Evaluating Maternal Serum SHH Levels in the First Trimester as a Potential Biomarker for Predicting Preeclampsia

To determine whether first-trimester maternal serum Sonic Hedgehog (SHH) predicts subsequent preeclampsia and to compare its predictive performance with soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF).

In a prospective cohort study, women with singleton pregnancies were enrolled at 8-13 weeks' gestation, clinical data were recorded, and fasting serum was collected. SHH, sFlt-1, and PlGF were quantified by ELISA in triplicate with coefficients of variation <10%. Associations between SHH and subsequent preeclampsia were tested using multivariable logistic regression with adjusted confounders; discriminative ability was evaluated by ROC analysis and stratified for early-onset (≤34 weeks) and late-onset (>34 weeks) preeclampsia.

Among 2532 enrolled pregnancies, 271 developed preeclampsia and 2261 remained normotensive. First-trimester SHH concentrations were significantly lower in pregnancies that later developed preeclampsia, with the greatest decrement in early-onset disease. Compared to the highest SHH tertile, adjusted odds of preeclampsia were higher in the middle (OR 2.64; 95% CI 1.334-5.38) and lowest tertiles (OR 5.21; 95% CI 3.15-8.42). SHH achieved an AUC of 0.86 (95% CI 0.62-0.91), with 81.46% sensitivity and 76.58% specificity at 58.26 ng/mL; sFlt-1 and PlGF yielded AUCs of 0.71 and 0.62, respectively. Performance was strongest for early-onset preeclampsia with an AUC of 0.93 (95% CI 0.67-0.97); sensitivity 87.73%; specificity 82.43% at 62.37 ng/mL, and modest for late-onset preeclampsia with an AUC of 0.75 (95% CI 0.54-0.86); sensitivity 73.42%; specificity 68.24% at 55.78 ng/mL.

Lower maternal serum SHH level in the first trimester is independently associated with later development of preeclampsia and provides clinically significant early prediction, particularly for early-onset disease. Incorporating SHH into first-trimester multiparametric screening alongside maternal factors and angiogenic markers may improve risk stratification and enable earlier prophylaxis and individualized antenatal surveillance.