Long-term follow-up of children born in the PETN studies (LOOP)

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This is a full proposal (observational trial, no intervention planned) as follow-up study of the PETN multicenter study. The PETN-study investigated the effect of the NO-donor pentaerithrityltetranitrate (PETN) compared to placebo on pregancies with placentation failure, identified at mid gestation to be at risk for the development of fetal growth restriction (FGR). FGR is the most important cause of perinatal mortality and morbidity, negatively affecting short and long-term physical and neurocognitive outcome of the respective children. In a pilot study, treatment with PETN reduced relative risk for FGR or perinatal death by 38%. 317 pregnant women took part in the PETN-study multicenter-trial. Results could not confirm the effect on the primary composite outcome “development of fetal growth restriction or perinatal death” but preterm was reduced by 30% and significantly less mothers developed hypertensive pregnancy complications. The PETN-study covered the follow of the study children at the age of 12 months. These data show a significant higher proportion of children with normal age adjusted development in the PETN group (publication to be submitted). Regardless of the results retrieved, any drug treatment during pregnancy mandatorily needs long-term follow-up data of the children born from these pregnancies before treatment can be recommended. Thus, this proposal will cover the long-term follow-up of the children born during the PETN-study and the pilot trial. Since 43% of the children born in the study were growth restricted, this follow up investigation will reveal follow up data of growth restricted as well as of appropriate grown children from this randomized trial. Our hypotheses are (1): Regarding child development, the long-term outcome of PETN treatment is not inferior to Placebo treatment (2): PETN treatment improves the long-term outcome of children born growth restricted. All surviving PETN study children will be invited for participation. Primary endpoint will be the total score of the Child-Behaviour-Checklist (CBCL, assessment of everyday functional level). Secondary endpoints are physical health (weight, height, blood analysis, blood pressure, pulse wave velocity, CIMT, Tanner stages), general developmental outcome (score: FTF 5-15-R), cognitive, motoric and executive function as well as neurocognitive outcome. CBCL, 6-18-R and YSR 6-18-R, physical data from regular pediatric check-up visits and Tanner stages will be collected in a postal survey. Additional on-site visits to obtain physical and cognitive data are offered. The primary endpoint will be analyzed by one-sided t-test for two independent samples (confirmatory analysis, p = 0.05). Continuous secondary endpoints will be analyzed by two-sided independent samples t-test or two-sided Mann-Whitney-U-tests (explorative analysis, p = 0.05). Sample size planning (parameters: SD/CBCL, power: 80%, p = 0.05) resulted in 204 data sets needed.