NEWBORN SCREENING FOLLOW-UP STUDY OF CONGENITAL CYTOMEGALOVIRUS (CCMV) INFECTION

先天性巨细胞病毒(CCMV)是最常见的先天性感染，估计发生在所有妊娠的0.6%，在美国每年影响到约23,000名新生儿。这使得CCMV比目前推荐的统一筛查小组(RUSP)上的大多数情况更常见。CCMV的表现具有很高的变异性，包括感觉神经性听力损失(SNHL)、发育迟缓和视力障碍。出生时的极端表现是小头畸形、肝脾肿大、瘀斑、癫痫发作和黄疸，约占感染新生儿的10%-15%，在有症状的新生儿中导致婴儿死亡的比例为5%-10%。此外，在那些有症状的新生儿中，50%-90%将会有长期的神经和发育并发症。然而，其余90%患有CCMV的新生儿在出生时将没有临床症状。对于无症状的新生儿，长期后遗症的风险约为10%至15%，通常表现为孤立性SNHL，可能无法通过新生儿听力筛查发现，因为它可能起病晚或进展快，表现为5岁。 如果被诊断为CCMV的婴儿出现症状，抗病毒药物(静脉注射更昔洛韦、口服valganciclovir)的治疗已被证明改善了听力和发育方面的结果，尽管其中一些进展在最近的综述中没有得到维持。然而，短暂性中性粒细胞减少是治疗的一个已知副作用，这导致一些专家不建议对无症状感染的婴儿进行抗病毒治疗。尽管如此，识别患有CCMV的无症状婴儿可以进行神经发育评估、随访和听力损失监测，并及时进行治疗，以防止这一高危人群中的语言延迟或语言丧失。在该人群中，建议在5岁之前每隔6个月进行一次听力监测，当听力水平发生变化或直到儿童说话时，更频繁地每3个月监测一次。对于后天严重听力损失的儿童，建议植入人工耳蜗以改善言语和语言结果。国家统计局对CCMV进行筛查，无论是在整个人群中进行筛查，还是只针对未通过新生儿听力筛查的婴儿进行筛查，都引发了重要的伦理和公共卫生考虑，包括对诊断不足和过度诊断、对无症状筛查阳性婴儿的过度治疗、父母焦虑和脆弱儿童综合征，以及州公共卫生项目的额外负担。 最近关于CCMV的RUSP提名被退回给提交者，因为缺乏证据，包括需要更多的数据来确定哪些病例将从治疗中受益，全人群早期诊断相对于听力筛查失败的反射测试所提供的临床效用不确定，以及针对筛查阳性婴儿的推荐随访和治疗方案。前瞻性地确定CCMV阳性的婴儿队列，并进行纵向数据收集，将有助于记录感染的自然历史，从而增强我们对结局和潜在风险的理解，并修改预测这些新生儿结局的因素。 尤尼斯·肯尼迪·施莱弗国家儿童健康与人类发展研究所(NICHD)有兴趣通过支持对筛查阳性婴儿的后续研究来扩大获奖的CCMV试点研究，以更好地了解将CCMV筛查纳入国家统计局项目的影响，以便为考虑将CCMV筛查纳入其国家统计局项目的州项目解决重要的证据空白。这项工作将支持对筛查阳性婴儿进行更多的后续数据收集，以收集有关听力、发育和神经学结果的纵向数据，以及对受感染婴儿及其照顾者的生活质量的测量。

Congenital cytomegalovirus (cCMV) is the most common congenital infection and is estimated to occur in 0.6% of all pregnancies, impacting ~23,000 births in the United States each year. This makes cCMV more common than most conditions currently on the Recommended Uniform Screening Panel (RUSP). The manifestations of cCMV are highly variable and include sensorineural hearing loss (SNHL), developmental delays, and visual impairment. The extreme presentation at birth is one of microcephaly, hepatosplenomegaly, petechiae, seizures, and jaundice, occurring in ~10-15% of infected newborns and resulting in infant death in 5-10% of those with symptoms. In addition, of those newborns who are symptomatic, 50-90% will have long-term neurologic and developmental complications. However, the remaining ~90% of newborns with cCMV will be clinically asymptomatic at birth. For asymptomatic newborns, the risk of long-term sequelae is ~10% to 15%, which often presents as isolated SNHL, and may not be detected through newborn hearing screening as it may be late onset or progressive, presenting through age 5 years. If an infant diagnosed with cCMV develops symptoms, treatment with antiviral medications (IV ganciclovir, oral valganciclovir) has been shown to improve outcomes with regard to hearing and development, although some of these gains have not been sustained in more recent reviews. However, transient neutropenia is a known side effect of the treatment, which has led some experts to not routinely recommend antiviral treatment of asymptomatic infected infants. Nonetheless, identification of asymptomatic infants with cCMV allows for neurodevelopmental evaluation, follow-up, and monitoring for hearing loss, with prompt treatment to prevent language delays or language loss in this high-risk population. Frequent audiologic monitoring at 6-month intervals has been recommended in this population until age 5 years, with more frequent monitoring every 3 months when hearing levels are changing or until the child is talking. Cochlear implants are recommended for children with acquired severe hearing loss to improve speech and language outcomes. NBS screening for cCMV, whether population-wide or targeted only to infants who fail their newborn hearing screening, raises important ethical and public health considerations, including concerns about both under- and over-diagnosis, overtreatment of asymptomatic screen-positive infants, parental anxiety and vulnerable child syndrome, and the added burden on state public health programs. The recent RUSP nomination for cCMV was returned to the submitters for lack of evidence including the need for more data on how to identify which cases will benefit from treatment, uncertain clinical utility afforded by population-wide early diagnosis relative to reflex testing for failed hearing screens, and the recommended follow-up and treatment protocol for screen-positive infants. A prospectively identified cCMV-positive cohort of infants with longitudinal data collection would help record the natural history of the infection, thereby enhancing our understanding of outcomes and of potential risk and modifying factors that predict outcomes for these newborns. The Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD) is interested in expanding on the awarded cCMV pilot study by supporting a follow-up study of screen positive infants to better understand the impacts of incorporating cCMV screening into NBS programs, in order to address important evidence gaps for state programs considering adding cCMV screening to their NBS program. This effort will support additional follow-up data collection on screen-positive infants to gather longitudinal data on audiologic, developmental, and neurological outcomes, as well as measurements of quality of life for infected infants and their caregivers.