Neurodevelopmental delay in children exposed to maternal SARS-CoV-2 in-utero

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AbstractIt is unclear if SARS CoV-2 infection during pregnancy is associated with adverse neurodevelopmental repercussions to infants. We assessed pediatric neurodevelopmental outcomes in children born to mothers with laboratory-confirmed SARS CoV-2 infection during pregnancy. Neurodevelopmental outcomes of in-utero exposed children were compared to that of pre-pandemic control children in Los Angeles (LA), CA, USA and Rio de Janeiro, Brazil.

摘要目前尚不清楚怀孕期间SARS-CoV-2感染是否与婴儿的不良神经发育反应有关。我们评估了怀孕期间实验室确诊的SARS-CoV-2感染母亲所生儿童的儿科神经发育结局。将子宫内暴露儿童的神经发育结果与美国加利福尼亚州洛杉矶（LA）和巴西里约热内卢的大流行前控制儿童的神经发育结果进行了比较。

Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III), the gold standard tool for evaluating neurodevelopment until 36 months of age and Ages and Stages Questionnaires (ASQ-3), a frequently used screening instrument for evaluating neurodevelopment in this same age group were the assessment tools used.

Bayley婴幼儿发育量表，第3版（Bayley III），用于评估36个月大之前神经发育的金标准工具以及年龄和阶段问卷（ASQ-3），这是一种常用的筛查工具，用于评估同一年龄组的神经发育。

Developmental delay (DD) was defined as having a score < − 2 SD below the norm (< 70) in at least one of three Bayley-III domains, (cognitive, motor or language) or a score below the cut-off (dark zone) in at least one of five ASQ-3 domains (communication, gross motor, fine motor, problem solving, personal-social).

发育迟缓（DD）被定义为得分 < − 低于正常值2 SD(< 70）在三个Bayley III领域（认知，运动或语言）中的至少一个领域，或在五个ASQ-3领域（沟通，粗大运动，精细运动，解决问题，个人社交）中的至少一个领域低于临界值（暗区）。

Exposed children were born between April 2020 and December 2022 while control children were born between January 2016 to December 2019. Neurodevelopmental testing was performed in 300 children total: 172 COVID-19 exposed children between 5–30 months of age and 128 control children between 6–38 months of age. Bayley-III results demonstrated that 12 of 128 exposed children (9.4%) had DD versus 2 of 128 controls (1.6%), p = 0.0007.

暴露儿童出生于2020年4月至2022年12月，而对照儿童出生于2016年1月至2019年12月。总共对300名儿童进行了神经发育测试：172名5-30个月大的新型冠状病毒暴露儿童和128名6-38个月大的对照儿童。Bayley III结果表明，128名暴露儿童中有12名（9.4%）患有DD，而128名对照组中有2名（1.6%），p = 0.0007。

Eight of 44 additional exposed children had DD on ASQ-3 testing. Fully, 20 of 172 exposed children (11.6%) and 2 of 128 control children (1.6%), p = 0.0006 had DD. In Rio, 12% of exposed children versus 2.6% of controls, p = 0.02 had DD. In LA, 5.7% of exposed children versus .

另外44名暴露儿童中有8名在ASQ-3测试中患有DD。172名暴露儿童中有20名（11.6%）和128名对照儿童中有2名（1.6%），p = 0.0006人患有DD。在里约，12%的暴露儿童与2.6%的对照组相比，p = 0.02有DD。在洛杉矶，5.7%的暴露儿童与。

IntroductionSARS-CoV-2 causes adverse pregnancy outcomes worldwide, including maternal mortality and morbidity due to obstetrical complications and preterm delivery1,2,3,4. Cumulative research studies have correlated in-utero exposure to respiratory pathogens in pregnancy and higher risk of future pervasive neurodevelopmental or neuropsychiatric conditions in the offspring; potentially linking maternal immune activation (MIA) as the biological mechanism for these outcomes5,6,7,8,9,10,11,12,13.

引言SARS-CoV-2在全球范围内引起不良妊娠结局，包括产科并发症和早产引起的孕产妇死亡率和发病率1,2,3,4。累积的研究表明，怀孕期间子宫内暴露于呼吸道病原体与后代未来普遍存在的神经发育或神经精神疾病的风险较高有关；可能将母体免疫激活（MIA）作为这些结果的生物学机制联系起来5,6,7,8,9,10,11,12,13。

The role of SARS-CoV-2 infection in pregnancy and long term neurodevelopmental outcomes in the offspring is not well understood. Preterm birth and low birth weight are more prevalent in infants born to pregnant persons with symptomatic COVID-1914,15,16. Prematurity in itself is a risk factor for developmental delay (DD)17.During the COVID-19 pandemic, we initiated a longitudinal observational cohort study of maternal-infant outcomes in pregnancy, the COVID Outcomes in Mother-Infant Pair (COMP) Study, which recruited mother-infant dyads in Los Angeles (LA), CA and Rio de Janeiro (Rio), Brazil, two regions disproportionately affected by the pandemic18,19,20,21.

SARS-CoV-2感染在妊娠和后代长期神经发育结局中的作用尚不清楚。早产和低出生体重在有症状的COVID-1914,15,16孕妇所生的婴儿中更为普遍。早产本身是发育迟缓（DD）17的危险因素。在新型冠状病毒肺炎大流行期间，我们启动了一项关于妊娠期母婴结局的纵向观察性队列研究，即母婴对新型冠状病毒结局（COMP）研究，该研究在加利福尼亚州洛杉矶（LA）和巴西里约热内卢（Rio）招募了母婴二元体，这两个地区受疫情影响不成比例18,19,20,21。

We utilized the infrastructure and approach implemented by our group during the ZIKV epidemic of 2015–201622,23,24,25,26 to evaluate potential repercussions of COVID-19 in pregnancy, assuming a novel pathogen carries risk to pregnant patients and their offspring. Although some vertically transmitted viruses are knowingly neurotropic, SARS-CoV-2 may potentially be deleterious to progeny through the indirect mechanism of MIA.

我们利用我们小组在2015-201622,23,24,25,26年ZIKV疫情期间实施的基础设施和方法来评估妊娠期新型冠状病毒肺炎的潜在影响，假设一种新的病原体对孕妇及其后代有风险。尽管一些垂直传播的病毒具有明显的神经营养性，但SARS-CoV-2可能通过MIA的间接机制对后代有害。

We hypothesize that MIA, by creating a hostile in utero inflammatory environment during the course of COVID-19 may potentially adversely affect infant neurodevelopment.In the present analysis, we evaluated.

我们假设MIA在COVID-19过程中通过在子宫内产生敌对的炎症环境可能会对婴儿的神经发育产生不利影响。在目前的分析中，我们进行了评估。

Table 1 Comparison of maternal demographic variables and obstetric and neonatal outcomes between SARS-CoV-2 exposed cases and controls.Full size tableAs seen in Table 2, there were significant differences between participants enrolled in Rio and LA. Mothers in LA tended to be older and have diverse racial/ethnic backgrounds.

表1 SARS-CoV-2暴露病例与对照组之间孕产妇人口统计学变量以及产科和新生儿结局的比较。全尺寸表如表2所示，里约热内卢和洛杉矶的参与者之间存在显着差异。洛杉矶的母亲往往年龄较大，具有不同的种族/民族背景。

In Rio, 72% of mothers were Black or mixed racial/ethnic backgrounds and all participants had government sponsored health care (p < 0.001). As seen in Table 2, LA mothers had a higher frequency of co-morbidities. No participants in Rio were vaccinated before COVID-19, while 30.4% of LA women had received COVID-19 vaccination before infection, p < 0.001.

在里约，72%的母亲是黑人或种族/民族混合背景，所有参与者都有政府资助的医疗保健（p < 0.001）。如表2所示，洛杉矶母亲的合并症频率较高。里约没有参与者在新型冠状病毒肺炎之前接种过疫苗，而30.4%的洛杉矶女性在感染前接种了新型冠状病毒肺炎疫苗，p < 0.001。

In parallel, 8.8% of mothers in LA had severe COVID-19 versus 34.6% of mothers in Rio, p < 0.001. Infant outcomes were similar for both groups except for more NICU admissions in LA (21.6% vs. 5.3%, p = 0.002) likely reflecting NICU access. In total, 20.5% of infants were preterm, with no differences between sites (Table 2)..

与此同时，洛杉矶有8.8%的母亲患有严重的新型冠状病毒肺炎，而里约有34.6%的母亲患有严重的新型冠状病毒肺炎 < 0.001。两组婴儿的结局相似，除了洛杉矶NICU入院率较高（21.6%比5.3%，p = 0.002）可能反映了NICU的访问。总共有20.5%的婴儿是早产儿，不同地点之间没有差异（表2）。。

Table 2 Demographics of pregnant participants infected with SARS-CoV-2 and obstetric/neonatal outcomes.Full size tablePrevalence of neurodevelopmental outcomesIn the LA cohort, Bayley-III median composite scores for cognitive, language and motor domains in cases and controls respectively were 110 and 120, p < 0.001, 103 and 106, p = 0.31 and 107 and 110, p = 0.15 (Fig. 1).

表2感染SARS-CoV-2的孕妇的人口统计学和产科/新生儿结局。全尺寸表神经发育结果的患病率在LA队列中，病例组和对照组的Bayley III认知，语言和运动领域的中位综合得分分别为110和120，p < 0.001、103和106，p = 0.31、107和110，p = 0.15（图1）。

In the Rio cohort, Bayley-III median composite scores for the cognitive domain in cases versus controls were 100 and 98, p = 0.8, in the language domain were 83 and 89, p = 0.01 and in the motor domain were 97 and 94, p = 0.21. The COVID-19 cohort tended to have more children with developmental delay (< − 2 SD) as compared to pre-pandemic controls (Fig. 2).

在里约队列中，病例组与对照组的认知领域Bayley III综合评分中位数分别为100和98，p = 0.8，在语言领域分别为83和89，p = 0.01，运动域分别为97和94，p = 零点二一。新型冠状病毒肺炎队列往往有更多发育迟缓的儿童(< − 2 SD）与大流行前对照相比（图2）。

In addition, in Rio, 9 of 75 children (12%) were delayed in the COVID-19 cohort, as opposed to 2 of 78 children (2.6%) in the control group, p = 0.02. In LA, 3 of 53 children (5.7%) were delayed as compared to none in the control group, p = 0.12. The lower scores were driven primarily by the language domain.

此外，在里约，COVID-19队列中75名儿童中有9名（12%）被延迟，而对照组中78名儿童中有2名（2.6%）被延迟，p = 零点零二。在洛杉矶，53名儿童中有3名（5.7%）被延迟，而对照组没有，p = 零点一二。较低的分数主要是由语言领域驱动的。

In Rio, a higher number of children (n = 33, 44%) were found to be at rDD in the COVID-19 cohort versus the control group (n = 19, 24.3%), p = 0.01. Only one child was at rDD in LA versus 2 controls (Table 3). Overall, combining Bayley-III results for Rio and LA, 12 of 128 children (9.4%) exposed to maternal COVID-19 had scores below 70, indicative of severe DD, as compared to 2 of 128 control children (1.6%), p = 0.007 (Table 3).Figure 1Bayley-III assessments for children exposed to maternal COVID-19 in Rio de Janeiro, RJ, Brazil (n = 75) and Los Angeles (n = 53), CA, USA [n = 128] compared to pre-pandemic control children from Rio de Janeiro (n = 78) and Los Angeles (n = 50), [n = 128].

在里约，儿童人数较多（n = 33,44%）在COVID-19队列中与对照组（n = 19，24.3%），p = 零点零一。洛杉矶只有一个孩子患有rDD，而对照组只有2个（表3）。总体而言，结合里约和洛杉矶的Bayley III结果，暴露于母体COVID-19的128名儿童中有12名（9.4%）得分低于70，表明存在严重的DD，而128名对照儿童中有2名（1.6%），p = 0.007（表3）。图1巴西里约热内卢暴露于母体新型冠状病毒肺炎的儿童的贝利III评估（n = 75）和洛杉矶（n = 53），加利福尼亚州，美国 = 128]与来自里约热内卢的大流行前控制儿童（n = 78）和洛杉矶（n = 50），[n = 128页]。

Total = 256. Distribution of Bayley-III scores for cogni.

总计 = cogni的Bayley III分数分布。

Data availability

数据可用性

Deidentified data are available upon reasonable request.

可根据合理要求提供身份不明的数据。

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Download referencesFundingThe funding was provided by National Institutes of Health (Grant Nos. T32MH080634, AI140718, AI140718), Simons Foundation (Grant No. 866410) and W. M. Keck Foundation (Grant No. 9999).Author informationAuthors and AffiliationsDavid Geffen, UCLA School of Medicine, Los Angeles, CA, USAViviana Fajardo-Martinez, Mary Catherine Cambou, Tara Kerin, Sophia Paiola, Thalia Mok, Rashmi Rao, Jyodi Mohole, Ramya Paravastu, Sai Iyer, Kalpashri Kesavan & Karin Nielsen-SainesUniversidade do Rio de Janeiro, Rio de Janeiro, RJ, BrazilFatima FerreiraUCLA Institute for the Environment and Sustainability, Los Angeles, CA, USATrevon FullerDepartment of Child and Adolescent Psychiatry, Center for Psychosocial Medicine, Heidelberg University, Heidelberg, GermanyDajie Zhang & Peter MarschikChild and Adolescent Psychiatry and Psychotherapy, University Medical Center Göttingen and Leibniz ScienceCampus Primate Cognition, Göttingen, GermanyDajie Zhang & Peter MarschikInterdisciplinary Developmental Neuroscience (IDN), Division of Phoniatrics, Medical University of Graz, Graz, AustriaDajie Zhang & Peter MarschikFundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, BrazilMaria da Conceição Borges Lopes, José Augusto A.

下载参考资助资金由美国国立卫生研究院（批准号T32MH080634，AI140718，AI140718），西蒙斯基金会（批准号866410）和W.M.Keck基金会（批准号9999）提供。作者信息作者和附属机构加州大学洛杉矶分校医学院维德·格芬，加利福尼亚州洛杉矶，USAViviana Fajardo Martinez，玛丽·凯瑟琳·坎布，塔拉·柯林，索菲亚·帕约拉，塔利亚·莫克，拉什米·拉奥，乔迪·莫霍尔，拉米娅·帕拉瓦斯托，赛耶，卡尔帕什里·凯萨万和卡林·尼尔森·萨伊内斯大学里约热内卢，里约热内卢，RJ，巴西法蒂玛·费雷拉克拉环境与可持续发展研究所，加利福尼亚州洛杉矶，USATrevon FULLERY儿童与青少年精神病学系，海德堡心理医学中心德国埃尔格大学，海德堡，德国达杰·张和彼得·马希克儿童和青少年精神病学和心理治疗，哥廷根大学医学中心和莱布尼茨科学校园灵长类动物认知，哥廷根，德国达杰·张和彼得·马希金跨学科发展神经科学（IDN），格拉茨医科大学，格拉茨，澳大利亚达杰·张和彼得·马希克·芬达·奥斯瓦尔多·克鲁兹（菲奥克鲁兹），里约热内卢，巴西圣母院博尔赫斯·洛佩斯，JoséAugusto A。

Britto, Maria Elisabeth Moreira & Patricia BrasilAuthorsViviana Fajardo-MartinezView author publicationsYou can also search for this author in.

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PubMed Google ScholarContributionsK.N.-S., P.B., and V.F.-M. conceptualized the study. K.N.-S. and V.F.-M. wrote the original draft. J.M., K.K., R.P., S.I., and S.P. and were responsible for data curation. T.F. and T.K. were responsible for formal analysis. K.N.-S. and P.B. were responsible for funding acquisition.

PubMed谷歌学术贡献SK。N、 -S.，P.B。和V.F.-M.对这项研究进行了概念化。K、 N.S.和V.F.M.撰写了原稿。J、 M.，K.K.，R.P.，S.I。和S.P。负责数据管理。T、 F.和T.K.负责正式分析。K、美国国家安全局（N.S.）和公共安全局（P.B.）负责资金收购。

F.F., J.A.B., M.C., and V.F.-M. were responsible for investigation and data collection. D.Z. and P.M. designed the methodology. J.A.B., M.C.B.L., M.E.M., R.R., and T.M. provisioned study resources and patients. K.N.-S., M.E.M., P.B., and R.R. provided supervision of the research. All authors reviewed the manuscript.Corresponding authorCorrespondence to.

F、 F.，J.A.B.，M.C。和V.F.-M.负责调查和数据收集。D、 Z.和P.M.设计了该方法。J、 A.B.，M.C.B.L.，M.E.M.，R.R。和T.M.提供了研究资源和患者。K、美国国家安全局、M.E.M.、P.B.和R.R.对这项研究进行了监督。所有作者都审阅了手稿。对应作者对应。

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Reprints and permissionsAbout this articleCite this articleFajardo-Martinez, V., Ferreira, F., Fuller, T. et al. Neurodevelopmental delay in children exposed to maternal SARS-CoV-2 in-utero.

转载和许可本文引用本文Fajardo Martinez，V.，Ferreira，F.，Fuller，T。等人。子宫内暴露于母体SARS-CoV-2的儿童的神经发育迟缓。

Sci Rep 14, 11851 (2024). https://doi.org/10.1038/s41598-024-61918-2Download citationReceived: 11 November 2023Accepted: 10 May 2024Published: 24 May 2024DOI: https://doi.org/10.1038/s41598-024-61918-2Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Sci Rep 1411851（2024）。https://doi.org/10.1038/s41598-024-61918-2Download引文接收日期：2023年11月11日接收日期：2024年5月10日发布日期：2024年5月24日OI：https://doi.org/10.1038/s41598-024-61918-2Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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