AbstractBackgroundPrediction of pregnancy-related disorders is mostly done based on established and easily measured risk factors. However, these measures are at best moderate at discriminating between high and low risk women. Recent advances in metabolomics may provide earlier and more accurate prediction of women at risk of pregnancy-related disorders.Methods and FindingsWe used data collected from women in the Born in Bradford (BiB; n=8,212) and UK Pregnancies Better Eating and Activity Trial (UPBEAT; n=859) studies to create and validate prediction models for pregnancy-related disorders. These were gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), small for gestational age (SGA), large for gestational age (LGA) and preterm birth (PTB). We used ten-fold cross-validation and penalised regression to create prediction models. We compared the predictive performance of 1) risk factors (maternal age, pregnancy smoking status, body mass index, ethnicity and parity) to 2) nuclear magnetic resonance-derived metabolites (N = 156 quantified metabolites, collected at 24-28 weeks gestation) and 3) risk factors and metabolites combined. The multi-ethnic BiB cohort was used for training and testing the models, with independent validation conducted in UPBEAT, a study of obese pregnant women of multiple ethnicities.In BiB, discrimination for GDM, HDP, LGA and SGA was improved with the addition of metabolites to the risk factors only model. Risk factors area under the curve (AUC 95% confidence interval (CI)): GDM (0.69 (0.64, 0.73)), HDP (0.74 (0.70, 0.78)) and LGA (0.71 (0.66, 0.75)), and SGA (0.59 (0.56,0.63)). Combined AUC 95% (CI)): GDM (0.78 (0.74, 0.81)), HDP (0.76 (0.73, 0.79)) and LGA (0.75 (0.70, 0.79)), and SGA (0.66 (0.63,0.70)). For GDM, HDP, LGA, but not SGA, calibration was good for a combined risk factor and metabolite model. Prediction of PTB was poor for all models. Independent validation in UPBEAT at 24-28 weeks and 15-18 weeks gestation confirmed similar patterns of results, but AUC were attenuated. A key limitation was our inability to identify a large general pregnancy population for independent validation.ConclusionsOur results suggest metabolomics combined with established risk factors improves prediction GDM, HDP and LGA, when compared to risk factors alone. They also highlight the difficulty of predicting PTB, with all models performing poorly.Author SummaryBackgroundCurrent methods used to predict pregnancy-related disorders exhibit modest discrimination and calibration.Metabolomics may enable improved prediction of pregnancy-related disorders.Why Was This Study Done?We require tools to identify women with high-risk pregnancies earlier on, so that antenatal care can be more appropriately targeted at women who need it most and tailored to women’s needs and to facilitate early intervention.It has been suggested that metabolomic markers might improve prediction of future pregnancy-related disorders. Previous studies tend to be small and rarely undertake external validation.What Did the Researchers Do and Find?Using BiB (8,212 pregnant women of multiple ethnicities), we created prediction models, using established risk factors and 156 NMR-derived metabolites, for five pregnancy-related disorders. These were gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), small for gestational age (SGA), large for gestational age (LGA) and preterm birth (PTB). We sought external validation in UPBEAT (859 obese pregnant women).We compared the predictive discrimination (area under the curve - AUC) and calibration (calibration slopes) of the models. The prediction models we compared were 1) established risk factors (pregnancy smoking, maternal age, body mass index (BMI), maternal ethnicity and parity) 2) NMR-derived metabolites measured in the second trimester and 3) a combined model of risk factors and metabolites.Inclusion of metabolites with risk factors improved prediction of GDM, HDP, LGA and SGA in BiB. Prediction of PTB was poor with all models. Result patterns were similar in validation using UPBEAT, particularly for GDM and HDP, but AUC were attenuated.What Do These Findings Mean?These findings indicate that combining current risk factor and metabolomic data could improve the prediction of GDM, HDP, LGA and SGA. These findings need to be validated in larger, general populations of pregnant women.
Birth Size and Maternal, Social, and Environmental Factors in the Province of Jujuy, Argentina
