Oral cleft prevention program

描述(由申请人提供)：唇腭裂(CLP)占人类出生缺陷的很大一部分，并与一系列健康并发症有关。它们需要手术、牙科、言语、医疗和行为干预，并造成巨大的经济和社会负担。CLP是美国最常见的出生缺陷，每年约有6800例新病例，包括唇裂和/或腭裂，孤立和非孤立出生。对于一种相关的出生缺陷-神经管缺陷(NTD)，有一种有充分证据的、安全和廉价的预防措施。在怀孕前和怀孕早期补充叶酸表明，每天4毫克的叶酸可以将NTD复发的风险降低约70%。一些研究也表明，叶酸可降低口腔裂隙复发的风险，但这些研究受到严重的设计限制，叶酸对CLP复发的真正影响仍有待证实。重要的是进行一项强有力的、大规模的、双盲、随机的临床试验，清楚地解决这个问题。在本项目中，我们将完成对高剂量叶酸(4 Mg)和低剂量(0.4 mg)叶酸对预防CLP复发的效果的评估。五年前，在NIDCR、NICHD和盖茨基金会的赞助下，我们发起了这项研究。这项提议是利用现有的研究基础设施来完成目前的研究。我们将继续与最佳参与者网站、我们廉价叶酸补充剂的药物合作伙伴以及我们经验丰富的临床试验合作伙伴RTI进行数据管理。主要目的是评估每天补充4毫克叶酸对减少CLP复发的效果，在保守假设下，功率为0.80的CLP的复发减少50%。次要目标包括比较两种叶酸剂量对健康结局的影响，包括血清和红细胞叶酸水平；试验母亲的子代CLP的严重程度；流产和其他出生缺陷率；以及对出生体重和胎龄的影响。在单独的资助下，我们还将研究参与叶酸代谢的基因对叶酸、B12和同型半胱氨酸水平的作用。该项目解决了一个或多个患有唇裂的家庭在临床护理中面临的一个根本挑战，即如何管理复发预防。目前，据估计，美国每年有1000名患有唇裂的儿童出生于高危家庭。如果我们实现中电在这些家庭中减少50%，仅在美国，我们就可以减轻每个孩子和家庭的个人负担，并每年节省1亿美元与唇裂相关的经济成本。

DESCRIPTION (provided by applicant): Clefts of the lip and palate (CLP) comprise a large fraction of human birth defects, and are associated with a range of health complications. They require surgical, dental, speech, medical and behavioral interventions and impose a substantial economic and societal burden. CLP is the most prevalent birth defect in the United States, with about 6,800 new cases which includes cleft lip and/or palate, isolated and non-isolated born each year. There is a well documented, safe and inexpensive prevention for a related birth defect - those of the neural tube (NTD). Folic acid supplementation prior to pregnancy and during the first trimester shows that 4 mg per day will decrease NTD recurrence risks by about 70%. A few studies have also suggested decreased risks of recurrence of oral clefts with folic acid but these studies suffer from serious design limitations, and the real effect of folic acid on CLP recurrence remains to be demonstrated. It is critical to conduct a robust, large-scale, double-blinded, randomized clinical trial that clearly addresses this question. In this project we will complete the evaluation of the effect on prevention of CLP recurrence of periconceptual supplementation with high dose folic acid (4 mg) versus low dose (0.4 mg). We initiated this study five years ago under the sponsorship of the NIDCR, NICHD and the Gates Foundation. This proposal is to complete the current study by using the existing research infrastructure. We will continue involvement of the best participant sites, our pharmaceutical partner for inexpensive folate supplements and our experienced clinical trials partner, RTI, for data management. The primary aim is to assess the effect of folic acid supplementation of 4 mg/day on reducing the recurrence of CLP with power of 0.80 to see a 50% reduction under conservative assumptions. Secondary aims include comparing the effects of the two folic acid doses on health outcomes including serum and red cell folate levels; severity of CLP in offspring of trial mothers; rates of miscarriages and other birth defects; and effects on birth weight and gestational age. Under separate funding we will also examine the role of genes involved in folate metabolism on folate, B12 and homocysteine levels. This project addresses a fundamental challenge in the clinical care of families with one or more individuals with a cleft; that is, how to manage recurrence prevention. There are currently an estimated 1,000 births a year of children with clefts coming from high risk families in the US. If we were to realize a 50% reduction in CLP in these families, in the US alone, we would decrease the personal burden on each individual child and family and save $100 million in cleft-related economic costs per year.