Abstract / Summary
The fetal fraction (FF) of cell-free DNA determines the reliability of non-invasive prenatal testing (NIPT); whether first-trimester placental biomarkers add information beyond maternal factors is unclear. We linked NIPT samples from a single fetal medicine center over ten years (1162 pregnancies) to first-trimester screening records and modeled log FF with hierarchical regression (maternal/technical covariates → PAPP-A → free β-hCG), cluster-robust standard errors, and an order-independent bootstrapped partition of the biomarker contribution. In the primary complete-case model (n = 292), FF was 3.4% lower per kg/m2 of BMI (95% CI −4.4 to −2.3) and 24% lower after IVF/ICSI. Free β-hCG was independently associated with FF (+11.0% per doubling of MoM, 95% CI +5.3 to +16.9; semi-partial R2 = 0.046), whereas the PAPP-A association was weaker and less consistent (+4.8%, 95% CI −0.6 to +10.4; semi-partial R2 = 0.010). The β-hCG association persisted after excluding high-risk NIPT calls, documented multiple gestation and IVF/ICSI, within platform-restricted subsets and with a restricted documentation-to-draw interval. No independent association with gestational age was identified in the primary model; low-FF and no-call results were too few for adjusted inference. Free β-hCG carries independent information on FF, consistent with, but not proof of, a link to syncytiotrophoblast biology.