Association of AAT/ SERPINA1 PI*Z Variant with Gestational Duration and Prevention of Premature Birth in Knockout Mice by AAT-Supplementation

About 10% of pregnancies end prematurely before 37 weeks, without effective prevention therapies. Previously, we identified rare damaging variants in SERPINA1 encoding Alpha-1-antitrypsin (AAT) in families with recurrent spontaneous preterm births (SPTB) and detected decreased protein and mRNA levels of AAT/ SERPINA1 from placentas in SPTB. Here, we investigated genetic associations between SERPINA1 variants and gestational duration and evaluated AAT supplementation as a therapeutic intervention in a mouse model of preterm birth. SERPINA1 Pi*Z variant (rs28929474-T) was associated with gestational duration ( P < 5×10 ^-8 ) in European-ancestry mothers with preterm and term deliveries. We detected a nine-day decrease in gestational duration and a fourfold Odds for preterm birth vs. term birth in Pi*Z homozygotes (Pi*ZZ), compared to other genotypes. In transgenic mice without endogenous AAT, exogenous Prolastina ^® treatment inhibited LPS-induced preterm births ( P < 0.05). Supplemented AAT was preferentially deposited in the placenta. Our findings support AAT’s protective role in SPTB and highlight its therapeutic potential, particularly in SERPINA1 Pi*ZZ genotype carriers.