External validation, update and development of prediction models for pre-eclampsia using an Individual Participant Data (IPD) meta-analysis: the International Prediction of Pregnancy Complication Network (IPPIC pre-eclampsia) protocol.

Background: Pre-eclampsia, a condition with raised blood pressure and proteinuria is associated with an increased risk of maternal and offspring mortality and morbidity. Early identification of mothers at risk is needed to target management. Methods/design: We aim to systematically review the existing literature to identify prediction models for pre-eclampsia. We have established the International Prediction of Pregnancy Complication Network (IPPIC), made up of 72 researchers from 21 countries who have carried out relevant primary studies or have access to existing registry databases, and collectively possess data from more than two million patients. We will use the individual participant data (IPD) from these studies to externally validate these existing prediction models and summarise model performance across studies using random-effects meta-analysis for any, late (after 34 weeks) and early (before 34 weeks) onset pre-eclampsia. If none of the models perform well, we will recalibrate (update), or develop and validate new prediction models using the IPD. We will assess the differential accuracy of the models in various settings and subgroups according to the risk status. We will also validate or develop prediction models based on clinical characteristics only; clinical and biochemical markers; clinical and ultrasound parameters; and clinical, biochemical and ultrasound tests. Discussion: Numerous systematic reviews with aggregate data meta-analysis have evaluated various risk factors separately or in combination for predicting pre-eclampsia, but these are affected by many limitations. Our large-scale collaborative IPD approach encourages consensus towards well developed, and validated prognostic models, rather than a number of competing non-validated ones. The large sample size from our IPD will also allow development and validation of multivariable prediction model for the relatively rare outcome of early onset pre-eclampsia. Trial registration: The project was registered on Prospero on the 27 November 2015 with ID: CRD42015029349

Effects of tocolysis with nifedipine or atosiban on child outcome: follow‐up of the APOSTEL III trial

Objective To compare the long‐term effects of tocolysis with nifedipine or atosiban on child outcome at age 2.5–5.5 years. Design The APOSTEL III trial was a multicentre randomised controlled trial that compared tocolysis with nifedipine or atosiban in 503 women with threatened preterm birth. Neonatal outcomes did not differ between both treatment arms, except for a higher incidence of intubation in the atosiban group. Methods Parents were asked to complete four questionnaires regarding neurodevelopment, executive function, behaviour problems and general health. Main outcome measures The main long‐term outcome measure was a composite of abnormal development at the age of 2.5–5.5 years. Results Of the 426 women eligible for follow‐up, 196 (46%) parents returned the questionnaires for 115 children in the nifedipine group and 110 children in the atosiban group. Abnormal development occurred in 32 children (30%) in the nifedipine group and in 38 children (38%) in the atosiban group (OR 0.74, 95% CI 0.41–1.34). The separate outcomes for neurodevelopment, executive function, behaviour, and general health showed no significant differences between the groups. Sensitivity analysis for all children of the APOSTEL III trial, including a comparison of deceased children, resulted in a higher rate of healthy survival in the nifedipine group (64 versus 54%), but there was no significant difference in the overall mortality rate (5.4 versus 2.7%). There were no significant subgroup effects. Conclusion Outcomes on broad child neurodevelopment, executive function, behaviour and general health were comparable in both groups. Neither nifedipine nor atosiban can be considered as the preferred treatment for women with threatened preterm birth. Tweetable abstract Nifedipine‐ and atosiban‐exposed children had comparable long‐term outcomes, including neurodevelopment, executive function and behaviour

Pre-eclampsia

Pre-eclampsia is a multisystem disorder of pregnancy, characterised by hypertension and proteinuria, occurring after 20 weeks of gestation. As well as being associated with pregnancy complications such as preterm delivery and foetal growth restriction, pre-eclampsia is now increasingly known to be associated with cardiovascular diseases in later life. Despite decades of research into the condition, it remains difficult to predict, difficult to diagnose and difficult to treat. In this chapter pathophysiological mechanisms and origins of disease will be discussed, with a focus on placental and cardiovascular factors. Potential markers to improve early prediction of disease and therapeutic strategies will be discussed, as well as the relationship between pre-eclampsia and future maternal health problems

Effects of tocolysis with nifedipine or atosiban on child outcome: follow‐up of the APOSTEL III trial

Objective To compare the long‐term effects of tocolysis with nifedipine or atosiban on child outcome at age 2.5–5.5 years. Design The APOSTEL III trial was a multicentre randomised controlled trial that compared tocolysis with nifedipine or atosiban in 503 women with threatened preterm birth. Neonatal outcomes did not differ between both treatment arms, except for a higher incidence of intubation in the atosiban group. Methods Parents were asked to complete four questionnaires regarding neurodevelopment, executive function, behaviour problems and general health. Main outcome measures The main long‐term outcome measure was a composite of abnormal development at the age of 2.5–5.5 years. Results Of the 426 women eligible for follow‐up, 196 (46%) parents returned the questionnaires for 115 children in the nifedipine group and 110 children in the atosiban group. Abnormal development occurred in 32 children (30%) in the nifedipine group and in 38 children (38%) in the atosiban group (OR 0.74, 95% CI 0.41–1.34). The separate outcomes for neurodevelopment, executive function, behaviour, and general health showed no significant differences between the groups. Sensitivity analysis for all children of the APOSTEL III trial, including a comparison of deceased children, resulted in a higher rate of healthy survival in the nifedipine group (64 versus 54%), but there was no significant difference in the overall mortality rate (5.4 versus 2.7%). There were no significant subgroup effects. Conclusion Outcomes on broad child neurodevelopment, executive function, behaviour and general health were comparable in both groups. Neither nifedipine nor atosiban can be considered as the preferred treatment for women with threatened preterm birth. Tweetable abstract Nifedipine‐ and atosiban‐exposed children had comparable long‐term outcomes, including neurodevelopment, executive function and behaviour

Effects of tocolysis with nifedipine or atosiban on child outcome:follow-up of the APOSTEL III trial

Objective: To compare the long-term effects of tocolysis with nifedipine or atosiban on child outcome at age 2.5–5.5 years. Design: The APOSTEL III trial was a multicentre randomised controlled trial that compared tocolysis with nifedipine or atosiban in 503 women with threatened preterm birth. Neonatal outcomes did not differ between both treatment arms, except for a higher incidence of intubation in the atosiban group. Methods: Parents were asked to complete four questionnaires regarding neurodevelopment, executive function, behaviour problems and general health. Main outcome measures: The main long-term outcome measure was a composite of abnormal development at the age of 2.5–5.5 years. Results: Of the 426 women eligible for follow-up, 196 (46%) parents returned the questionnaires for 115 children in the nifedipine group and 110 children in the atosiban group. Abnormal development occurred in 32 children (30%) in the nifedipine group and in 38 children (38%) in the atosiban group (OR 0.74, 95% CI 0.41–1.34). The separate outcomes for neurodevelopment, executive function, behaviour, and general health showed no significant differences between the groups. Sensitivity analysis for all children of the APOSTEL III trial, including a comparison of deceased children, resulted in a higher rate of healthy survival in the nifedipine group (64 versus 54%), but there was no significant difference in the overall mortality rate (5.4 versus 2.7%). There were no significant subgroup effects. Conclusion: Outcomes on broad child neurodevelopment, executive function, behaviour and general health were comparable in both groups. Neither nifedipine nor atosiban can be considered as the preferred treatment for women with threatened preterm birth. Tweetable abstract: Nifedipine- and atosiban-exposed children had comparable long-term outcomes, including neurodevelopment, executive function and behaviour