A randomised controlled trial to compare two different doses of maternal B12 supplementation in improving infant B12 deficiency and neurodevelopment

维生素B12，也称为钴胺素，是一种水溶性维生素，在大脑和神经系统的正常运作中起着关键作用。据报告，在某些人群中，多达74%的妇女在产前期间患有营养不良。由于维生素B12在神经元健康（大脑和神经细胞健康）以及胎儿和婴儿大脑发育中的作用，新生儿缺乏B12是有问题的。我们建议这项研究比较两种不同剂量（治疗剂量与已知仅预防进一步缺乏的剂量相比）的产妇维生素B12补充剂在消除婴儿B12缺乏和神经发育方面的有效性。我们建议在印度和尼泊尔进行多中心试验，因为这些国家报告的维生素B12缺乏症发生率很高。我们将从新德里Sitaram Bhartia科学研究所和尼泊尔加德满都Paropakar Indrarajayalaxmi妇产医院妇产科的产前诊所招募720名孕妇。受试者将在首次到产前诊所就诊时被招募，并且应该是素食者，因为他们处于B12缺乏症的高风险中。年龄>35岁的母亲，已经补充B12，有多胎妊娠，慢性疾病，已知的心理疾病或那些预计在分娩前/后搬出城市的人将被排除在研究之外。被招募的母亲将被随机分配到2个相等的组（每组360人）。第1组（干预组）将在整个妊娠期和产后6个月内每天向母亲补充250微克维生素B12。第2组（对照组）将在整个妊娠期和产后6个月内向母亲补充50微克维生素B12。将记录母亲的概况信息，包括年龄、身高、体重、种族、教育、社会经济状况、母亲饮食评估（通过食物频率问卷）、任何补充剂（铁、叶酸、维生素D）摄入量等。维生素B12剂量将在入组时提供，然后每月提供给母亲。母亲的血液水平的维生素B12状态和其他缺陷将被提请。这些生化检测的采样将与这些阶段的其他常规检测相结合，以避免母亲的任何额外不适。分娩时，将监测和记录新生儿的分娩和分娩后过程，以了解可能影响神经发育的任何问题。出院后，所有新生儿将按照标准方案接受常规预防和疫苗接种护理。在例行访问期间，将记录包括体重、身长和头围在内的人体测量数据，并注意微量营养素缺乏症（特别是贫血和佝偻病）的迹象。在此期间，儿童所患的任何疾病都将被记录下来。两组母亲的补充将在分娩后6个月停止，然后在9个月时进行评估。神经发育评估和家庭环境评估将由发育治疗师进行，补充喂养评估由营养师进行。沿着9个月时Hb筛查的常规采样，将确定婴儿B12水平状态。然后将在两组之间比较婴儿神经发育评分的评估、婴儿和母亲的B12状态的生化指标，以观察接受较高剂量（250 mcg）的组的神经发育和/或B12状态是否更好和安全。阳性或阴性结果将产生科学证据，说明素食孕妇是否应该补充B12，以防止B12缺乏及其对婴儿神经发育的影响。这也将有助于制定政策和框架，在高风险人群中常规/更广泛地使用这种补充剂。

Vitamin B12, also called cobalamin, is a water-soluble vitamin that has a key role in the normal functioning of the brain and nervous system. Up to 74% women are reported deficient during antenatal period in some populations. Deficiency of B12 in newborns is problematic given the role Vitamin B12 plays in neuronal health (brain and nerve cells health) and in the development of foetal and infant brain. We propose this research to compare two different doses (a treatment dose in comparison with a dose known to just prevent further deficiency) of maternal Vitamin B12 supplementation in terms of their effectiveness in removing infant B12 deficiency and neurodevelopment.We propose to undertake a multi-centric trial in India and Nepal as these are countries where high incidence of deficiency is reported. We will recruit 720 pregnant women from the antenatal clinics of the department of Gynaecology and Obstetrics at Sitaram Bhartia institute of Science and Research, New Delhi and Paropakar Indrarajayalaxmi Maternity Hospital, Kathmandu, Nepal. The subjects will be recruited at their first presentation to the antenatal clinic and should be vegetarian as they are at high-risk of B12 deficiency. Mothers who are >35 years of age, are already on B12 supplementation, have multiple gestation, chronic medical conditions, known psychological illnesses or those who anticipate moving out of the city before/after delivery will be excluded from the study. Recruited mothers will be randomly allocated to 2 equal groups (360 each). Group 1 (Intervention) will receive daily 250 micrograms Vitamin B12 supplementation to the mother through pregnancy and up to 6 months post-partum. Group 2 (Control) will receive 50 micrograms Vitamin B12 supplementation to the mother through pregnancy and up to 6 months post-partum. The profile information of the mother including age, height, weight, ethnicity, education, socioeconomic status, maternal dietary assessment (by Food Frequency Questionnaire), intake of any supplements (iron, folate, Vitamin-D) etc. will be recorded. Vitamin B12 dosage will be provided at enrolment and then monthly to mothers. Mother's blood levels for Vitamin B12 status and other deficiencies will be drawn. Sampling for these biochemical tests will be combined with other routine tests at these stages to avoid any additional discomfort for the mother. At childbirth, the delivery and post-delivery course of the new-born will be monitored and documented for any problems potentially influencing neurodevelopment. After discharge, all neonates will be routinely followed with preventive and vaccination care as per standard protocols. During routine visits, anthropometric measurements including weight, length and head circumference will be recorded and signs of micronutrient deficiency (especially anaemia and rickets) will be noted. Any illnesses suffered by the child in the intervening period will be recorded. Supplementation of the mother in both groups will be stopped at 6 months after childbirth followed by evaluation at 9 months. The neurodevelopmental assessment and home environment assessment will be done by a developmental therapist and complementary feeding assessment by a nutritionist. Along with routine sampling for Hb screening at 9 months, infant B12 levels status will be determined. The assessment of the infant neurodevelopment scores, the biochemical measures of B12 status of the infant and those of the mother will then be compared between the two groups to see if the neurodevelopment and/or B12 status in the group receiving the higher dose (250 mcg) is better and safe. A positive or a negative result will generate scientific evidence on whether B12 should be supplemented in vegetarian pregnant women with a view to preventing B12 deficiency and its neurodevelopmental consequences in the infant. This will also allow the development of policies and frameworks for routine/wider usage of this supplement in high-risk populations