Impact of gestational SARS-CoV-2 and maternal inflammation on child growth and neurodevelopment in a malaria-endemic setting

疟疾流行环境中妊娠期 SARS-CoV-2 和母体炎症对儿童生长和神经发育的影响

• 批准号: 10722878
• 负责人: Karen Blake Jacobson
• 金额: $ 19.33万
• 依托单位: KAISER FOUNDATION RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722878
• 关键词: 2 year old; 2019-nCoV; 4 year old; Address; Adverse effects; Africa South of the Sahara; African; Age; Antimalarials; Birth; COVID-19 pandemic; Caring; Chemoprevention; Child; Childhood; Clinical; Clinical Data; Clinical Management; Clinical Trials; Cohort Studies; Collaborations; Communicable Diseases; Complex; Data; Data Set; Development; Diagnostic; Discipline of obstetrics; Enrollment; Epidemiology; Exclusion; Exposure to; Funding; Future; Goals; Growth; Immune; Immune response; Immunity; Immunology; Impairment; Incidence; Infant; Infection; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1; Intervention; Knowledge; Long-Term Effects; Low Birth Weight Infant; Malaria; Mediating; Mentorship; Mothers; Neurocognitive; Neurocognitive Deficit; Neuropsychology; Outcome; Pathway interactions; Pediatrics; Perinatal Infection; Placebos; Plasma; Population; Pregnancy; Pregnant Women; Premature Birth; Prevention trial; Proteomics; Pyrimethamine; Randomized; Regimen; Research; Research Personnel; Resource-limited setting; Resources; Risk; SARS-CoV-2 exposure; SARS-CoV-2 immunity; SARS-CoV-2 infection; SARS-CoV-2 variant; Sampling; Serology test; Signal Pathway; Sulfadoxine; Testing; Toddler; Training; Translational Research; Uganda; Underweight; United States National Institutes of Health; Vaccines; Woman; career development; clinically significant; co-infection; cohort; cytokine; early childhood; experience; fighting; geographic population; global health; improved; infant outcome; inflammatory marker; neurocognitive test; neurodevelopment; offspring; pathogen; seropositive; therapeutic target; translational scientist; vigilance; wasting

PROJECT SUMMARY / ABSTRACT Since the emergence of SARS-CoV-2 in 2020, millions of pregnancies in malaria-endemic sub-Saharan Africa have been impacted by SARS-CoV-2 infection. High rates of SARS-CoV-2 and malaria co-infections during pregnancy will continue as new SARS-CoV-2 variants emerge and cause re-infections in subsequent waves. SARS-CoV-2 and malaria in pregnancy are both associated with adverse birth and infant outcomes – including preterm birth, low birth weight, and impaired growth and neurodevelopment – possibly mediated through maternal inflammation. Data on long-term developmental effects of gestational SARS-CoV-2 in highly malaria exposed populations are lacking. To address this gap, I will leverage samples and data from mother-infant dyads enrolled in two complementary ongoing NIH-funded antimalarial chemoprevention trials in Busia, Uganda. In the pregnancy trial, pregnant women are randomized to one of three antimalarial chemoprevention regimens and followed through delivery; infants born to these women are being randomized in a separate clinical trial to receive antimalarial chemoprevention or placebo and followed to age 4 years. These trials have coincided with Uganda’s early SARS-CoV-2 surges, and preliminary data indicate high incidence of both SARS-CoV-2 and malaria during pregnancy. Using clinical data and samples collected as part of the ongoing trials, I will test the hypothesis that infants exposed to gestational SARS-CoV-2 will have impaired growth and neurodevelopment in early childhood when compared with unexposed infants, and that this is mediated by maternal inflammation. I further hypothesize that exposure to both SARS-CoV-2 and malaria in pregnancy increases adverse infant outcomes due to the synergistic inflammatory effects of both pathogens. In Aim 1, I will use serologic testing of stored plasma samples to retrospectively identify mothers who experienced SARS-CoV-2 during pregnancy and compare the growth of infants with and without gestational SARS-CoV-2 exposure through age 4 years. In Aim 2, I will compare neurocognitive test scores at ages 24 and 42 months among infants with and without gestational SARS-CoV-2. In Aim 3, I will explore maternal proteomic immune signatures of SARS-CoV-2 in pregnancy and determine if the effect of gestational SARS-CoV-2 on infant growth and neurodevelopment is mediated by specific inflammatory pathways. This cohort is uniquely poised to address the impact of SARS-CoV-2 in pregnancy in a malaria endemic setting, with longitudinal data and samples collected before widespread baseline SARS-CoV- 2 immunity. To accomplish these aims and become an independent translational researcher in tropical perinatal infections, I have assembled an interdisciplinary mentorship team of experts in in infectious diseases, obstetrics, pediatrics, neuropsychology, immunology, and global health. Results from this proposed study have immediate implications for improving care of at-risk infants, and could identify diagnostic or therapeutic targets for future clinical interventions.

项目摘要 /摘要 自2020年SARS-COV-2出现以来，疟疾 - 萨哈拉以下非洲的数百万妊娠 已受到SARS-COV-2感染的影响。 SARS-COV-2和疟疾共同感染的高率 随着新的SARS-COV-2变体的出现并在随后的波浪中引起重新感染，怀孕将继续。 怀孕中的SARS-COV-2和疟疾既与出生和婴儿结局有关，包括 早产，低出生体重以及生长和神经发育受损 - 可能通过 母体炎症。关于妊娠SARS-COV-2在高度疟疾中的长期发育影响的数据 缺乏裸露的人群。为了解决这一差距，我将利用母亲二元组的样本和数据 在乌干达Busia的两项持续正在进行的NIH资助的抗疟疾化学预防试验中招收。在 妊娠试验，孕妇被随机分为三种抗疟疾化学预防方案之一和 随后交付；这些妇女出生的婴儿在另一项临床试验中被随机分配 抗疟疾化学预防或安慰剂，然后到4岁。这些审判与乌干达的 早期的SARS-COV-2激增和初步数据表明SARS-COV-2和疟疾在 怀孕。使用临床数据和作为正在进行的试验的一部分收集的样本，我将测试以下假设。 暴露于妊娠SARS-COV-2的婴儿在童年时期将受损的生长和神经发育 与未暴露的婴儿相比，这是由母子注射介导的。我进一步假设 怀孕中对SARS-COV-2和疟疾的暴露会增加逆境婴儿结果 两种病原体的协同炎症作用。在AIM 1中，我将使用存储的血浆样品的血清学测试 回顾性地识别怀孕期间经历过SARS-COV-2的母亲 有或没有妊娠SARS-COV-2暴露于4岁的婴儿。在AIM 2中，我将比较 患有和没有妊娠SARS-COV-2的婴儿的24岁和42个月的神经认知测试评分。 在AIM 3中，我将探索妊娠中SARS-COV-2的母体蛋白质组学免疫特征，并确定是否是否 妊娠SARS-COV-2对婴儿生长和神经发育的影响是由特定的 炎症途径。该队列被中毒以解决SARS-COV-2在怀孕中的影响 疟疾内在环境，纵向数据和样品在宽度基线sars-cov之前收集 2免疫。实现这些目标并成为热带围产期的独立翻译研究人员 感染，我已经组建了一个跨学科的心态团队，专家是传染病，妇产科， 儿科，神经心理学，免疫学和全球健康。这项拟议研究的结果立即 改善高危婴儿护理的影响，并可以确定未来的诊断或治疗靶标 临床干预措施。