Prenatal Metal Exposures and Infants’ Developmental Outcomes in a Navajo Population

Early-life exposure to environmental toxicants can have detrimental effects on children’s neurodevelopment. In the current study, we employed a causal modeling framework to examine the direct effect of specific maternal prenatal exposures on infants’ neurodevelopment in the context of co-occurring metals. Maternal metal exposure and select micronutrients’ concentrations were assessed using samples collected at the time of delivery from mothers living across Navajo Nation with community exposure to metal mixtures originating from abandoned uranium mines. Infants’ development across five domains was measured at ages 10 to 13 months using the Ages and Stages Questionnaire Inventory (ASQ:I), an early developmental screener. After adjusting for effects of other confounding metals and demographic variables, prenatal exposure to lead, arsenic, antimony, barium, copper, and molybdenum predicted deficits in at least one of the ASQ:I domain scores. Strontium, tungsten, and thallium were positively associated with several aspects of infants’ development. Mothers with lower socioeconomic status (SES) had higher lead, cesium, and thallium exposures compared to mothers from high SES backgrounds. These mothers also had infants with lower scores across various developmental domains. The current study has many strengths including its focus on neurodevelopmental outcomes during infancy, an understudied developmental period, and the use of a novel analytical method to control for the effects of co-occurring metals while examining the effect of each metal on neurodevelopmental outcomes. Yet, future examination of how the effects of prenatal exposure on neurodevelopmental outcomes unfold over time while considering all potential interactions among metals and micronutrients is warranted.

Plasma vitamin B12 concentration is positively associated with cognitive development in healthy Danish 3-year-old children; the SKOT cohort studies

Adequate vitamin B12 and folate concentrations are essential for neural development in early childhood but studies in well-nourished children are lacking. We investigated the relation between plasma vitamin B12 and folate at 9 and 36 months and psychomotor development at 36 months in well-nourished Danish children. Subjects from the SKOT cohorts with vitamin B12 measurement and completed Ages and Stages Questionnaire (ASQ-3) at 36 months were included (n=280). Dietary intake, vitamin B12- and folate concentrations were collected at 9 and 36 months, and ASQ-3 was assessed at 36 months. Associations between vitamin B12 and folate at 9 and 36 months and ASQ-3 were analyzed using regression models. Associations between diet and vitamin B12 were also investigated. No children had insufficient vitamin B12(<148pmol/L) at 36 months. Vitamin B12 at 36 month was positively associated with total ASQ-3 corresponding to an increase of 100 pmol/L vitamin B12 per 1.5 increase in total ASQ-3 score; p=0.019) which remained significant after adjustment for potential confounders including 9 months values. Vitamin B12 at 9 months or folate at any time point was not associated with total ASQ-3. Intake of milk products was associated with vitamin B12 at 36 months (p=0.003) and showed a trend at 9 months (p=0.069). Intake of meat products was not associated with vitamin B12. In conclusion, vitamin B12 was positively related to psychomotor development at 3 years in well-nourished children, indicating that the impact of having marginally low vitamin B12 status on psychomotor development in well-nourished children should be examined further.

Neurodevelopmental outcomes of infants secondary to in utero exposure to maternal SARS-CoV-2 infection: A national prospective study in Kuwait

Background An increasing proportion of women are being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Intrauterine viral infections induce an increase in the levels of proinflammatory cytokines, which inhibit the proliferation of neuronal precursor cells and stimulate oligodendrocyte cell death, leading to abnormal neurodevelopment. Whether a maternal cytokine storm can affect neonatal brain development is unclear. The objective of the present study is to assess neurodevelopmental outcomes in neonates born to mothers with SARS-CoV-2 infections during pregnancy. Methods In this prospective cohort study, the neurodevelopment status of infants (N=298) born to women with SARS-CoV-2 infections during pregnancy was assessed at 10-12 months post-discharge using the Ages and Stages Questionnaire, 3rd edition (ASQ-3). The ASQ-3 scores were classified into developmental delays (cutoff score: ≤2 standard deviations (SDs) below the population mean) and no delay (score >2 SDs above the population mean). Results Approximately 10% of infants born to mothers with SARS-CoV-2 infections during pregnancy showed developmental delays. Two of 298 infants tested positive for SARS-CoV-2, and both had normal ASQ-3 scores. The majority of the pregnant women had SARS-CoV-2 infection during their third trimester. The risk of developmental delays among infants was higher in those whose mothers had SARS-CoV-2 infections during the first (P=0.039) and second trimesters (P=0.001) than in those whose mothers had SARS-CoV-2 infections during the third trimester. Infants born at <31 weeks gestation were more prone to developmental delays than those born at >31 weeks gestation (10% versus 0.8%; P=0.002). Conclusion The findings of the study highlight the need for long-term neurodevelopmental assessment of infants born to mothers with SARS-CoV-2 infection.

Prospective association of air purifier use during pregnancy with the neurodevelopment of toddlers in the Japan Environment and Children’s Study

We examined the association between maternal air purifier use during pregnancy and neurodevelopmental delay in toddlers by analysing data from 82,457 mother-toddler pairs. Air purifier use was measured using a simple yes/no question. Developmental delays at 1.5, 2.0, 2.5, and 3.0 years were assessed using the Ages and Stages Questionnaire, Third Edition. Generalized additive mixed model analysis with 21 covariates revealed that air purifier use was associated with lower prevalence of developmental delay in all five areas—communication, gross motor, fine motor, problem solving, and personal-social—at all four time points (adjusted risk ratios ranged from 0.827 to 0.927, and only one 95% confidence interval crossed the reference). These findings suggest a negative association between air purifier use during pregnancy and neurodevelopmental delay in toddlers.Trial registration: UMIN000030786 (15/01/2018).

Head Growth and Neurodevelopment of Preterm Infants with Surgical Necrotizing Enterocolitis and Spontaneous Intestinal Perforation

Spontaneous intestinal perforation (SIP) and surgical necrotizing enterocolitis (NEC) are intestinal conditions requiring surgical intervention in preterm infants. We aimed to compare the head growth and neurodevelopment of preterm infants with SIP and surgical NEC. A retrospective single-center study was performed in preterm infants born at less than 32 weeks of gestation and who had undergone surgery for NEC or SIP. Data from the Bayley Scales of Infant and Toddler Development 3rd Edition (Bayley-III) at 24 months of corrected age (CA) and the Korean Ages and Stages Questionnaire (K-ASQ) or Korean Developmental Screening Test (K-DST) at 36 months were collected. Among 82 eligible infants, 60 infants had surgical NEC, and 22 infants were diagnosed with SIP. Head growth was faster until CA 4 months in preterm infants with SIP than in those with surgical NEC. At 36 months, abnormal findings in the K-ASQ or K-DST were more prevalent in the NEC group than in the SIP group in the gross motor (48.2% vs. 0%, p = 0.015), fine motor (40.7% vs. 0%, p = 0.037), cognitive (55.6% vs. 12.5%, p = 0.047), and social domains (44.4% vs. 0%, p = 0.032). More studies evaluating the neurodevelopmental outcomes of preterm infants with surgical NEC and SIP are required.

Safety and Outcomes in Infants Born to Mothers Participating in Retosiban Treatment Trials: ARIOS Follow-Up Study

Objective Retosiban, an oxytocin receptor antagonist, was developed for treating spontaneous preterm labor (sPTL) in women with intact membranes. This ARIOS follow-up study aimed to characterize clinical safety, morbidity, and mortality of infants exposed to retosiban or comparator over 2 years. Study Design ARIOS prospectively assessed outcomes in infants whose mothers received at least one dose of retosiban or comparator (placebo/atosiban) in two Phase 3 sPTL trials. Both trials were terminated prematurely owing to poor enrolment. Infants could be enrolled into ARIOS from 28 days after estimated due date until hospital discharge or up to 9 months (corrected age). An internally developed questionnaire detailing medical conditions, mortality and resource use (Child Health Inventory; CHI), Ages and Stages Questionnaire-3 (ASQ-3), Modified Checklist for Autism in Toddlers–Revised with Follow-Up, and Child Behavior Checklist for Ages 1.5 to 5 were completed remotely by parents or legal guardians at prespecified intervals. Serious adverse events (SAEs) were primarily captured via CHI. No comparative statistical analysis was conducted between treatment arms. Results A total of 49 (86%) infants who had received retosiban and 49 (78%) infants who had received a comparator were enrolled in ARIOS. No deaths occurred during the study. Nine infants experienced SAEs: 6/49 (12.2%) infants in the comparators group and 3/49 (6.1%) in the retosiban group. Of the nine SAEs, seven were due to infections, three, and four in the retosiban and comparators groups, respectively. Based on ASQ-3 score, the incidence of neurodevelopmental delay at 18 and 24 months were 0/18 (0%) and 2/25 (8%) with retosiban and 7/22 (31.8%) and 3/21 (14.3%) with comparator, respectively. Conclusion The current study showed no unexpected adverse outcome or impairment with retosiban based on safety monitoring and neurodevelopment assessments. No further follow-up is intended owing to the discontinuation of clinical development of retosiban. Key Points

Biological Risk Factors and Early Developmental Delay Assessment in Infants Using Ages and Stages Questionnaire, Version 3 (ASQ-3)

Background: Development during early years of life is very crucial in the context of overall development of an individual. This is especially true for infants who have biological risk factors for maldevelopment. This study aimed to find the association of biological risk factors and developmental delay in infants aged 3-18 months. Materials and Methods: For this study, enrolment of 460 infants was done in the age group of 3-18 months who were attending Immunization Clinic in district level Civil Hospital, Faridkot, Punjab. Developmental assessment in the five areas including Gross motor, Fine motor, Communication, Problem solving and Personal-social development was done using a standardized tool called Ages and Stages Questionnaire, version 3 (ASQ-3). Results: Most of the study subjects viz., 426 (92.6%) were born full term whereas 34 (7.3%) infants were born preterm. Mean birth weight of infants was 2.9 ± 0.387 kgs. Out of the total, 259 (56.3%) study subjects were males and 201(43.7%) were females. Biological risk factors like gestation age and birth weight had statistically significant association with all domains of developmental delay except in the area of personal social development. On the other hand, gender had no association with any domain of developmental delay. Conclusion: Gestation age and birth weight are the typical risk factors having significant impact on all domains of developmental delay except for the personal social delay. However, gender of infant had no association with developmental delay. Keywords: Infant, Gestation age, birth weight, Developmental delay, ASQ.

Prevalence and Characteristics of Social Withdrawal Tendency Among 3–24 Months in China: A Pilot Study

Background: Sustained withdrawal behavior is an obstacle for child development. The present study aimed to preliminarily evaluate the prevalence of social withdrawal tendency in young Chinese children using the Alarm Distress Baby Scale (ADBB) and describe the characteristics of socially withdrawn children.Method: This was a cross-sectional analysis as part of a prospective cohort study. A total of 114 children aged 3–24 months were included. The following instruments were administered: the Chinese version of ADBB, the Ages and Stages Questionnaire (ASQ-3), the Ages and Stages Questionnaire: Social-Emotional (ASQ:SE), and the Infant Temperamental Questionnaire. The tendency of social withdrawal in children was assessed using the ADBB. Social withdrawal was defined as an ADBB score of 5 or above. Student's t-test, χ2 test, and Fisher's exact test were performed to identify the differences in maternal and child characteristics between the children with and without social withdrawal. Age-specific indicators of development in these two groups were also presented.Results: About 16.7% of the children were socially withdrawn. Compared with those without social withdrawal, children with social withdrawal were older and had higher proportions of boys (68.4 vs. 42.1%) and social-emotional development delay (63.2 vs. 0%). In age-specific analyses, social-emotional development was poorer in children with social withdrawal across all age groups from 3 to 24 months.Conclusion: Assessed by the ADBB, the prevalence of social withdrawal tendency in young Chinese children was similar to that reported in the European population; children with social withdrawal tended to have poorer social-emotional development. Further research with larger sample sizes is needed to validate the scale and confirm these findings.

Isolated CHDs and neurodevelopmental follow-up using the Bayley Scales of Infant and Toddler Development and the Ages and Stages Questionnaire at 18 and 36 months

Objectives: To compare early neurocognitive development in children born with and without isolated CHD using the Bayley Scales of Infant and Toddler Development (3rd edition) and the Ages and Stages Questionnaire (3rd edition). Methods: Recruitment took place before birth. Women expecting fetuses with and without CHD causing disturbances in the flow of oxygenated blood to the fetal brain were included in a prospective cohort study comprising fetal MRI (previously published) and neurodevelopmental follow-up. We now present the 18- and 36-month neurodevelopmental follow-up using the Bayley Scales according to age and the 6-month-above-age Ages and Stages Questionnaire in 15 children with and 27 children without CHD. Results: Children with CHD had, compared with the children without CHD, an increased risk of scoring ≤ 100 in the Bayley Scales cognition category at 18 and 36 -months; relative risk 1.7 (95% confidence interval (CI): 1.0–2.8) and 3.1 (CI: 1.2–7.5), respectively. They also achieved lower scores in the 6-month-above-age Ages and Stages Questionnaires (24 and 42 months) communication; mean z-score difference −0.72 (CI: −1.4; −0.1) and −1.06 (CI: −1.8; −0.3) and gross motor; mean z-score difference: −0.87 (CI: −1.7; −0.1) and −1.22 (CI: −2.4; −0.02) categories. Conclusions: The children with CHD achieved lower scores in the Bayley Scales cognition category and the Ages and Stages Questionnaire communication and gross motor categories possibly indicative of early neurodevelopmental deficiencies. We recommend early screening and monitoring for neurodevelopmental delays in children with CHD in order to improve further neurodevelopment and educational achievements.