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

这是一项完整的建议（观察性试验，无干预计划）作为PETN多中心研究的后续研究。PETN研究调查了no供体四硝基季戊四酸（PETN）与安慰剂对妊娠中期发现有胎儿生长受限（FGR）风险的胎盘失败孕妇的影响。FGR是围产期死亡和发病的最重要原因，对相应儿童的短期和长期身体和神经认知结果产生负面影响。在一项初步研究中，使用PETN治疗可将FGR或围产期死亡的相对风险降低38%。317名孕妇参加了petn研究的多中心试验。结果不能证实对主要综合结局“胎儿生长受限或围产期死亡的发展”的影响，但早产减少了30%，发生高血压妊娠并发症的母亲明显减少。petn研究涵盖了12个月大的研究儿童。这些数据显示，在PETN组中，年龄调整后发育正常的儿童比例明显更高（待提交的出版物）。无论检索到的结果如何，在推荐治疗之前，任何孕期药物治疗都必须需要这些妊娠所生儿童的长期随访数据。因此，这项建议将包括在pet - n研究和试点试验期间出生的儿童的长期随访。由于研究中出生的儿童中有43%是生长受限的，因此本次随访调查将揭示该随机试验中生长受限以及适当成年儿童的随访数据。我们的假设是：(1)：在儿童发育方面，PETN治疗的长期结局不逊于安慰剂治疗(2):PETN治疗改善了出生时生长受限儿童的长期结局。所有幸存的PETN研究儿童将被邀请参加。主要终点是儿童行为检查表（CBCL，日常功能水平评估）的总分。次要终点是身体健康（体重、身高、血液分析、血压、脉搏波速度、CIMT、Tanner分期）、一般发育结局（评分：FTF 5-15-R）、认知、运动和执行功能以及神经认知结局。CBCL， 6-18-R和YSR 6-18-R，儿童定期检查和坦纳阶段的身体数据将通过邮寄调查收集。还提供额外的实地访问，以获得身体和认知数据。主要终点将通过两个独立样本的单侧t检验进行分析（验证性分析，p = 0.05）。连续次要终点采用双侧独立样本t检验或双侧mann - whitney - u检验（探索性分析，p = 0.05）进行分析。样本量计划（参数：SD/CBCL，功率：80%，p = 0.05）结果需要204个数据集。

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.