Serum uric acid in pregnancy and hypertensive status: a U-shaped association in NHANES with external cohort analysis

Hypertensive disorders of pregnancy (HDP) are a major cause of maternal and perinatal morbidity. Serum uric acid (SUA) has been implicated in the pathophysiology of HDP, particularly preeclampsia, but the shape and clinical interpretation of this association remain uncertain. We investigated the cross-sectional association between gestational SUA levels and hypertensive status during pregnancy in a nationally representative sample and examined whether similar patterns were present in an independent clinical cohort. We conducted a cross-sectional analysis of pregnant women aged 18 to 49 years from the National Health and Nutrition Examination Survey (NHANES) 1999–2018. Survey-weighted logistic regression, restricted cubic splines, and generalized additive models were used to evaluate potential non-linear associations between SUA and hypertensive status during pregnancy. To reduce small-event bias, parsimonious adjustment models and penalized regression were applied. The fixed quadratic model derived from NHANES was subsequently evaluated in a cohort from the First Affiliated Hospital of Harbin Medical University. In the external cohort, additional exploratory analyses were performed separately for preeclampsia and gestational hypertension. Among 1,220 pregnant women in NHANES, 30 cases of concurrent pregnancy-onset hypertension were identified after exclusion of self-reported pre-pregnancy hypertension. Survey-weighted spline analyses suggested a possible non-linear (U-shaped) association between SUA and hypertensive status. The estimated nadir of predicted probability ranged from approximately 3.8 to 4.1 mg/dL across modeling approaches, although confidence intervals were wide because of the limited number of events. In the external cohort ( n = 291; HDP n = 53; mean gestational age at sampling, 35 weeks), SUA was associated with concurrent hypertensive status during pregnancy. Discriminative performance differed by subtype: the area under the receiver operating characteristic curve was 0.83 for preeclampsia versus controls and 0.64 for gestational hypertension versus controls. In this cross-sectional analysis, gestational SUA levels showed a U-shaped association with hypertensive status during pregnancy in NHANES, and a similar directional pattern was observed in an external clinical cohort. However, because SUA and blood pressure were measured concurrently in both datasets, especially late in pregnancy in the validation cohort, temporal relationships cannot be established and reverse causality cannot be excluded. These findings should therefore be interpreted as associative rather than predictive. Prospective longitudinal studies with early-pregnancy sampling are needed to clarify causality and clinical utility.