelihood of developing PIH, there has been considerable interest in metabolic factors that may contribute. Studies have shown that women with PIH demonstrate exaggerated hyperinsulinemia compared with those with normal pregnancy. In a prospective cohort study, Hamasaki et al. found that the incidence of gestational hypertension was higher among patients with hyperinsulinemia than among controls (24.1% vs. 7.3%, p < 0.005) (172). The risk remained after controlling for BMI, age and parity (RR 1.19, CI 1.03-1.38). Laivuori et al. found that women with a history of preeclamptic pregnancy 17 years prior had higher insulin levels, regardless of BMI (173). In a case control study by Solomon et al., women who developed PIH had higher fasting insulin levels even after adjustment for BMI and age (RR 1.12, p = 0.03) (174).
Hyperinsulinemia may increase renal reabsorption of sodium and stimulate the sympathetic nervous system, both of which can increase the risk of developing hypertension (115). Furthermore, insulin resistance and/or its associated factors have been shown to be associated with PIH even years after pregnancy (175-180). Insulin resistance or associated hyperglycemia may impair endothelial function, which may decrease prostacyclin production (39). The hyperinsulinemic insulin resistance intrinsic to PCOS may therefore increase the risk of PIH.
Further support for this hypothesis comes from several studies that have found an association between GDM and PIH (181-184). Some of the studies had small sample sizes and did not account for confounders such as race and BMI. However, in a large, population-based study, Bryson et al. found a significantly increased risk of gestational hypertension (OR 1.4, CI 1.2-1.6) and preeclampsia among women with GDM that persisted even after adjusting for BMI (185). The association was stronger among women who received less prenatal care and among African-American women.
Given the risk for PIH in those with insulin resistance, it is not surprising that studies have found an association between women with PCOS and PIH. Diamant et al. found that preeclampsia was 11 times more common in anovulatory patients with PCOS undergoing ovulation induction than in normal controls (186). PCOS women were also more likely to have preeclampsia than anovulatory women without PCOS. The study did not control for BMI. Gjonnaess followed 62 pregnancies of PCOS women who conceived after LOD and found the prevalence of preeclampsia to be 12.9%, which is higher than the risk in the general population (187). While the most overweight women had the highest risk and normal weight women did not differ from the general population, even women who were mildly overweight had an increased risk of preeclampsia, implicating increased weight as a risk factor (187). However, Urman et al. also found an increased risk of PIH even when lean PCOS patients were compared with lean controls (162).
To further investigate the role of obesity in PIH in women with PCOS, de Vries et al. performed a retrospective case-control study examining the incidence of PIH in patients with and without PCOS who were treated for infertility (188). While the overall incidence of PIH was similar in both groups, PCOS patients had a higher incidence of preeclampsia (14% vs. 2.5%, p = 0.02) regardless of BMI, ovulation induction, age and parity. A retrospective cohort study by Radon et al. found that women with PCOS had an increased risk of preeclampsia during pregnancy (OR 15.0, CI 1.9-121.5) compared to age- and weight-matched controls (163). In a prospective cohort study, Bjercke et al. found an increased incidence of gestational hypertension among PCOS women compared to controls who had undergone assisted reproduction (11.5% vs. 0.3%, p < 0.01) (189). Additionally, preeclampsia was increased among insulin-resistant PCOS patients compared to noninsulin-resistant PCOS patients and controls, supporting the association between hyperinsulinemia and PIH.
While some authors have postulated that PCOS patients are more likely to have PIH due to ovulation induction, several studies have found PCOS to be associated with PIH even when controlling for infertility treatment. A retrospective case-control study of patients who had undergone ovulation induction by Kashyap et al. showed a higher incidence of PIH among PCOS patients than among controls (31.8% vs. 3.7%, p = 0.016) (190). Additionally, de Vries et al. stratified women according to treatment regimens for ovulation induction and found no relationship between the method used and preeclampsia (188).
Blood pressure readings during pregnancy in PCOS women provide further support for the association between PCOS and PIH. While a retrospective case control study found no differences in blood pressure during the first and second trimester between PCOS and control women, a significant increase in blood pressure occurred during the third trimester and labor in PCOS women (191). Similarly, in a prospective case-control study, Hu et al. demonstrated that women with PCOS had higher blood pressure throughout pregnancy than controls who were matched for age, BMI, parity and ethnicity (192). In addition, 27% (6/22) of the women with PCOS developed PIH compared with none in the control group (p = 0.011). The authors postulated that women with PCOS have decreased arterial elasticity, which worsens as gestation progresses, causing vascular maladaptation and elevated blood pressure (192).
Not all studies have found an association between PCOS and PIH. Turhan et al. found the prevalence of preeclampsia to be higher in PCOS women than in controls, although it did not reach statistical significance (165). In a retrospective case-control study, Haakova et al. reported no significant difference in the prevalence of PIH between PCOS patients and controls matched by age and weight (166). Overall, the studies support an association that was confirmed in the meta-analysis by Boomsma et al., which demonstrated a significantly higher chance of developing PIH (OR 3.67, CI 1.98-6.81) for women with PCOS (167). The increased risk remained in a subgroup analysis of two higher validity studies (OR 3.71, CI 1.72-17.49). Furthermore, women with PCOS demonstrated a higher risk of preeclampsia. The authors suggested that the association of PCOS with PIH suggested an increase in placental insufficiency, which could confer considerable risk to the fetus. While the initial analysis found a higher risk of premature deliveries, perinatal mortality and admission to the neonatal intensive care unit, a subgroup analysis of higher validity studies did not support this association.
Hyperandrogenemia has also been examined as a possible contributor to the increased risk of PIH in PCOS patients. Laivuori et al. found mild hyperandrogenism among women with a history of preeclampsia 17 years after delivery, suggesting that the patients may have had PCOS (193). Hu et al. noted a possible role for the hyperandrogenemia of PCOS in the pathogenesis of PIH in that androgens induce production of vasoconstrictors such as endothelin and angiotensinogen (192). They found elevated total testosterone levels in PCOS patients than in controls, but no differences in DHEAS. Furthermore, studies in animal models have shown that androgens decrease the production of prostacyclin (194), which could also be a factor in the development of PIH.
Gestational hypertension and preeclampsia have important short- and long-term implications. Women with gestational hypertension have higher rates of induction of labor and cesarean delivery than the general population (171). Even more consequentially, severe preeclampsia is associated with increased perinatal and maternal mortality and morbidity, particularly if the condition develops before 32-weeks gestation (171). Furthermore, studies have shown that women with a history of PIH have an increased risk of developing chronic hypertension and cardiovascular disease than women who remain normotensive during pregnancy (195-198). This may be due to endothelial dysfunction and insulin resistance along with effects of hyperandrogenism (195). For these reasons it is important to minimize the risk of PIH in patients with PCOS. Preconception counseling should include lifestyle interventions to promote weight loss in obese patients. Whether insulin-sensitizing agents, such as metformin, could be used for prevention of PIH in patients with PCOS remains to be determined.
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