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Elevated Circulating and Placental SPINT2 Is Associated with Placental DysfunctionMurphy, Ciara N.; orcid: 0000-0001-6996-7250; email: email@example.com; Walker, Susan P.; email: firstname.lastname@example.org; MacDonald, Teresa M.; email: email@example.com; Keenan, Emerson; orcid: 0000-0003-1966-2293; email: firstname.lastname@example.org; Hannan, Natalie J.; email: email@example.com; Wlodek, Mary E.; orcid: 0000-0002-8490-9099; email: firstname.lastname@example.org; Myers, Jenny; email: Jenny.Myers@manchester.ac.uk; Briffa, Jessica F.; email: email@example.com; Romano, Tania; orcid: 0000-0002-8581-2256; email: firstname.lastname@example.org; Roddy Mitchell, Alexandra; email: email@example.com; et al. (MDPI, 2021-07-12)Biomarkers for placental dysfunction are currently lacking. We recently identified SPINT1 as a novel biomarker; SPINT2 is a functionally related placental protease inhibitor. This study aimed to characterise SPINT2 expression in placental insufficiency. Circulating SPINT2 was assessed in three prospective cohorts, collected at the following: (1) term delivery (n = 227), (2) 36 weeks (n = 364), and (3) 24–34 weeks’ (n = 294) gestation. SPINT2 was also measured in the plasma and placentas of women with established placental disease at preterm (34 weeks) delivery. Using first-trimester human trophoblast stem cells, SPINT2 expression was assessed in hypoxia/normoxia (1% vs. 8% O2), and following inflammatory cytokine treatment (TNFα, IL-6). Placental SPINT2 mRNA was measured in a rat model of late-gestational foetal growth restriction. At 36 weeks, circulating SPINT2 was elevated in patients who later developed preeclampsia (p = 0.028; median = 2233 pg/mL vs. controls, median = 1644 pg/mL), or delivered a small-for-gestational-age infant (p = 0.002; median = 2109 pg/mL vs. controls, median = 1614 pg/mL). SPINT2 was elevated in the placentas of patients who required delivery for preterm preeclampsia (p = 0.025). Though inflammatory cytokines had no effect, hypoxia increased SPINT2 in cytotrophoblast stem cells, and its expression was elevated in the placental labyrinth of growth-restricted rats. These findings suggest elevated SPINT2 is associated with placental insufficiency.