使用二甲双胍预防先兆子痫:一项随机对照试验 (PREMET)
研究概览
详细说明
先兆子痫 (PET) 是孕产妇发病率和死亡率的主要原因之一。 其病理生理学知之甚少。 因此,没有有效的预防和治疗方式。 PET 与显着的围产期发病率和死亡率相关,包括住院时间延长,并且是大部分医源性早产的主要原因。 患有 PET 的女性在以后的生活中患高血压和心血管疾病的风险更大,并且更有可能过早死亡。 由于 PET 的唯一治疗方法是分娩,因此降低发病率和后果的合理方法是预防。 为使其有效,必须确定处于风险中的人并及时采取任何干预措施。
风险因素包括产妇年龄、肥胖、抗磷脂综合征等医学疾病、高血压疾病、肾病糖尿病和既往 PET。 PET 病史使复发风险增加 7 倍,而受累妊娠在分娩时发生 GA 则更加复杂。 此外,慢性高血压和既往糖尿病都会增加 PET 的风险,而这种风险会因血糖控制程度而进一步增加。 有趣的是,母亲和父亲的糖尿病和高血压病史与 PET 风险增加有关。 此外,产妇年龄 > 40 岁和妊娠间隔 > 10 年分别使 PET 的风险增加两到三倍。BMI > 35 使经产和未生育妇女的 PET 风险增加 4 倍。 此外,辅助生殖技术和多胎妊娠也与 PET 风险增加有关。 在卡塔尔患病率很高的糖尿病和肥胖症的结合会显着增加 PET 的风险。 尽管有这些风险因素,但只有一小部分高风险人群最终会发展为 PET,因为目前的预测标准并不具体。
几个小组/研究人员已经调查和尝试了预测、预防和治疗先兆子痫的各种措施。 然而,这些都不是很成功,主要是因为 PET 是一种理论疾病,其主要病理生理学不明确,因此这些预测工具或干预措施都没有明确的目标。 然而,证据确实表明,在有发生 PET 风险的患者中,滋养细胞浸润不足、胎盘灌注不足和内皮细胞活化不足。 这是子宫动脉多普勒测速最广泛的无创临床工具的基础;但同样,它的灵敏度很差。 血管内皮生长因子 (VEGF) 和胎盘生长因子 (PIGF)(减少)等促血管生成因子和可溶性 FMS 样酪氨酸激酶 -1 (sFlt-1)(增加)等抗血管生成因子的失衡与发生 PET 的女性螺旋动脉重塑不足(这对于维持正常的胎盘灌注至关重要)。
血管内皮生长因子 (VEGF) 是健康和疾病(如癌症、肾脏疾病和 PET)中的重要信号蛋白。 VEGF 家族由五个成员和三个酪氨酸激酶受体组成。 信号蛋白是:VEGFA、VEGFB、VEGFC、VEGFD 和胎盘生长因子 (PlGF)(综述于 (20))。 受体酪氨酸激酶由VEGFR1(又称Flt-1)、VEGFR2和VEGF3组成,与VEGF蛋白的结合能力不同。 还鉴定了一种可溶性 Fms,如酪氨酸激酶-1 (sFlt-1),一种截短形式的 VEGFR1,它缺乏 VEGFR1 胞质结构域。 除了配体结合外,VEGFR 已被证明可通过非配体结合和机械力激活。 VEGF 蛋白在缺氧条件下如 PET、生长因子信号和雌激素等激素上调。PET 的特点是缺氧环境,导致母体白细胞基因表达发生相当大的变化,VEGF 信号通路和 AMP 激活蛋白激酶的表达改变(AMPK) 和 sFlt-1 分泌到母体循环中。包括 PIGF 在内的 VEGF 已被确定为胎盘发育过程中血管生成和血管生成信号通路的关键。事实上,小鼠中单个 VEGF 等位基因的缺失导致胚胎致死,因为未成熟的血管生成。 细胞滋养细胞侵入母体螺旋动脉对于充足的氧气和营养供应至关重要。 该过程被认为是由 VEGF 和 PIGF 与 Flt-1 的结合介导的。 此外,Flt-1 区域的胎儿 DNA 变异与 PET 相关,最近也有报道。 然而,PET 的病理生理学仍不清楚,需要了解其分子机制。 已观察到 VEGF 和 PIGF 游离形式的水平降低,这归因于先兆子痫女性中 sFlt-1 水平升高的阻断作用。 事实上,将 sFlt-1 引入怀孕大鼠会导致高血压和蛋白尿,这与 PET 女性中所见相似。 此外,已发现血清 PIGF/sFlt-1 比率的改变与 PET 诊断和疾病严重程度相关。 事实上,现在有一种使用这一比率来筛查有 PET 风险的妇女的动力,但大部分数据是在妊娠晚期而不是妊娠早期产生的——此时干预措施已被证明具有最大的影响。 从对发展 PET 的女性潜在生理变化的更深入理解看来,任何有可能改变这种环境的干预措施都更有可能成功。最近一项双盲、安慰剂对照试验,随机分配体重指数超过 35 的非糖尿病孕妇在妊娠 12 至 18 周直至分娩期间接受二甲双胍(每天 3.0 克)或安慰剂(每组 225 名妇女)显示显着降低在接受二甲双胍治疗的患者中 PET 的发生率。 由于二甲双胍现在经常用于肥胖的 II 型糖尿病女性和饮食血糖控制不佳的妊娠期糖尿病患者,因此假设在那些有 PET 风险的人群中,二甲双胍不仅会降低 PET 的发生率,还会改变 PIGF/s-Flt -1 比率有利于正常怀孕。
研究类型
注册 (预期的)
阶段
- 不适用
联系人和位置
学习联系方式
- 姓名:Jyothi Lakshmi, MSc
- 电话号码:+97431152937
- 邮箱:jyothilakshmij84@gmail.com
研究联系人备份
- 姓名:Mariam Maducolil, MD
- 邮箱:MMaducolil@hamad.qa
学习地点
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Doha、卡塔尔、3050
- Women Wellness and Research Center
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接触:
- Jyothi Lakshmi, MSc
- 电话号码:+97431152937
- 邮箱:jyothilakshmij84@gmail.com
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接触:
- Mariam Maducolil, MD
- 电话号码:+97433938513
- 邮箱:MMaducolil@hamad.qa
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参与标准
资格标准
适合学习的年龄
接受健康志愿者
有资格学习的性别
描述
纳入标准:
- 确认怀孕
- 胎龄 < 12+0 周
- 预约超声波扫描时的活胎儿(妊娠 11+0 至 13+6 周之间)
- 被认为是先兆子痫的高风险
排除标准:
- 18岁以下
- 妊娠剧吐
- 无法签署同意书
- 1 型或 2 型糖尿病
- 早期妊娠糖尿病
- 自身免疫性疾病
- 扫描时发现的胎儿异常(妊娠 11+0 至 13+6 周之间)
- 出血性疾病
- 消化性溃疡
- 对阿司匹林或二甲双胍过敏
- 干预开始前长期使用非甾体抗炎药
- 对二甲双胍或阿司匹林有禁忌症并参加了另一项同时进行的试验。
学习计划
研究是如何设计的?
设计细节
- 主要用途:预防
- 分配:随机化
- 介入模型:并行分配
- 屏蔽:无(打开标签)
武器和干预
参与者组/臂 |
干预/治疗 |
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无干预:标准护理
对照组将根据 ACOG 指南接受包括阿司匹林在内的标准护理治疗。
对照组估计入组人数为 207 名患者。
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实验性的:二甲双胍
除了标准护理外,干预组还将每天口服 3 次二甲双胍 500 毫克。
预计入组人数为 207 名患者。
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二甲双胍是一种用于治疗糖尿病的药物。
在这项研究中,它将用于探索它在预防先兆子痫中的潜在作用。
该药物将在怀孕 12 周之前开始并持续到分娩
其他名称:
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研究衡量的是什么?
主要结果指标
结果测量 |
措施说明 |
大体时间 |
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PET的发生率
大体时间:通过学习完成期(3年)
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比较二甲双胍组(干预组)与对照组的 PET 发生率
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通过学习完成期(3年)
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在卡塔尔评估 PIGF/sFlt-1 作为 PET 的预后标志物
大体时间:通过学习完成期(3年)
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比较两组显影前后的 PIGF/sFlt-1 比率
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通过学习完成期(3年)
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次要结果测量
结果测量 |
措施说明 |
大体时间 |
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PIGF/sFlt-1 作为 PET 患者的预后标志物
大体时间:通过学习完成期(3年)
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比较接受二甲双胍的 PET 患者与标准治疗组 PET 患者的 PIGF/sFlt-1 比率
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通过学习完成期(3年)
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产妇结局
大体时间:通过学习完成期(3年)
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比较研究组之间 PET 开始时的胎龄、分娩时的胎龄和 PET 严重程度
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通过学习完成期(3年)
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合作者和调查者
调查人员
- 首席研究员:Mahmoud Mohamed, MSc、Hamad Medical Corporation
- 学习椅:Justin Konje, MD, PhD、Hamad Medical Corporation
- 研究主任:Mohamed Bashir, MD、Hamad Medical Corporation
- 研究主任:Damien Chausabel, PhD、Sidra Medicine
- 研究主任:Bara Al Jarrah, BSE、Hamad Medical Corporation
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二甲双胍的临床试验
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Poznan University of Medical SciencesUniversity of California, San Diego未知
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Boehringer IngelheimEli Lilly and Company完全的
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Boehringer IngelheimEli Lilly and Company完全的