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Additional file 3: Supplementary Table 3. Median duration of use of domperidone in weeks according to maternal and infant characteristics.

Additional file 2: Supplementary Table 2. Postpartum timing of starting domperidone use by mothers in different groups.

Additional file 1: Supplementary Table 1. Maximum dose of domperidone used during lactation according to maternal and infant characteristics.

Additional file 1. Table S1: Study questionnaire. Table S2: 14 items OHIP scale. Fig. S3: Goodness of fit.

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management. Objective : To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers. Design: This was an individual participant data meta-analysis of cohort studies. Setting: Source data from secondary and tertiary care. Predictors: We identified predictors from systematic reviews, and prioritised for importance in an international survey. Primary outcomes Early-onset (delivery at = 34 weeks' gestation) and any-onset pre-eclampsia. Analysis: We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration. We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for C-statistics of >= 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using l(2) and tau(2). A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals. Result The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary C-statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia. Limitations: Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data. Conclusion: For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings. Future work: Recalibration of model parameters within populations may improve calibration performance. Additional strong predictors need to be identified to improve model performance and consistency. Validation, including examination of calibration heterogeneity, is required for the models we could not validate.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting. METHODS: IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis. RESULTS: Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model's calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions appeared small and limited to probability thresholds between 5 and 7%. CONCLUSIONS: The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across multiple UK settings before consideration for use in practice. TRIAL REGISTRATION: PROSPERO ID: CRD42015029349 .

Additional file 1: Supplementary methods: Additional details for handling missing data and evaluating predictive performance of models. Table S1: Search strategy for pre-eclampsia prediction models. Table S2: Predictors evaluated in the models externally validated in the IPPIC-UK cohorts. Table S3: Prediction models and equations identified from the literature search. Table S4: Study level characteristics of IPPIC-UK cohorts. Table S5: Patient characteristics of IPPIC-UK cohorts. Table S6: Number and proportion missing for each predictor in each cohort used for external validation. Table S7: Risk of bias assessment of the IPPIC-UK cohorts using the PROBAST tool. Table S8: Summary of linear predictor values and predicted probabilities for each model in each cohort. Table S9: Predictive performance statistics for models in the individual IPPIC-UK cohorts. Table S10: Predictive performance statistics for models in nulliparous women in all cohorts and in the POP cohort. Fig. S1: Decision curves for early pre-eclampsia models in SCOPE, UPBEAT and POP. Fig. S2: Decision curves for late pre-eclampsia models in SCOPE, Allen 2017, UPBEAT and POP.