Randomized Trial: Maternal Vitamin D Supplementation to Prevent Childhood Asthma

描述（由申请人提供）： 哮喘是儿童发病的主要原因之一，所有病例中有60%在3岁时确诊。因此，找到可以导致预防这种疾病的因素将具有重大的公共卫生意义。维生素D缺乏症在孕妇中非常普遍，因此是预防疾病的一个潜在的可改变因素。由于维生素D在调节免疫反应中的作用，我们认为孕妇缺乏维生素D会导致新生儿免疫系统发育不良，使其易患哮喘和过敏。我们从两项独立的出生队列研究中获得的观察数据表明，孕妇在怀孕期间摄入较高的维生素D与3岁和5岁儿童复发性喘息和哮喘的风险降低50%独立相关。然而，为了推荐这种方法作为预防哮喘的通用治疗方法，需要进行随机对照临床试验。因此，我们建议进行一项双盲、安慰剂对照、随机化的维生素D临床试验，以确定孕妇较高的维生素D摄入量和水平是否会预防3岁儿童的哮喘和过敏。我们将从参与本试验的三个临床中心的产科诊所中确定患有哮喘或过敏症或其伴侣患有哮喘或过敏症的孕妇。我们将在妊娠前三个月招募870名孕妇，并将其随机分配至4年临床试验的两个治疗组之一：4000 IU维生素D+常规产前维生素，n=435;和常规产前维生素单独治疗，n=435。我们的主要具体目标是确定孕妇补充足够的维生素D是否与婴儿出生后3年内哮喘发病率的降低有关。本研究的子目标将包括：（1）确定孕妇补充足够的维生素D是否与儿童在出生后3年内（a）过敏性致敏、（B）医生诊断的湿疹和（c）下呼吸道感染的次要结局减少相关;和（2）通过测量孕妇血浆、脐带血、以及1岁和3岁儿童的血液。公共卫生相关性：我们认为，维生素D缺乏可能对始于20世纪80年代初的哮喘流行产生了重大影响。更多的时间呆在室内，使用防晒霜导致阳光照射减少，维生素D的产生减少;缺乏足够的膳食补充剂来补偿这些行为变化，导致维生素D水平非常低。我们相信，如果孕妇服用足够剂量的维生素D，我们可以预防其后代一半的哮喘病例，并最终将疾病患病率降低到1980年前的水平。如果成功，这项试验将最终减少50%的哮喘发病率，从而减少80亿美元的医疗费用。这种干预是廉价的，安全的，并将导致重大的公共卫生利益。它也代表了过去30年来最具创新性和新颖性的哮喘治疗和预防方法。

DESCRIPTION (provided by applicant): Asthma is one of the leading causes of morbidity in children with 60% of all cases diagnosed by age 3. Thus, finding factors that can lead to prevention of this disease would be of great public health importance. Vitamin D deficiency is highly prevalent among pregnant women, and thus, represents a potentially modifiable factor for the prevention of disease. Due to the effect of vitamin D in modulating immune responses, we believe that vitamin D deficiency in pregnant mothers leads to faulty immune system development in the neonate, predisposing them to asthma and allergy. We have observational data from two independent birth cohort studies that higher maternal intakes of vitamin D during pregnancy are each independently associated with a 50% reduction in risk for recurrent wheezing and asthma in 3- and 5-yr old children. However, in order to recommend this as a universal treatment to prevent asthma, a randomized, controlled, clinical trial is necessary. Therefore, we propose a two arm, double-blind, placebo controlled, randomized, clinical trial of Vitamin D, to determine whether higher vitamin D intake and levels in the pregnant mother will prevent asthma and allergy in the child at age 3. We will identify pregnant women who have asthma or allergies or whose partner has asthma or allergies, from obstetric clinics in the three clinical centers participating in this trial. We will recruit 870 pregnant women during the first trimester of pregnancy and randomize them to one of two treatment arms of a 4-year clinical trial: 4000 IU of Vitamin D in addition to usual prenatal vitamins, n=435; and usual prenatal vitamins alone, n=435. Our primary specific aim is to determine whether adequate vitamin D supplementation in the pregnant mother is associated with reduced incidence of asthma in the child during the first 3 years of life. The sub-aims of the study will include (1) To determine whether adequate vitamin D supplementation in the pregnant mother is associated with reduced secondary outcomes in the child of (a) allergic sensitization, (b) doctor's diagnosis of eczema and (c) lower respiratory tract infections during the first 3 years of life; and (2) To determine whether adequate vitamin D supplementation in the pregnant mother is associated with improved vitamin D status in the mothers and their offspring through measurement of 25(OH)D levels in maternal plasma, cord blood, and children's blood at 1 and 3 yrs of age. Public Health Relevance: We believe that it is likely that Vitamin D deficiency has had a significant impact on the asthma epidemic that began in the early 1980's. Greater time spent indoors, and use of sun screen has resulted in reduced sun exposure and decreased production of vitamin D; and lack of adequate dietary supplementation to compensate for these behavioral changes, results in very low vitamin D levels. We believe that with adequate dosing of vitamin D in pregnant women, we can prevent half of all asthma cases in their offspring and ultimately reduce disease prevalence to pre-1980 levels. If successful, this trial will ultimately decrease asthma incidence by 50% and consequently decrease health care costs by 8 billion dollars. This intervention is cheap, safe, and will result in major public health benefit. It also represents the most innovative and novel approach to asthma treatment and prevention in the last 30 years.