AI-based analysis of fetal growth restriction in a prospective obstetric cohort quantifies compound risks for perinatal morbidity and mortality and identifies previously unrecognized high risk clinical scenarios.

Background: Fetal growth restriction (FGR) is a leading risk factor for stillbirth, yet the diagnosis of FGR confers considerable prognostic uncertainty, as most infants with FGR do not experience any morbidity. Our objective was to use data from a large, deeply phenotyped observational obstetric cohort to develop a probabilistic graphical model (PGM), a type of "explainable artificial intelligence (AI)", as a potential framework to better understand how interrelated variables contribute to perinatal morbidity risk in FGR. Methods: Using data from 9,558 pregnancies delivered at ≥ 20 weeks with available outcome data, we derived and validated a PGM using randomly selected sub-cohorts of 80% (n = 7645) and 20% (n = 1,912), respectively, to discriminate cases of FGR resulting in composite perinatal morbidity from those that did not. We also sought to identify context-specific risk relationships among inter-related variables in FGR. Performance was assessed as area under the receiver-operating characteristics curve (AUC). Results: Feature selection identified the 16 most informative variables, which yielded a PGM with good overall performance in the validation cohort (AUC 0.83, 95% CI 0.79-0.87), including among "N of 1" unique scenarios (AUC 0.81, 0.72-0.90). Using the PGM, we identified FGR scenarios with a risk of perinatal morbidity no different from that of the cohort background (e.g. female fetus, estimated fetal weight (EFW) 3-9th percentile, no preexisting diabetes, no progesterone use; RR 0.9, 95% CI 0.7-1.1) alongside others that conferred a nearly 10-fold higher risk (female fetus, EFW 3-9th percentile, maternal preexisting diabetes, progesterone use; RR 9.8, 7.5-11.6). This led to the recognition of a PGM-identified latent interaction of fetal sex with preexisting diabetes, wherein the typical protective effect of female fetal sex was reversed in the presence of maternal diabetes. Conclusions: PGMs are able to capture and quantify context-specific risk relationships in FGR and identify latent variable interactions that are associated with large differences in risk. FGR scenarios that are separated by nearly 10-fold perinatal morbidity risk would be managed similarly under current FGR clinical guidelines, highlighting the need for more precise approaches to risk estimation in FGR.