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Fetal sex-specific associations between first trimester (9–13 weeks) maternal serum inflammatory biomarkers and spontaneous preterm birth: a case control study

Year: 2026

Type: article

Abstract: Elevated levels of circulating inflammatory biomarkers in pregnant people have been associated with spontaneous preterm birth (sPTB), but few studies have investigated whether these biomarker signatures are detectable in the first trimester. In addition, despite emerging evidence that fetal sex shapes inflammatory signalling, few studies have explored whether fetal sex modifies the relationship with sPTB. Thus, this study sought to explore the association between six inflammatory mediators: interleukin-6 (IL-6), interleukin-1β (IL-1β), tumour necrosis factor-alpha (TNF-α), interleukin-8 (IL-8), interleukin-10 (IL-10), and 15-hydroxyeicosatetraenoic acid (15-HETE) and sPTB, with consideration of fetal sex. First trimester (9–13 + 6 weeks) serum samples from n = 164 sPTB and n = 164 term pregnancies were collected as part of the Early Risk Assessment pregnancy program in Calgary, Canada. Inflammatory biomarkers were analysed using a multiplexed immunoassay and ELISA. Associations were determined using univariate and multivariate logistic regression, and potential effect modification by fetal sex was assessed. Potential predictive power was assessed using elastic net logistic regression, unregularized logistic regression and random forest approaches. Lower serum TNF-α was associated with sPTB (adjusted OR = 0.37[0.20–0.65], p = 0.001). In sex-stratified analyses, IL-1β was positively associated (aOR = 1.64[1.08–2.54], p = 0.024) and IL-8 negatively associated (aOR = 0.50[0.28–0.88], p = 0.019) with sPTB in female-bearing pregnancies, however, fetal sex showed no significant effect modification ( p > 0.05 for all biomarkers) suggesting no true sex modification in this sample. A random forest model incorporating these biomarkers classified sPTB with an AUC of 0.69 [0.65–0.72]. These results reveal that first trimester serum inflammatory biomarkers are associated with sPTB, highlighting the potential for TNF-α-mediated signalling in sPTB pathophysiology.

Source: BMC Pregnancy and Childbirth

DOI: 10.1186/s12884-026-10075-7