Validation and development of models using clinical, biochemical and ultrasound markers for predicting pre-eclampsia: an individual participant data meta-analysis.

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.

OBJECTIVES

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), late-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

RESULTS

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

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.

STUDY REGISTRATION

This study is registered as PROSPERO CRD42015029349.

FUNDING

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in

WHAT IS THE PROBLEM?

Pre-eclampsia, a condition in pregnancy that results in raised blood pressure and protein in the urine, is a major cause of complications for the mother and baby.

WHAT IS NEEDED?

A way of accurately identifying women at high risk of pre-eclampsia to allow clinicians to start preventative interventions such as administering aspirin or frequently monitoring women during pregnancy.

WHERE ARE THE RESEARCH GAPS?

Although over 100 tools (models) have been reported worldwide to predict pre-eclampsia, to date their performance in women managed in the UK NHS is unknown.

WHAT DID WE PLAN TO DO?

We planned to comprehensively identify all published models that predict the risk of pre-eclampsia occurring at any time during pregnancy and to assess if this prediction is accurate in the UK population. If the existing models did not perform satisfactorily, we aimed to develop new prediction models.

WHAT DID WE FIND?

We formed the International Prediction of Pregnancy Complications network, which provided data from a large number of studies (78 studies, 25 countries, 125 researchers, 3,570,993 singleton pregnancies). We were able to assess the performance of 24 out of the 131 models published to predict pre-eclampsia in 11 UK data sets. The models did not accurately predict the risk of pre-eclampsia across all UK data sets, and their performance varied within individual data sets. We developed new prediction models that showed promising performance on average across all data sets, but their ability to correctly identify women who develop pre-eclampsia varied between populations. The models were more clinically useful when used in the care of first-time mothers pregnant with one child, compared to a strategy of treating them all as if they were at high-risk of pre-eclampsia.

WHAT DOES THIS MEAN?

Before using the International Prediction of Pregnancy Complications models in various populations, they need to be adjusted for characteristics of the particular population and the setting of application.