Haptoglobin Phenotype, Preeclampsia Risk and the Efficacy of Vitamin C and E Supplementation to Prevent Preeclampsia in a Racially Diverse Population

Abstract

Haptoglobin’s (Hp) antioxidant and pro-angiogenic properties differ between the 1-1, 2-1, and 2-2 phenotypes. Hp phenotype affects cardiovascular disease risk and treatment response to antioxidant vitamins in some non-pregnant populations. We previously demonstrated that preeclampsia risk was doubled in white Hp 2-1 women, compared to Hp 1-1 women. Our objectives were to determine whether we could reproduce this finding in a larger cohort, and to determine whether Hp phenotype influences lack of efficacy of antioxidant vitamins in preventing preeclampsia and serious complications of pregnancy-associated hypertension (PAH). This is a secondary analysis of a randomized controlled trial in which 10,154 low-risk women received daily vitamin C and E, or placebo, from 9-16 weeks gestation until delivery. Hp phenotype was determined in the study prediction cohort (n = 2,393) and a case-control cohort (703 cases, 1,406 controls). The primary outcome was severe PAH, or mild or severe PAH with elevated liver enzymes, elevated serum creatinine, thrombocytopenia, eclampsia, fetal growth restriction, medically indicated preterm birth or perinatal death. Preeclampsia was a secondary outcome. Odds ratios were estimated by logistic regression. Sampling weights were used to reduce bias from an overrepresentation of women with preeclampsia or the primary outcome. There was no relationship between Hp phenotype and the primary outcome or preeclampsia in Hispanic, white/other or black women. Vitamin supplementation did not reduce the risk of the primary outcome or preeclampsia in women of any phenotype. Supplementation increased preeclampsia risk (odds ratio 3.30; 95% confidence interval 1.61–6.82, p<0.01) in Hispanic Hp 2-2 women. Hp phenotype does not influence preeclampsia risk, or identify a subset of women who may benefit from vitamin C and E supplementation to prevent preeclampsia.

Haptoglobin phenotype and abnormal uterine artery Doppler in a racially diverse cohort

“…The largest case-control studies suggested that Hp 1-1 was associated with a lower preeclampsia risk compared to Hp 2-1 [18], or Hp 2-1 and 2-2 [17]. However, we found no relationship between Hp phenotype and preeclampsia risk in 4,500 women from the present trial, suggesting that the results of small case-control studies may have been spurious findings [21]. This highlights the need for large, prospective studies [21, 23].…”

“…However, we were unable to confirm a relationship between Hp phenotype and preeclampsia risk in large cohorts of low-risk nulliparous women [21] or women with Type 1 diabetes [22] participating in randomized controlled trials of antioxidants for preeclampsia prevention. This highlights the importance of using large cohort studies when examining Hp phenotype and pregnancy outcome to reduce the likelihood of spurious findings [23].…”

“…Hp 2-2 is associated with increased vascular stiffness in Type 2 diabetes [13, 14], however little is known about Hp phenotype and vascular stiffness in other populations. We conducted a pre-planned secondary analysis to determine whether Hp phenotype was associated with abnormal UAD in the trial of low risk nulliparous women [21]. We hypothesized that Hp 2-2 women would be more likely to have abnormal UAD at 17 weeks gestation and persistent notching at 24 weeks gestation.…”

Preeclampsia and Diabetes

“…The first examined low risk primiparous women [51], while the second enrolled women with type 1 diabetes [28]. Hp phenotype was not associated with preeclampsia risk in either trial [56, 57]. Furthermore, the authors found no evidence that vitamins C and E prevented preeclampsia in women of any Hp phenotype [56, 57].…”

“…Hp phenotype was not associated with preeclampsia risk in either trial [56, 57]. Furthermore, the authors found no evidence that vitamins C and E prevented preeclampsia in women of any Hp phenotype [56, 57]. Despite proven effects in other disease states, it appears that Hp phenotype does not play a significant role in preeclampsia risk or responsiveness to antioxidant vitamin supplementation to prevent preeclampsia.…”