Improving Neonatal health Through Rapid malaria testing in Early Pregnancy with high-sensitivity Diagnostics (INTREPiD)

项目摘要/摘要 全球新生儿健康状况有所改善，但在资源有限的情况下，仍迫切需要减少 新生儿死亡率。撒哈拉以南非洲地区几乎所有的婴儿死亡都发生在体型较小或较低的婴儿身上。 出生体重，通常是由于产前感染恶性疟原虫造成的。这些疟疾影响可能 通过针对怀孕的措施，包括每月产前剂量的管理，部分缓解 作为妊娠期间歇预防治疗的磺胺多辛-乙胺(IPTp-SP)，但这些不是 通常实施到第二个三个月，因此不能减少第一个三个月的感染风险。它 现在可以在怀孕初期对疟疾寄生虫进行筛查，原因是：i)更新了世卫组织指南， 建议8个ANC联系人的扩展时间表，第一个在怀孕12周之前，ii) 增强低密度检测的高灵敏度疟疾快速诊断试验(HS-RDT)的可用性 感染，以及三)累积的安全数据，使蒿甲醚-鲁米芬三(AL)能够用于疟疾 妊娠前三个月的治疗。我们假设，与进入非国大并获得通常 护理，在怀孕前三个月筛查HS-RDT的妇女将有较低的贫困患病率 妊娠结局，我们将通过快速疟疾检测改善新生儿健康来测试这一点 在肯尼亚西部和民主党进行的早期妊娠高敏感性诊断(无畏)研究 刚果(金)。在目标1中，勇敢的研究将招募怀孕前三个月的女性，并 将他们按1：1随机分为常规护理或HS-RDT筛查，然后用AL治疗阳性， 然后跟着他们直到送货。在第一个三个月的干预之后，所有的妇女都将像往常一样 ANC，包括IPTp-SP。主要结局将是低出生体重儿、小儿科 胎龄、早产、胎儿丧失或新生儿死亡。在目标2中，我们将测量治疗效果 通过遵循标准的人群PK研究在妊娠早期给药的药代动力学 给药并将PK参数与历史对照进行比较。在目标3中，我们将使用试验数据来模拟 增强敏感性诊断和替代治疗方案对风险的潜在增量好处 为了最大限度地发挥我们试验数据的影响，对不良妊娠结局进行评估。总的来说，这些数据将 指导制定和实施新的方法，在怀孕早期和 从而提高妊娠结局和新生儿健康。

Project Summary/Abstract Newborn health has improved globally but there remains a critical need in resource-limited settings to reduce neonatal mortality. Nearly all infant deaths in sub-Saharan Africa occur in babies that are small or low birthweight, which often result from antenatal infections with Plasmodium falciparum. These malaria effects can be partially mitigated by pregnancy-specific measures including the administration of monthly antenatal doses of sulfadoxine-pyrimethamine as intermittent preventive therapy during pregnancy (IPTp-SP), but these are not typically implemented until the 2nd trimester, and so do not mitigate the risks of infection in the 1st trimester. It is now feasible to include 1st trimester screening for malaria parasites owing to: i) updated WHO guidelines that recommend an expended schedule of 8 ANC contacts, with the first prior to 12 weeks gestation, ii) the availability of high-sensitivity malaria rapid diagnostic tests (HS-RDT) with enhanced detection of low-density infections, and iii) accumulated safety data that enable the use of Artemether-Lumefantrine (AL) for malaria treatment in the 1st trimester. We hypothesize that, compared to women who enter ANC and receive usual care, women who are screened in the 1st trimester with an HS-RDT will have a lower prevalence of a poor pregnancy outcome, and we will test this through the Improving Neonatal health Through Rapid malaria testing in Early Pregnancy with high-sensitivity Diagnostics (INTREPiD) study in Western Kenya and the Democratic Republic of the Congo (DRC). In Aim 1, the INTREPiD study will enroll women in the 1st trimester and randomize them 1:1 to usual care or to screening with an HS-RDT followed by treatment of positives with AL, and then follow them through delivery. Following the 1st trimester intervention, all women will receive usual ANC, including IPTp-SP. The primary outcome will be the composite outcome of low birthweight, small-for- gestational age, preterm birth, fetal loss, or neonatal death. In Aim 2, we will measure the therapeutic efficacy and pharmacokinetics of AL administration in the 1st trimester through a population PK study following standard AL dosing and compare PK parameters with historical controls. In Aim 3, we will use trial data to model the potential incremental benefits of enhanced-sensitivity diagnostics and alternate treatment regimens on the risk of an adverse pregnancy outcome in order to maximize the impact of our trial data. Collectively these data will guide the development and implementation of fresh approaches to intercept parasites early in pregnancy and thereby enhance pregnancy outcomes and newborn health.