Neurodevelopment in preschool children exposed and unexposed to Zika virus in utero in Nicaragua: a prospective cohort study.

BACKGROUND: Data on long-term neurodevelopmental outcomes of normocephalic children (born with normal head circumference) exposed to Zika virus in utero are scarce. We aimed to compare neurodevelopmental outcomes in normocephalic children up to age 48 months with and without Zika virus exposure in utero. METHODS: In this prospective cohort study, we included infants from two cohorts of normocephalic children born in León and Managua, Nicaragua during the 2016 Zika epidemic. In León, all women pregnant during the two enrolment periods were eligible. In Managua, mother-child pairs were included from three districts in the municipality of Managua: all women who became pregnant before June 15, 2016, and had a due date of Sept 15, 2016 or later were eligible. Infants were serologically classified as Zika virus-exposed or Zika virus-unexposed in utero and were followed up prospectively until age 48 months. At 36 months and 48 months of age, the Mullen Scales of Early Learning (MSEL) assessment was administered. Primary outcomes were MSEL early learning composite (ELC) scores at 30-48 months in León and 36-48 months in Managua. We used an inverse probability weighting generalised estimating equations model to assess the effect of Zika virus exposure on individual MSEL cognitive domain scores and ELC scores, adjusted for maternal education and age, poverty status, and infant sex. FINDINGS: The initial enrolment period for the León cohort was between Jan 31 and April 5, 2017 and the second was between Aug 30, 2017, and Feb 22, 2018. The enrolment period for the Managua cohort was between Oct 24, 2019, and May 5, 2020. 478 mothers (482 infants) from the León cohort and 615 mothers (609 infants) from the Managua cohort were enrolled, of whom 622 children (303 from the León cohort; 319 from the Managua cohort) were included in the final analysis; four children had microcephaly at birth and thus were excluded from analyses, two from each cohort. 33 (11%) of 303 children enrolled in León and 219 (69%) of 319 children enrolled in Managua were exposed to Zika virus in utero. In both cohorts, no significant differences were identified in adjusted mean ELC scores between Zika virus-exposed and unexposed infants at 36 months (between-group difference 1·2 points [95% CI -4·2 to 6·5] in the León cohort; 2·8 [-2·4 to 8·1] in the Managua cohort) or at 48 months (-0·9 [-10·8 to 8·8] in the León cohort; 0·1 [-5·1 to 5·2] in the Managua cohort). No differences in ELC scores between Zika virus-exposed and unexposed infants exceeded 6 points at any time between 30 months and 48 months in León or between 36 months and 48 months in Managua, which was considered clinically significant in other settings. INTERPRETATION: We found no significant differences in neurodevelopmental scores between normocephalic children with in-utero Zika virus exposure and Zika virus-unexposed children at age 36 months or 48 months. These findings are promising, supporting typical neurodevelopment in Zika virus-exposed normocephalic children, although additional follow-up and research is warranted. FUNDING: National Institute of Child Health and Development, National Institute of Allergy and Infectious Diseases, and Fogarty International Center. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Prenatal SARS-CoV-2 infection results in neurodevelopmental and behavioral outcomes in mice.

Prenatal exposure to viral pathogens has been known to cause the development of neuropsychiatric disorders in adulthood. Furthermore, COVID-19 has been associated with a variety of neurological manifestations, raising the question of whether in utero SARS-CoV-2 exposure can affect neurodevelopment, resulting in long-lasting behavioral and cognitive deficits. Using a human ACE2-knock-in mouse model, we have previously shown that prenatal exposure to SARS-CoV-2 at later stages of development leads to fetal brain infection and gliosis in the hippocampus and cortex. In this study, we aimed to determine whether infection of the fetal brain results in long-term neuroanatomical alterations of the cortex and hippocampus or in any cognitive deficits in adulthood. Here, we show that infected mice developed slower and weighed less in adulthood. We also found altered hippocampal and amygdala volume and aberrant newborn neuron morphology in the hippocampus of adult mice infected in utero. Furthermore, we observed sex-dependent alterations in anxiety-like behavior and locomotion, as well as hippocampal-dependent spatial memory. Taken together, our study reveals long-lasting neurological and cognitive changes as a result of prenatal SARS-CoV-2 infection, identifying a window for early intervention and highlighting the importance of immunization and antiviral intervention in pregnant women.

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

It 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. 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. 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). 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. 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 0 controls, p = 0.12 had DD. Severe/critical maternal COVID-19 predicted below average neurodevelopment in the exposed cohort (OR 2.6, 95% CI 1.1-6.4). Children exposed to antenatal COVID-19 have a tenfold higher frequency of DD as compared to controls and should be offered neurodevelopmental follow-up.

Neurodevelopment in normocephalic children with and without prenatal Zika virus exposure.

OBJECTIVE: Zika virus (ZIKV) targets neural stem cells in the developing brain. However, the majority of ZIKV-exposed children are born without apparent neurological manifestations. It remains unclear if these children were protected from ZIKV neurotropism or if they harbour subtle pathology that is disruptive to brain development. We assess this by comparing neurodevelopmental outcomes in normocephalic ZIKV-exposed children relative to a parallel control group of unexposed controls. DESIGN: Cohort study. SETTING: Public health centres in Grenada, West Indies. PATIENTS: 384 mother-child pairs were enrolled during a period of active ZIKV transmission (April 2016-March 2017) and prospectively followed up to 30 months. Child exposure status was based on laboratory assessment of prenatal and postnatal maternal serum. MAIN OUTCOME MEASURES: The INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) package and Cardiff Vision Tests, administered and scored by research staff masked to child's exposure status. RESULTS: A total of 131 normocephalic ZIKV exposed (n=68) and unexposed (n=63) children were assessed between 22 and 30 months of age. Approximately half of these children completed vision testing. There were no group differences in sociodemographics. Deficits in visual acuity (31%) and contrast sensitivity (23%) were apparent in the ZIKV-exposed infants in the absence of cognitive, motor, language or behavioural delays. CONCLUSIONS: Overall neurodevelopment is likely to be unaffected in ZIKV-exposed children with normal head circumference at birth and normal head growth in the first 2 years of life. However, the visual system may be selectively vulnerable, which indicates the need for vision testing by 3 years of age.

Childhood seizures after prenatal exposure to maternal influenza infection: a population-based cohort study from Norway, Australia and Canada.

OBJECTIVE: To assess whether clinical and/or laboratory-confirmed diagnosis of maternal influenza during pregnancy increases the risk of seizures in early childhood. DESIGN: Analysis of prospectively collected registry data for children born between 2009 and 2013 in three high-income countries. We used Cox regression to estimate country-level adjusted HRs (aHRs); fixed-effects meta-analyses were used to pool adjusted estimates. SETTING: Population-based. PARTICIPANTS: 1 360 629 children born between 1 January 2009 and 31 December 2013 in Norway, Australia (New South Wales) and Canada (Ontario). EXPOSURE: Clinical and/or laboratory-confirmed diagnosis of maternal influenza infection during pregnancy. MAIN OUTCOME MEASURES: We extracted data on recorded seizure diagnosis in secondary/specialist healthcare between birth and up to 7 years of age; additional analyses were performed for the specific seizure outcomes 'epilepsy' and 'febrile seizures'. RESULTS: Among 1 360 629 children in the study population, 14 280 (1.0%) were exposed to maternal influenza in utero. Exposed children were at increased risk of seizures (aHR 1.17, 95% CI 1.07 to 1.28), and also febrile seizures (aHR 1.20, 95% CI 1.07 to 1.34). There was no strong evidence of an increased risk of epilepsy (aHR 1.07, 95% CI 0.81 to 1.41). Risk estimates for seizures were higher after influenza infection during the second and third trimester than for first trimester. CONCLUSIONS: In this large international study, prenatal exposure to influenza infection was associated with increased risk of childhood seizures.

POTENTIAL RISK OF BRAIN DAMAGE AND POOR DEVELOPMENTAL OUTCOMES IN CHILDREN PRENATALLY EXPOSED TO SARS-COV-2: A SYSTEMATIC REVIEW.

OBJECTIVE: To perform a systematic literature review to analyze existing data on the neurological effects of coronavirus on newborns. DATA: sources: We followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P), and searched the PubMed and Embase platforms for the keywords [brain damage OR pregnancy OR developmental outcomes] and [coronavirus OR SARS-CoV-2 OR SARS-CoV OR MERS-CoV] between January 1, 2000 and June 1, 2020. DATA: synthesis: Twenty-three reports described the course of pregnant women exposed to SARS-CoV-2, SARS-CoV, or MERS-CoV during the gestational period, eight to SARS-CoV-2, eight to SARS-CoV, and seven to MERS-CoV. No data were found on abnormalities in brain development or on a direct link between the virus and neurological abnormalities in the human embryo, fetus, or children. Spontaneous miscarriage, stillbirth, and termination of pregnancy were some complications connected with SARS/MERS-CoV infection. SARS-CoV-2 is not currently associated with complications in the gestational period. CONCLUSIONS: The literature has no data associating exposure to coronavirus during pregnancy with brain malformations and neurodevelopmental disorders. However, despite the lack of reports, monitoring the development of children exposed to SARS-CoV-2 is essential given the risk of complications in pregnant women and the potential neuroinvasive and neurotropic properties found in previous strains.

Longitudinal interrelationship between HIV viral suppression, maternal weight change, breastfeeding, and length in HIV-exposed and uninfected infants participating in the Kabeho study in Kigali, Rwanda.

PURPOSE: The health of infants that are HIV-exposed and -uninfected (HEU) is a major public health concern as HIV becomes a chronic condition. We investigate the interrelationship between maternal viral suppression, maternal weight status, breastfeeding, and infants that are HEU. METHODS: The Kabeho study followed 502 HEU infants in Kigali, Rwanda, for 24 months from 2013 to 2014. We use a structural equation modeling approach to investigate the dynamic relationships between viral suppression, maternal weight change, breastfeeding, and infant length-for-age z-score (LAZ) as defined by the WHO. RESULTS: Older mothers are more likely to be virally suppressed and to breastfeed. Viral suppression and the mother being on antiretroviral treatment for longer were related to lower infant LAZ at three months. A more positive maternal weight change was related to higher infant LAZ at the end of each period. At 12 months, a higher infant LAZ was related to increased probability of continued breastfeeding. At 18 months, continued breastfeeding was related to lower LAZ, and food shortages were related to higher LAZ. CONCLUSION: There is a complex interrelationship between viral suppression, maternal weight change, breastfeeding, and infant LAZ. These relationships demonstrate the link between maternal and infant health in the context of HIV.

Will prenatal exposure to SARS-CoV-2 define a birth cohort with accelerated aging in the century ahead?

The 1918 Influenza pandemic had long-term impacts on the cohort exposed in utero which experienced earlier adult mortality, and more diabetes, ischemic heart disease, and depression after age 50. It is possible that the Coronavirus Disease 2019 (COVID-19) pandemic will also have long-term impacts on the cohort that was in utero during the pandemic, from exposure to maternal infection and/or the stress of the pandemic environment. We discuss how COVID-19 disease during pregnancy may affect fetal and postnatal development with adverse impacts on health and aging. Severe maternal infections are associated with an exaggerated inflammatory response, thromboembolic events, and placental vascular malperfusion. We also discuss how in utero exposure to the stress of the pandemic, without maternal infection, may impact health and aging. Several recently initiated birth cohort studies are tracking neonatal health following in utero severe acute respiratory syndrome virus 2 (SARS-CoV-2) exposure. We suggest these cohort studies develop plans for longer-term observations of physical, behavioral, and cognitive functions that are markers for accelerated aging, as well as methods to disentangle the effects of maternal infection from stresses of the pandemic environment. In utero exposure to COVID-19 disease could cause developmental difficulties and accelerated aging in the century ahead. This brief review summarizes elements of the developmental origins of health, disease, and ageing and discusses how the COVID-19 pandemic might exacerbate such effects. We conclude with a call for research on the long-term consequences of in utero exposure to maternal infection with COVID-19 and stresses of the pandemic environment.

Evolution of ocular defects in infant macaques following in utero Zika virus infection.

Congenital Zika syndrome (CZS) is associated with microcephaly and various neurological, musculoskeletal, and ocular abnormalities, but the long-term pathogenesis and postnatal progression of ocular defects in infants are not well characterized. Rhesus macaques are superior to rodents as models of CZS because they are natural hosts of the virus and share similar immune and ocular characteristics, including blood-retinal barrier characteristics and the unique presence of a macula. Using a previously described model of CZS, we infected pregnant rhesus macaques with Zika virus (ZIKV) during the late first trimester and characterized postnatal ocular development and evolution of ocular defects in 2 infant macaques over 2 years. We found that one of them exhibited colobomatous chorioretinal atrophic lesions with macular and vascular dragging as well as retinal thinning caused by loss of retinal ganglion neuron and photoreceptor layers. Despite these congenital ocular malformations, axial elongation and retinal development in these infants progressed at normal rates compared with healthy animals. The ZIKV-exposed infants displayed a rapid loss of ZIKV-specific antibodies, suggesting the absence of viral replication after birth, and did not show any behavioral or neurological defects postnatally. Our findings suggest that ZIKV infection during early pregnancy can impact fetal retinal development and cause congenital ocular anomalies but does not appear to affect postnatal ocular growth.

In Utero HIV Exposure and the Early Nutritional Environment Influence Infant Neurodevelopment: Findings from an Evidenced Review and Meta-Analysis.

The developing brain is especially vulnerable to infection and suboptimal nutrition during the pre- and early postnatal periods. Exposure to maternal human immunodeficiency virus (HIV) infection and antiretroviral therapies (ART) in utero and during breastfeeding can adversely influence infant (neuro) developmental trajectories. How early life nutrition may be optimised to improve neurodevelopmental outcomes for infants who are HIV-exposed has not been well characterised. We conducted an up-to-date evidence review and meta-analysis on the influence of HIV exposure in utero and during breastfeeding, and early life nutrition, on infant neurodevelopmental outcomes before age three. We report that exposure to maternal HIV infection may adversely influence expressive language development, in particular, and these effects may be detectable within the first three years of life. Further, while male infants may be especially vulnerable to HIV exposure, few studies overall reported sex-comparisons, and whether there are sex-dependent effects of HIV exposure on neurodevelopment remains a critical knowledge gap to fill. Lastly, early life nutrition interventions, including daily maternal multivitamin supplementation during the perinatal period, may improve neurodevelopmental outcomes for infants who are HIV-exposed. Our findings suggest that the early nutritional environment may be leveraged to improve early neurodevelopmental trajectories in infants who have been exposed to HIV in utero. A clear understanding of how this environment should be optimised is key for developing targeted nutrition interventions during critical developmental periods in order to mitigate adverse outcomes later in life and should be a priority of future research.

Examining the Association of Socioeconomic Position with Microcephaly and Delayed Childhood Neurodevelopment among Children with Prenatal Zika Virus Exposure.

Increased rates of Zika virus have been identified in economically deprived areas in Brazil at the population level; yet, the implications of the interaction between socioeconomic position and prenatal Zika virus exposure on adverse neurodevelopmental outcomes remains insufficiently evaluated at the individual level. Using data collected between September 2015 and September 2019 from 163 children with qRT-PCR and/or IgM-confirmed prenatal exposure to Zika virus participating in a prospective cohort study in Rio de Janeiro, Brazil (NCT03255369), this study evaluated the relationships of socioeconomic indicators with microcephaly at birth and Bayley-III neurodevelopmental scores during the early life course. Adjusted logistic regression models indicated increased odds of microcephaly in children born to families with lower household income (OR, 95% CI: 3.85, 1.43 to 10.37) and higher household crowding (OR, 95% CI: 1.83, 1.16 to 2.91), while maternal secondary and higher education appeared to have a protective effect for microcephaly compared to primary education (OR, 95% CI: 0.33, 0.11 to 0.98 and 0.10, 0.03 to 0.36, respectively). Consistent with these findings, adjusted linear regression models indicated lower composite language (-10.78, 95% CI: -19.87 to -1.69), motor (-10.45, 95% CI: -19.22 to -1.69), and cognitive (-17.20, 95% CI: -26.13 to -8.28) scores in children whose families participated in the Bolsa Família social protection programme. As such, the results from this investigation further emphasise the detrimental effects of childhood disadvantage on human health and development by providing novel evidence on the link between individual level socioeconomic indicators and microcephaly and delayed early life neurodevelopment following prenatal Zika virus exposure.

Maternal cytomegalovirus immune status and hearing loss outcomes in congenital cytomegalovirus-infected offspring.

OBJECTIVES: The purpose of this study is to determine the relationship between maternal primary and recurrent CMV infection during pregnancy, symptoms at birth in the newborn, and long term hearing loss through18 years of age. PATIENTS AND METHODS: 237 mother-infant pairs in the Houston, Texas area identified through maternal CMV IgG and IgM antibody serologic screening and newborn screening using urine CMV culture to identify congenital CMV infection were enrolled in the Houston Congenital CMV Longitudinal Study. Mothers were categorized as having primary or recurrent or unknown maternal CMV infections, and newborns were categorized at birth as having symptomatic or asymptomatic congenital CMV infection, or as uninfected controls. All three newborn groups were followed longitudinally with serial hearing evaluations up to 18 years of age. The relationship between type of maternal CMV infection, newborn classification, and the occurrence of hearing loss over time was determined through Kaplan-Meier survival analysis, life table analysis, and a simulated ascertainment of maternal infection type for the unknown categories. RESULTS: Of 77 newborns with symptomatic congenital CMV infection, 12 (16%) of mothers had a primary CMV infection during pregnancy; 4 (5%) had a non-primary infection, and the type of infection in 48 (79%) could not be determined and were classified as unknown type of maternal infection. Fifty Seven (74%) of the 77 symptomatic children had hearing loss by 18 years of age, including 9 of the 12 (75%) who were born to mothers with primary infection and 48 (79%) of the 61 with unknown type of maternal infection. Of the 109 newborns with asymptomatic congenital CMV infection, 51 (47%) were born to mothers with a primary CMV infection during pregnancy, 18 (17%) to mothers with a recurrent infection; and 40 (37%) had unknown type of infection. Of these 109 asymptomatic cases, 22 (20%) developed hearing loss, including 14 out of 51 (28%) of those born to mothers with primary infection, two out of the 18 (11%) born to mothers with recurrent infection, and 6 out of the 40 (15%) to mothers of unknown infection type. Of the 51 uninfected newborn controls, 10 (20%) of mothers had a primary CMV infection during pregnancy, 5 (10%) had a non-primary infection, 10 (20%) were never infected, and 26 (51%) were assigned unknown type of infection. Three controls (6%) developed hearing loss, with 1 being born to a mother with primary infection and 1 to a mother never infected with CMV. CONCLUSIONS: Both primary and non-primary maternal CMV infections during pregnancy resulted in symptomatic and asymptomatic congenital CMV infection. Symptomatic congenital CMV infection was more likely to occur after primary maternal CMV infection. Sensorineural hearing loss occurred in children born to mothers with both primary and non-primary CMV infections, and in both asymptomatic and symptomatic congenital CMV infection, but was more common after maternal primary infection. Most, but not all, hearing loss in children with cCMV associated hearing loss was first detected within the first year of life.

Maternal Influenza A Virus Infection Restricts Fetal and Placental Growth and Adversely Affects the Fetal Thymic Transcriptome.

Maternal influenza A viral infections in humans are associated with low birth weight, increased risk of pre-term birth, stillbirth and congenital defects. To examine the effect of maternal influenza virus infection on placental and fetal growth, pregnant C57BL/6 mice were inoculated intranasally with influenza A virus A/CA/07/2009 pandemic H1N1 or phosphate-buffered saline (PBS) at E3.5, E7.5 or E12.5, and the placentae and fetuses collected and weighed at E18.5. Fetal thymuses were pooled from each litter. Placentae were examined histologically, stained by immunohistochemistry (IHC) for CD34 (hematopoietic progenitor cell antigen) and vascular channels quantified. RNA from E7.5 and E12.5 placentae and E7.5 fetal thymuses was subjected to RNA sequencing and pathway analysis. Placental weights were decreased in litters inoculated with influenza at E3.5 and E7.5. Placentae from E7.5 and E12.5 inoculated litters exhibited decreased labyrinth development and the transmembrane protein 150A gene was upregulated in E7.5 placentae. Fetal weights were decreased in litters inoculated at E7.5 and E12.5 compared to controls. RNA sequencing of E7.5 thymuses indicated that 957 genes were downregulated ≥2-fold including Mal, which is associated with Toll-like receptor signaling and T cell differentiation. There were 28 upregulated genes. It is concluded that maternal influenza A virus infection impairs fetal thymic gene expression as well as restricting placental and fetal growth.

Inflammation, cytomegalovirus and the growth hormone axis in HIV-exposed uninfected Zimbabwean infants.

OBJECTIVES: Despite avoiding HIV infection, HIV-exposed uninfected (HEU) infants have poorer clinical outcomes than HIV-unexposed infants, including impaired growth. The growth hormone (GH) axis is an important regulator of infant growth through hepatic synthesis of insulin-like growth-factor-1 (IGF-1), and may be disrupted by chronic inflammation and acute infections, including cytomegalovirus (CMV). We tested the hypothesis that these factors lead to disruption of the GH axis in HEU infants, which might contribute to their impaired growth. DESIGN: Substudy of 343 infants from the ZVITAMBO trial in Harare, Zimbabwe. METHODS: IGF-1, growth parameters, C-reactive protein (CRP) and CMV viraemia were evaluated in 243 HEU infants and 100 HIV-unexposed infants. Univariable linear and logistic regression models were used to determine associations between IGF-1 and growth parameters, CRP and CMV. RESULTS: Mean 6-week IGF-1 was significantly lower in HEU compared with HIV-unexposed infants (29.6 vs. 32.6 ng/ml; P = 0.014), and associated with subsequent linear and ponderal growth through 6 months of age. CRP was inversely correlated with IGF-1 in all infants regardless of HIV exposure status (ß = -0.84; P = 0.03). CMV viral loads were inversely correlated with IGF-1 in HEU (ß = -1.16; P = 0.008) but not HIV-unexposed (ß = 0.21; P = 0.83) infants. CONCLUSION: Overall, we found evidence for greater disruption of the GH axis in HEU compared with HIV-unexposed infants as early as 6 weeks of age, suggesting a role for reduced IGF-1 in mediating growth impairment in HEU infants. Inflammation and coinfections may be drivers of growth impairment in HEU infants by disrupting the GH axis.

HIV-Exposed, Uninfected Infants in Uganda Experience Poorer Growth and Body Composition Trajectories than HIV-Unexposed Infants.

BACKGROUND: HIV-uninfected infants of HIV-positive women may experience worse growth and health outcomes than infants of HIV-negative women, but this has not been thoroughly investigated under the World Health Organization's most recent recommendations to reduce vertical transmission. OBJECTIVE: To determine whether HIV-exposed and -uninfected (HEU) infants whose mothers received Option B+ have higher odds of experiencing suboptimal growth trajectories than HIV-unexposed, -uninfected infants, and if this relationship is affected by food insecurity. DESIGN: Repeated anthropometric measures were taken on 238 infants (HEU = 86) at 1 week and 1, 3, 6, 9, and 12 months after delivery in Gulu, Uganda. Latent class growth mixture modeling was used to develop trajectories for length-for-age z-scores, weight-for-length z-scores, mid-upper arm circumference, sum of skinfolds, and arm fat area. Multinomial logistic models were also built to predict odds of trajectory class membership, controlling for socioeconomic factors. RESULTS: HEU infants had greater odds of being in the shortest 2 length-for-age z-scores trajectory classes [odds ratio (OR) = 3.80 (1.22-11.82), OR = 8.72 (1.80-42.09)] and higher odds of being in smallest sum of skinfolds trajectory class [OR = 3.85 (1.39-10.59)] vs. unexposed infants. Among HEU infants, increasing food insecurity was associated with lower odds of being in the lowest sum of skinfolds class [OR = 0.86 (0.76-0.98)]. CONCLUSIONS: There continues to be differences in growth patterns by HIV-exposure under the new set of World Health Organization guidelines for the prevention of mother-to-child transmission of HIV and the feeding of HEU infants in low-resource settings that are not readily identified through traditional mixed-effects modeling. Food insecurity was not associated with class membership, but differentially affected adiposity by HIV-exposure status.

Association Between Antenatal Exposure to Zika Virus and Anatomical and Neurodevelopmental Abnormalities in Children.

Importance: Zika virus (ZIKV) is a mosquito-borne flavivirus recognized as teratogenic since the 2015 to 2016 epidemic. Antenatal ZIKV exposure causes brain anomalies, yet the full spectrum has not been delineated. Objective: To characterize the clinical features of ZIKV infection at a pediatric referral center in Rio de Janeiro, Brazil, among children with antenatal ZIKV exposure. Design, Setting, and Participants: Retrospective cohort study conducted from May to July 2019 of a prospective cohort of 296 infants with antenatal ZIKV exposure followed up since December 2015 at a tertiary maternity-pediatric hospital. Exposures: Zika virus infection during pregnancy. Main Outcomes and Measures: Characterization of clinical features with anthropometric, neurologic, cardiologic, ophthalmologic, audiometric, and neuroimaging evaluations in infancy and neurodevelopmental assessments (Bayley Scales of Infant and Toddler Development, Third Edition) from 6 to 42 months of age, stratified by head circumference at birth (head circumference within the reference range, or normocephaly [NC] vs microcephaly [MC]). Results: Antenatal exposure to ZIKV was confirmed for 219 of 296 children (74.0%) referred to Instituto Fernandes Figueira with suspected ZIKV infection through positive maternal or neonatal polymerase chain reaction analysis or IgM serology results. Of these children, 110 (50.2%) were boys, ages ranged from 0 to 4 years, and 53 (24.2%) had congenital microcephaly. The anomalies observed in ZIKV-exposed children with MC or NC were failure to thrive (MC: 38 of 53 [71.7%]; NC: 73 of 143 [51.0%]), cardiac malformations (MC: 19 of 46 [41.3%]; NC: 20 of 100 [20.0%]), excess nuchal skin (MC: 16 of 22 [72.7%]; NC: 35 of 93 [37.6%]), auditory abnormalities (MC: 13 of 50 [26.0%]; NC: 14 of 141 [9.9%]), and eye abnormalities (MC: 42 of 53 [79.2%]; NC: 28 of 158 [17.7%]). Although they experienced fewer neurologic abnormalities than children born with MC, those with NC also had frequent neurologic abnormalities (109 of 160 [68.1%]), including hyperreflexia (36 of 136 [26.5%]), abnormal tone (53 of 137 [38.7%]), congenital neuromotor signs (39 of 93 [41.9%]), feeding difficulties (15 of 143 [10.5%]), and abnormal brain imaging results (44 of 150 [29.3%]). Among 112 children with NC with Bayley-III evaluations, 72 (64.3%) had average or above-average scores; 30 (26.8%) scored 1 SD below average in at least 1 domain; and 10 (8.9%) scored 2 SD below average in at least 1 domain. Among 112 children with NC, a smaller head circumference at birth was significantly associated with subsequent below-average cognitive scores (U = 499.5; z = -2.833; P = .004) and language scores (U = 235.5; z = -2.491; P = .01). Conclusions and Relevance: Children without MC who were exposed to ZIKV in utero had a high frequency of anatomical and neurodevelopmental abnormalities. The head circumference at birth for children with NC was associated with neurocognitive development. Recognition of the wide spectrum of clinical phenotypes is critical to ensure early referral to rehabilitative interventions.