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Association Between Cell-Free Fetal DNA and Placenta Accreta Spectrum: A Retrospective Cohort Study
Tianyue Zhang1,2, Pingping Li1,2, Donghao Liu2,3
1Department of Gynecology and Obstetrics, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
Background:
Prenatal diagnosis of placenta accreta spectrum (PAS) enables referral to specialized centers, reducing maternal and neonatal complications. However, imaging methods are not always reliable, and early studies suggest maternal serum cell-free fetal DNA (cffDNA) may be elevated in PAS.
Objective:
To evaluate the association between cffDNA levels derived from NIPT and PAS, and to assess its discriminative performance.
Methods:
This retrospective study included 81 PAS patients who underwent noninvasive prenatal testing (NIPT) at Beijing Hospital between January 2019 and December 2023, along with 810 matched controls (1:10 ratio; total n = 891). Clinical data and cffDNA levels were collected with informed consent. PAS was diagnosed clinically and confirmed histopathologically when hysterectomy was performed. Multivariable logistic regression and restricted cubic spline (RCS) analyses were used to evaluate the association between cffDNA and PAS, with inverse probability of treatment weighting (IPTW) applied to adjust for covariate imbalance. Model discrimination was assessed using receiver operating characteristic (ROC) curves, and the incremental value of cffDNA was evaluated by comparing AUC, net reclassification improvement (NRI), and integrated discrimination improvement (IDI).
Results:
Elevated cffDNA levels were associated with PAS (OR = 1.98, 95% CI: 1.03-3.81). Prior cesarean delivery (OR = 2.06) and gestational diabetes (OR = 1.74) were independent risk factors. RCS analysis showed a nonlinear, J-shaped association (p = 0.0101; inflection at 0.12). cffDNA alone showed limited discrimination (AUC = 0.573). The full model improved AUC to 0.630, but removing cffDNA resulted in only a small decrease (AUC = 0.604), with no significant incremental value based on NRI and IDI.
Conclusion:
CffDNA is nonlinearly associated with PAS but has limited discriminative ability as a standalone biomarker. It may serve as an adjunct in combination with other clinical or imaging factors.