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。他们需要手术、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是美国最普遍的出生缺陷，每年约有6，800例新病例，包括唇腭裂，孤立和非孤立出生。有一个良好的记录，安全和廉价的预防相关的出生缺陷-那些神经管（NTD）。在怀孕前和怀孕的第一个三个月期间补充叶酸，每天4毫克将使NTD复发风险降低约70%。一些研究也表明叶酸可降低唇腭裂复发的风险，但这些研究存在严重的设计局限性，叶酸对CLP复发的真实的作用仍有待证实。关键是要进行一个强大的，大规模的，双盲，随机临床试验，明确解决这个问题。在本项目中，我们将完成对高剂量叶酸（4 mg）与低剂量叶酸（0.4 mg）的围孕期补充预防CLP复发的效果评价。五年前，我们在NIDCR、NICHD和盖茨基金会的赞助下发起了这项研究。这项建议是利用现有的研究基础设施完成目前的研究。我们将继续参与最佳的参与地点，我们的制药合作伙伴廉价叶酸补充剂和我们经验丰富的临床试验合作伙伴RTI的数据管理。主要目的是评估叶酸补充4 mg/天对降低CLP复发的影响，把握度为0.80，在保守假设下可降低50%。次要目的包括比较两种叶酸剂量对健康结果的影响，包括血清和红细胞叶酸水平;试验母亲后代中CLP的严重程度;流产和其他出生缺陷的发生率;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。该项目解决了一个基本的挑战，在临床护理的家庭与一个或多个人与裂缝;也就是说，如何管理复发预防。据估计，美国每年有1,000名来自高风险家庭的婴儿出生。如果我们能在这些家庭中实现CLP减少50%，仅在美国，我们就能减轻每个儿童和家庭的个人负担，每年节省1亿美元与裂缝相关的经济成本。

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.