STUDY CLOSEOUT FOR THE INTERNATIONAL COHORT STUDY OF CHILDREN BORN TO WOMEN INFECTED WITH ZIKA VIRUS DURING PREGNANCY (ZIP 2.0)

寨卡病毒(Zika Virus，ZIKV)是黄病毒属的虫媒病毒。感染被认为是轻微的和自我限制的，直到2015年，在巴西最初观察到小头畸形症和其他出生缺陷的流行，因为母亲在怀孕期间感染了ZIKV。现在越来越多的证据表明，ZIKV是导致母亲在怀孕期间感染的新生儿各种出生缺陷的原因。孕妇中寨卡病毒感染与妊娠不良结局的关系是正在进行的评估对象。 到目前为止，对受感染妇女所生婴儿的研究往往集中在那些出生时患有严重出生缺陷的婴儿，这些出生缺陷构成了先天性寨卡综合征(CZS)，巴西最近的一项基于人群的研究表明，与没有CZS1的儿童相比，出生后头三年的死亡风险增加了11倍以上。美国寨卡病毒怀孕和婴儿登记处报告称，感染寨卡病毒的母亲在怀孕期间所生的婴儿中，约有5%患有与寨卡病毒相关的脑或眼睛缺陷，2与CZS一致。 但是，感染寨卡病毒的女性出生时没有感染CZS的95%的婴儿是否会对生长和发育产生潜在的影响，以及这些影响可能是什么，这一点仍有待阐明。需要对感染寨卡病毒的孕妇所生婴儿进行纵向研究，以评估宫内或分娩期间接触寨卡病毒的更广泛可能表现的更广泛的光谱和自然病史。 2016年，美国国立卫生研究院启动了一项关于婴儿和怀孕期间寨卡病毒流行病学、自然历史和发病机制的大型多中心国际观察性研究，即寨卡病毒孕期感染(ZIP)研究。这项ZIP研究跟踪了怀孕期间有寨卡病毒感染风险的妇女所生的婴儿在生命的前12个月内，并完成了2019年12月最后一次患者探视。2018年，美国国立卫生研究院发起了ZIP研究或类似研究中的寨卡病毒暴露儿童和未暴露儿童的国际队列研究(ZIP 2.0)，对42个月大的儿童进行跟踪，以评估寨卡病毒对儿童生长发育的影响。 最近的研究发现，在宫内接触ZIKV而没有CZS的婴儿似乎在生命的前18个月有异常神经发育结果的风险3，类似地，在没有小头畸形的儿童中，在子宫4暴露于ZIKV的儿童中观察到高频率的解剖和神经发育异常。一项研究发现，发育延迟的风险随着头围的不同而呈梯度变化，严重小头症儿童的延迟风险最高，而接触寨卡病毒的正常头儿童与未接触寨卡病毒的儿童表现出类似的风险。然而，其他几项研究也观察到了宫内ZIKV暴露的儿童在没有小头畸形的情况下神经发育异常6，7。这些报告表明，几乎所有这样的儿童都出现了至少一次发育迟缓，而且在宫内暴露于ZIKV的儿童中，有相当大比例的儿童出现了轻度认知迟缓和听觉行为异常。 这项任务令满足了美国国立卫生研究院对ZIP 2.0婴儿和儿童产前寨卡病毒感染影响进行评估的要求。考虑到迄今为止在科学文献中报道的可变的、有时是相互矛盾的发现，这个任务顺序将有助于确定是否、在多大程度上以及什么类型的较长期随访被指出。

Zika virus (ZIKV) is an arbovirus (vector-borne virus) of the genus Flaviviridae. Infections were thought to be mild and self-limiting until 2015, when an epidemic was observed initially in Brazil of microcephaly and other birth defects in newborns following infection of the mother during pregnancy with ZIKV. Increasing evidence now points to ZIKV as the agent responsible for a variety of birth defects in newborns of mothers who become infected during pregnancy. The relationship of ZIKV infections in pregnant women with adverse outcomes of pregnancy is the subject of ongoing evaluation. Studies to date of infants born to infected women have tended to focus on those born with serious birth defects that constitute the congenital Zika syndrome (CZS), which has been shown in a recent population-based study from Brazil to increase risk of death in the first three years of life more than 11-fold compared to children without CZS1. The U.S. Zika Pregnancy and Infant Registry reports that approximately 5% of infants born to women with ZIKV infection during pregnancy have Zika-associated brain or eye defects2 consistent with CZS. But whether there are latent effects on growth and development in the 95% of infants who are born without CZS to Zika-infected women, and what those effects may be, remains to be elucidated. Longitudinal studies of infants born to Zika-infected pregnant women are needed to assess the broader spectrum and natural history of a wider range of possible manifestations of intrauterine or intrapartum Zika exposure. In 2016, NIH initiated a large, multicenter, international observational study of the epidemiology, natural history, and pathogenesis of Zika in infants and pregnancy, the Zika Infections in Pregnancy (ZIP) Study. The ZIP Study followed infants born to women at risk for Zika infection during pregnancy through just the first 12 months of life and completed its last patient last visit December 2019. In 2018, NIH initiated the International Cohort Study of Children Born to Women Infected with Zika Virus During Pregnancy (ZIP 2.0) of Zika exposed children and unexposed control children from the ZIP Study or similar studies, following the children through 42 months of age to evaluate the effects of Zika on child growth and development. Recent studies have found that infants who had in utero ZIKV exposure without CZS appear to be at risk for abnormal neurodevelopmental outcomes in the first 18 months of life3 and similarly observed high frequencies of anatomical and neurodevelopmental abnormalities in children without microcephaly who were exposed to ZIKV in utero4. One study found a gradient of risk of development delay according to head circumference, with severely microcephalic children at highest risk for delays while normocephalic ZIKV-exposed children showed similar risk to unexposed control children5. However, several other studies have observed abnormal neurodevelopment in the absence of microcephaly among children with intrauterine ZIKV exposure6,7. Those reports indicate that nearly all such children presented at least one developmental delay and that a significant proportion of children exposed in utero to ZIKV developed mild cognitive delay and auditory behavioral abnormalities. This task order addresses NIH’s requirement to conduct an evaluation of the impact of prenatal Zika exposure among ZIP 2.0 infants and children. Given the variable and sometimes conflicting findings reported to date in the scientific literature, this task order will help to determine whether, to what extent, and what types of longer-term follow-up is indicated.