Prenatal organophosphate esters exposure and neurodevelopment trajectory in infancy: Evidence from the Shanghai Maternal-Child Pairs Cohort.

BACKGROUND: Concerns remain about the neurotoxic properties of the ubiquitous organophosphate esters (OPEs), the replacement of the toxicant polybrominated diphenyl ethers. OBJECTIVES: We examined the associations of prenatal exposure to OPEs and their mixtures with early-life neurodevelopment trajectories. METHODS: Totally 1276 mother-child pairs were recruited from the Shanghai Maternal-Child Pairs Cohort. A high-performance liquid chromatography-triple quadrupole mass spectrometer was used to measure the levels of 7 OPEs in cord serum. Ages and Stages Questionnaires was used to examine children's neuropsychological development at 2, 6, 12, and 24 months of age. Group-based trajectory models were applied to derive the neurodevelopmental trajectories. Multiple linear regression and logistic regression model were performed to assess the relationships between OPEs exposure and neurodevelopment and trajectories. Mixtures for widely detected OPEs (n = 4) were investigated using quantile-based g-computation. RESULTS: Tributyl phosphate (TBP), tris (2-butoxy ethyl) phosphate (TBEP), tris(1,3-dichloro-2-propyl) phosphate (TDCPP), and 2-ethylhexyl diphenyl phosphate (EHDPP), had detection rates >50 %. TDCPP had the highest median concentration (1.02 µg/L) in cord serum. EHDPP concentrations were negatively associated with scores in most domains at 12 months of age, with effect values (ß) ranging from -1.89 to -0.57. EHDPP could negatively affect the total ASQ (OR = 1.07, 95 % CI: 1, 1.15) and gross-motor (OR = 1.09, 95 % CI: 1.02, 1.17) trajectory in infancy. Joint exposure to OPEs was associated with decreased scores in the total ASQ, gross-motor, fine-motor and problem-solving domain of 12-month-old infants, with ß ranging from -5.93 to -1.25. In addition, the qgcomp models indicated significant positive associations between the concentrations of OPEs mixtures and risks of the persistently low group of the total ASQ, gross-motor and fine-motor development in early childhood. The impact of OPEs was more pronounced in boys. DISCUSSION: Our findings suggested OPEs, especially EHDPP, had a persistently negative effect on neurodevelopment during the first 2 years.

Developmental Windows for Effects of Choline and Folate on Excitatory and Inhibitory Neurotransmission During Human Gestation.

Choline and folate are critical nutrients for fetal brain development, but the timing of their influence during gestation has not been previously characterized. At different periods during gestation, choline stimulation of α7-nicotinic receptors facilitates conversion of γ-aminobutyric acid (GABA) receptors from excitatory to inhibitory and recruitment of GluR1-R2 receptors for faster excitatory responses to glutamate. The outcome of the fetal development of inhibition and excitation was assessed in 159 newborns by P50 cerebral auditory-evoked responses. Paired stimuli, S1, S2, were presented 500 msec apart. Higher P50 amplitude in response to S1 (P50S1microV) assesses excitation, and lower P50S2microV assesses inhibition in this paired-stimulus paradigm. Development of inhibition was related solely to maternal choline plasma concentration and folate supplementation at 16 weeks' gestation. Development of excitation was related only to maternal choline at 28 weeks. Higher maternal choline concentrations later in gestation did not compensate for earlier lower concentrations. At 4 years of age, increased behavior problems on the Child Behavior Checklist 1½-5yrs were related to both newborn inhibition and excitation. Incomplete development of inhibition and excitation associated with lower choline and folate during relatively brief periods of gestation thus has enduring effects on child development.

Glucocorticoid use and varying doses on the long-term outcomes of offspring born to patients with systemic lupus erythematosus.

This study aims to assess the impact of non-fluorinated glucocorticoid use and varying doses on the long-term physical, neurological, and social-emotional development outcomes of offspring born to patients with systemic lupus erythematosus (SLE). The goal is to provide guidance on the appropriate dosage of glucocorticoids during pregnancy in SLE patients. We conducted a follow-up study on the offspring of SLE patients who had pregnancies and were admitted to our obstetrics department between January 1, 2016, and September 30, 2021. Patients who received immunosuppressants and dexamethasone were excluded from the study. The SLE patients were categorized into three groups based on their glucocorticoid use during pregnancy: hormone-free group, ≤ 10 mg/day group, and > 10 mg/day group (equivalent to prednisone). Most patients in the three groups were used hydroxychloroquine during pregnancy. We assessed the physical development status, including weight, height (length), and other relevant factors in three groups. Additionally, we utilized the Age and Stages Questionnaires, Third Edition (ASQ-3) to evaluate the development of communication, gross motor, fine motor, problem-solving, and personal-social. The social-emotional development status was assessed using the Age and Stages Questionnaires: Social-Emotional (ASQ: SE). We standardized the weight, height (length), body mass index, and ASQ-3 domain scores of children of different ages and genders into Z-scores for comparison. The results of this study demonstrated no statistically significant differences in the long-term physical development, neurological development, and social-emotional development outcomes of the offspring of SLE patients in three groups. However, while not reaching statistical significance, it was found that the offspring of the > 10 mg/day group had lower height (length) Z-scores and communication Z-scores compared to the other groups.   Conclusion: The use of non-fluorinated glucocorticoids during pregnancy and varying doses did not have a significant impact on the long-term physical, neurological, and social-emotional development outcomes of offspring born to SLE patients. However, the offspring of SLE patients treated with glucocorticoids > 10 mg/day during pregnancy may be necessary to strengthen the monitoring of height (length) and communication skills in the long term. What is Known: • Fetal exposure to glucocorticoids can have implications for the development of multiple systems and may persist after birth, potentially increasing the risk of neurological abnormalities and other diseases. • There is limited research on the long-term development of offspring born to SLE patients, especially the patients treated with glucocorticoids. What is New: • The use of non-fluorinated glucocorticoids during pregnancy and varying doses did not have a significant impact on the long-term outcomes of offspring born to SLE patients. • The offspring of SLE patients treated with glucocorticoids >10 mg/day during pregnancy may be necessary to strengthen the monitoring of height (length) and communication skills in the long term.

Smoke Alarm.

As states relax their laws on cannabis, neuroscientist Yasmin Hurd is warning about the drug's dangers for the developing brain.

Air pollution during the perinatal period and neurodevelopment in children: A national population study in Taiwan.

AIM: To evaluate the association between ambient particulate matter no larger than 2.5 µm in diameter (PM2.5 ) during the prenatal and postnatal periods and infant neurodevelopmental parameters. METHOD: We conducted a population-based birth cohort study using the Taiwan Birth Cohort Study. Participants were assessed for developmental conditions through home interviews at 6 months and 18 months of age. Exposure to PM2.5 of mothers and infants during perinatal periods was estimated using hybrid kriging/land-use regression. The exposure was linked to each participant by home address. Logistic regression was then conducted to determine the risk of neurodevelopmental delay in relation to PM2.5 . RESULTS: A total of 17 683 term singletons without congenital malformations were included in the final analysis. PM2.5 during the second trimester was associated with increased risks of delays in gross motor neurodevelopmental milestones (adjusted odds ratio [aOR] 1.09 per 10 µg/m3 increase in exposure to PM2.5 ). Delayed fine motor development was also found to be related to exposure to PM2.5 in the second and third trimesters (aOR 1.06), as was personal-social skill (aOR 1.11 for the second trimester and 1.06 for the third). These neurodevelopmental parameters were unrelated to postnatal PM2.5 exposure. INTERPRETATION: Exposure to ambient PM2.5 during pregnancy was significantly related to delay in gross motor, fine motor, and personal-social development in this population-based study. WHAT THIS PAPER ADDS: Prenatal exposure to higher PM2.5 was associated with increased risk of delayed early neurodevelopment. The critical period for delayed gross motor development was the second trimester. The critical period for fine motor and personal-social development was the second and third trimesters.

Chronic Aflatoxin Exposure and Cognitive and Language Development in Young Children of Bangladesh: A Longitudinal Study.

Aflatoxin can cross the blood-brain barrier, damage brain tissues, and have the potential to harm the development of the human brain. Although dietary aflatoxin exposure is common in children, there is a paucity of data on aflatoxin exposure and child developmental outcomes. The child's cognitive, motor, and language functions were assessed using the Bayley Scales of Infant and Toddler Development-III or BSID-III at the same time points. Association between exposure to aflatoxin and subtests of BSID-III were examined using mixed-effect linear regression. Aflatoxin assays were performed on 194, 167, and 163 children at 15, 24, and 36 months of age, and chronic aflatoxin exposure was detected in 20.6%, 16.8%, and 60.7% of children, respectively. Multi-variable analyses showed that aflatoxin exposure was independently related to the children's cognitive score (ß: -0.69; 95% CI: -1.36, -0.02), receptive language score (ß: -0.90; 95% CI: -1.62, -0.17), and expressive language score (ß: -1.01; 95% CI: -1.96, -0.05). We did not observe any association between exposure to aflatoxin and the motor function of children. Chronic exposure to aflatoxin exposure was linked to reduced cognitive, expressive, and receptive language scores of the study children. Further research is needed in a different setting to confirm this novel finding.

Aminophylline in combination with caffeine citrate in neurodevelopmental treatment and follow-up of high-risk preterm infants using GMs assessment.

To explore the application effect of aminophylline combined with caffeine citrate and GMs in the evaluation of neurodevelopmental treatment and follow-up in high-risk preterm infants. A retrospective analysis of 66 high-risk preterm infants admitted to Hengshui People's Hospital from January 2020 to June 2021 was conducted. The children who received only conventional treatment were set as the control group, while those who received aminophylline and caffeine citrate on the basis of conventional treatment were set as the experimental group, 33 cases each group; GMs were used to evaluate the neurodevelopmental function of the children, and the treatment effect was analyzed. The normal proportion of GMs assessment results in the twisting phase and restless movement phase of the experimental group was superior to the control group (P<0.05); The proportion of children with normal neurodevelopment in the experimental group was significantly higher than that in the control group (P<0.05). Aminophylline in combination with caffeine citrate can help promote the neurodevelopment of children and improve their physical health using GMs assessment in the treatment and follow-up of high-risk preterm infants.

Do We Have Viable Protective Strategies against Anesthesia-Induced Developmental Neurotoxicity?

Since its invention, general anesthesia has been an indispensable component of modern surgery. While traditionally considered safe and beneficial in many pathological settings, hundreds of preclinical studies in various animal species have raised concerns about the detrimental and long-lasting consequences that general anesthetics may cause to the developing brain. Clinical evidence of anesthetic neurotoxicity in humans continues to mount as we continue to contemplate how to move forward. Notwithstanding the alarming evidence, millions of children are being anesthetized each year, setting the stage for substantial healthcare burdens in the future. Hence, furthering our knowledge of the molecular underpinnings of anesthesia-induced developmental neurotoxicity is crucially important and should enable us to develop protective strategies so that currently available general anesthetics could be safely used during critical stages of brain development. In this mini-review, we provide a summary of select strategies with primary focus on the mechanisms of neuroprotection and potential for clinical applicability. First, we summarize a diverse group of chemicals with the emphasis on intracellular targets and signal-transduction pathways. We then discuss epigenetic and transgenerational effects of general anesthetics and potential remedies, and also anesthesia-sparing or anesthesia-delaying approaches. Finally, we present evidence of a novel class of anesthetics with a distinct mechanism of action and a promising safety profile.

Prenatal choline supplementation improves child sustained attention: A 7-year follow-up of a randomized controlled feeding trial.

Numerous rodent studies demonstrate developmental programming of offspring cognition by maternal choline intake, with prenatal choline deprivation causing lasting adverse effects and supplemental choline producing lasting benefits. Few human studies have evaluated the effect of maternal choline supplementation on offspring cognition, with none following children to school age. Here, we report results from a controlled feeding study in which pregnant women were randomized to consume 480 mg choline/d (approximately the Adequate Intake [AI]) or 930 mg choline/d during the 3rd trimester. Sustained attention was assessed in the offspring at age 7 years (n = 20) using a signal detection task that showed benefits of maternal choline supplementation in a murine model. Children in the 930 mg/d group showed superior performance (vs. 480 mg/d group) on the primary endpoint (SAT score, p = .02) and a superior ability to maintain correct signal detections (hits) across the 12-min session (p = .02), indicative of improved sustained attention. This group difference in vigilance decrement varied by signal duration (p = .04). For the briefest (17 ms) signals, the 480 mg/d group showed a 22.9% decline in hits across the session compared to a 1.5% increase in hits for the 930 mg/d group (p = .04). The groups did not differ in vigilance decrement for 29 or 50 ms signals. This pattern suggests an enhanced ability to sustain perceptual amplification of a brief low-contrast visual signal by children in the 930 mg/d group. This inference of improved sustained attention by the 930 mg/d group is strengthened by the absence of group differences for false alarms, omissions, and off-task behaviors. This pattern of results indicates that maternal 3rd trimester consumption of the choline AI for pregnancy (vs. double the AI) produces offspring with a poorer ability to sustain attention-reinforcing concerns that, on average, choline consumption by pregnant women is approximately 70% of the AI.

Maternal drinking behaviour and co-exposure from smoking during and after pregnancy in relation to the neurocognitive function of school-children in the rural Western Cape.

BACKGROUND: Maternal substance use and its long-term effect on the neurocognitive functions of children is a global public health issue. Despite an increase in substance use in rural areas of low to middle-income countries, research is limited in these populations. OBJECTIVE: We have therefore explored the effect of maternal drinking and smoking behaviors on the neurocognitive functioning of rural school children. METHOD: A cross-sectional analysis on the determinants of current, past and gestational maternal alcohol use and gestational smoking on child neurocognitive functions was conducted on school-children (N = 482), embedded within the child health agricultural cohort (CapSA) study across seven schools in rural Western Cape, South Africa. Standardised neurocognitive assessment tools included the Cambridge Automated Neuropsychological Battery (CANTAB) and the KIDSCREEN-10 to measure health-related quality of life via a child questionnaire. Maternal smoking and drinking behaviour were captured using a parent/guardian questionnaire. RESULTS: Of the 482 parents/guardians who completed the survey, 29 % reported current drinking 27 % reported past drinking and 10 % reported maternal gestational drinking, while 31 % reported gestational smoking. Significant associations were observed between past and current maternal drinking and child's reduced rapid visual processing accuracy in attention [ß:-0.03; 95 % confidence interval (CI): -0.05;-0.004] and between maternal drinking during pregnancy and reduced child's spatial working memory (ß: -0.59; CI: -1.02; -0.15). Heavy (>5 cigarettes per day) gestational smoking was associated with lowered child's learning in memory (ß:-1.69; 95 % CI: -3.05; -0.33) and lower health-related quality of life (ß: -3.41; CI: -6.64; -0.17). The odds of a child repeating a grade were 1.69 (CI: 2.81-1.02) for those exposed to maternal gestational smoking and 1.68 (CI: 3.31-0.85) for those exposed to maternal gestational drinking compared to those who were not exposed. CONCLUSION: The consistent negative associations across all four maternal substance use proxies, six neurocognitive health outcomes and one health symptom is suggestive of adverse health effects, warranting longitudinal follow-up. Health policies to eliminate gestational substance use are recommended.

Developmental exposure to phytoestrogens found in soy: New findings and clinical implications.

Exposure to naturally derived estrogen receptor activators, such as the phytoestrogen genistein, can occur at physiologically relevant concentrations in the human diet. Soy-based infant formulas are of particular concern because infants consuming these products have serum genistein levels almost 20 times greater than those seen in vegetarian adults. Comparable exposures in animal studies have adverse physiologic effects. The timing of exposure is particularly concerning because infants undergo a steroid hormone-sensitive period termed "minipuberty" during which estrogenic chemical exposure may alter normal reproductive tissue patterning and function. The delay between genistein exposure and reproductive outcomes poses a unique challenge to collecting epidemiological data. In 2010, the U.S. National Toxicology Program monograph on the safety of the use of soy formula stated that the use of soy-based infant formula posed minimal concern and emphasized a lack of data from human subjects. Since then, several new human and animal studies have advanced our epidemiological and mechanistic understanding of the risks and benefits of phytoestrogen exposure. Here we aim to identify clinically relevant findings regarding phytoestrogen exposure and female reproductive outcomes from the past 10 years, with a focus on the phytoestrogen genistein, and explore the implications of these findings for soy infant formula recommendations. Research presented in this review will inform clinical practice and dietary recommendations for infants based on evidence from both clinical epidemiology and basic research advances in endocrinology and developmental biology from mechanistic in vitro and animal studies.

Association of Outdoor Ambient Fine Particulate Matter With Intracellular White Matter Microstructural Properties Among Children.

Importance: Outdoor particulate matter 2.5 µm or less in diameter (PM2.5) is a ubiquitous environmental neurotoxicant that may affect the developing brain. Little is known about associations between PM2.5 and white matter connectivity. Objectives: To assess associations between annual residential PM2.5 exposure and white matter microstructure health in a US sample of children 9 to 10 years of age and to examine whether associations are specific to certain white matter pathways or vary across neuroimaging diffusion markers reflective of intracellular and extracellular microstructural processes. Design, Setting, and Participants: This cross-sectional study, the Adolescent Brain and Cognitive Development (ABCD) Study, was composed of 21 study sites across the US and used baseline data collected from children 9 to 10 years of age from September 1, 2016, to October 15, 2018. Data analysis was performed from September 15, 2020, to June 30, 2021. Exposures: Annual mean PM2.5 exposure estimated by ensemble-based models and assigned to the primary residential addresses at baseline. Main Outcomes and Measures: Diffusion-weighted imaging (DWI) and tractography were used to delineate white matter tracts. The biophysical modeling technique of restriction spectrum imaging (RSI) was implemented to examine total hindered diffusion and restricted isotropic and anisotropic intracellular diffusion in each tract. Hierarchical mixed-effects models with natural splines were used to analyze the associations between PM2.5 exposure and DWI. Results: In a study population of 7602 children (mean [SD] age, 119.1 [7.42] months; 3955 [52.0%] female; 160 [ 21.%] Asian, 1025 [13.5%] Black, 1616 [21.3%] Hispanic, 4025 [52.9%] White, and 774 [10.2%] other [identified by parents as American Indian/Native American or Alaska Native; Native Hawaiian, Guamanian, Samoan, other Pacific Islander; Asian Indian, Chinese, Filipino, Japanese, Korean, Vietnamese, or other Asian; or other race]), associations were seen between annual ambient PM2.5 and hemispheric differences in white matter microstructure. Hemisphere-stratified models revealed significant associations between PM2.5 exposure and restricted isotropic intracellular diffusion in the left cingulum, in the left superior longitudinal fasciculus, and bilaterally in the fornix and uncinate fasciculus. In tracts with strong positive associations, a PM2.5 increase from 8 to 12 µg/m3 was associated with increases of 2.16% (95% CI, 0.49%-3.84%) in the left cingulum, 1.95% (95% CI, 0.43%-3.47%) in the left uncinate, and 1.68% (95% CI, 0.01%-3.34%) in the right uncinate. Widespread negative associations were observed between PM2.5 and mean diffusivity. Conclusions and Relevance: The findings of this cross-sectional study suggest that annual mean PM2.5 exposure during childhood is associated with increased restricted isotropic diffusion and decreased mean diffusivity of specific white matter tracts, potentially reflecting differences in the composition of white matter microarchitecture.

Effect of 3 Days of Oral Azithromycin on Young Children With Acute Diarrhea in Low-Resource Settings: A Randomized Clinical Trial.

Importance: World Health Organization (WHO) guidelines do not recommend routine antibiotic use for children with acute watery diarrhea. However, recent studies suggest that a significant proportion of such episodes have a bacterial cause and are associated with mortality and growth impairment, especially among children at high risk of diarrhea-associated mortality. Expanding antibiotic use among dehydrated or undernourished children may reduce diarrhea-associated mortality and improve growth. Objective: To determine whether the addition of azithromycin to standard case management of acute nonbloody watery diarrhea for children aged 2 to 23 months who are dehydrated or undernourished could reduce mortality and improve linear growth. Design, Setting, and Participants: The Antibiotics for Children with Diarrhea (ABCD) trial was a multicountry, randomized, double-blind, clinical trial among 8266 high-risk children aged 2 to 23 months presenting with acute nonbloody diarrhea. Participants were recruited between July 1, 2017, and July 10, 2019, from 36 outpatient hospital departments or community health centers in a mixture of urban and rural settings in Bangladesh, India, Kenya, Malawi, Mali, Pakistan, and Tanzania. Each participant was followed up for 180 days. Primary analysis included all randomized participants by intention to treat. Interventions: Enrolled children were randomly assigned to receive either oral azithromycin, 10 mg/kg, or placebo once daily for 3 days in addition to standard WHO case management protocols for the management of acute watery diarrhea. Main Outcomes and Measures: Primary outcomes included all-cause mortality up to 180 days after enrollment and linear growth faltering 90 days after enrollment. Results: A total of 8266 children (4463 boys [54.0%]; mean [SD] age, 11.6 [5.3] months) were randomized. A total of 20 of 4133 children in the azithromycin group (0.5%) and 28 of 4135 children in the placebo group (0.7%) died (relative risk, 0.72; 95% CI, 0.40-1.27). The mean (SD) change in length-for-age z scores 90 days after enrollment was -0.16 (0.59) in the azithromycin group and -0.19 (0.60) in the placebo group (risk difference, 0.03; 95% CI, 0.01-0.06). Overall mortality was much lower than anticipated, and the trial was stopped for futility at the prespecified interim analysis. Conclusions and Relevance: The study did not detect a survival benefit for children from the addition of azithromycin to standard WHO case management of acute watery diarrhea in low-resource settings. There was a small reduction in linear growth faltering in the azithromycin group, although the magnitude of this effect was not likely to be clinically significant. In low-resource settings, expansion of antibiotic use is not warranted. Adherence to current WHO case management protocols for watery diarrhea remains appropriate and should be encouraged. Trial Registration: ClinicalTrials.gov Identifier: NCT03130114.

Cord Blood Manganese Concentrations in Relation to Birth Outcomes and Childhood Physical Growth: A Prospective Birth Cohort Study.

Gestational exposure to manganese (Mn), an essential trace element, is associated with fetal and childhood physical growth. However, it is unclear which period of growth is more significantly affected by prenatal Mn exposure. The current study was conducted to assess the associations of umbilical cord-blood Mn levels with birth outcomes and childhood continuous physical development. The umbilical cord-blood Mn concentrations of 1179 mother-infant pairs in the Sheyang mini birth cohort were measured by graphite furnace atomic absorption spectrometry (GFAAS). The association of cord-blood Mn concentrations with birth outcomes, and the BMI z-score at 1, 2, 3, 6, 7 and 8 years old, were estimated separately using generalized linear models. The relationship between prenatal Mn exposure and BMI z-score trajectory was assessed with generalized estimating equation models. The median of cord-blood Mn concentration was 29.25 µg/L. Significantly positive associations were observed between Mn exposure and ponderal index (ß, regression coefficient = 0.065, 95% CI, confidence interval: 0.021, 0.109; p = 0.004). Mn exposure was negatively associated with the BMI z-score of children aged 1, 2, and 3 years (ß = -0.383 to -0.249, p < 0.05), while no significant relationships were found between Mn exposure and the BMI z-score of children at the age of 6, 7, and 8 years. Prenatal Mn exposure was related to the childhood BMI z-score trajectory (ß = -0.218, 95% CI: -0.416, -0.021; p = 0.030). These results indicated that prenatal Mn exposure was positively related to the ponderal index (PI), and negatively related to physical growth in childhood, which seemed most significant at an early stage.

Association Between Early Amino Acid Intake and Full-Scale IQ at Age 5 Years Among Infants Born at Less Than 30 Weeks' Gestation.

Importance: An international expert committee recently revised its recommendations on amino acid intake for very preterm infants, suggesting that more than 3.50 g/kg/d should be administered only to preterm infants in clinical trials. However, the optimal amino acid intake during the first week after birth in these infants is unknown. Objective: To evaluate the association between early amino acid intake and cognitive outcomes at age 5 years. Design, Setting, and Participants: Using the EPIPAGE-2 (Epidemiologic Study on Small-for-Gestational-Age Children-Follow-up at Five and a Half Years) cohort, a nationwide prospective population-based cohort study conducted at 63 neonatal intensive care units in France, a propensity score-matched analysis was performed comparing infants born at less than 30 weeks' gestation who had high amino acid intake (3.51-4.50 g/kg/d) at 7 days after birth with infants who did not. Participants were recruited between April 1 and December 31, 2011, and followed up from September 1, 2016, to December 31, 2017. Full-scale IQ (FSIQ) was assessed at age 5 years. A confirmatory analysis used neonatal intensive care unit preference for high early amino acid intake as an instrumental variable to account for unmeasured confounding. Statistical analysis was performed from January 15 to May 15, 2021. Exposures: Amino acid intake at 7 days after birth. Main Outcomes and Measures: The primary outcome was an FSIQ score greater than -1 SD (ie, ≥93 points) at age 5 years. A complementary analysis was performed to explore the association between amino acid intake at day 7 as a continuous variable and FSIQ score at age 5 years. Data from cerebral magnetic resonance imaging at term were available for a subgroup of preterm infants who participated in the EPIRMEX (Cerebral Abnormalities Detected by MRI, Realized at the Age of Term and the Emergence of Executive Functions) ancillary study. Results: Among 1789 preterm infants (929 boys [51.9%]; mean [SD] gestational age, 27.17 [1.50] weeks) with data available to determine exposure to amino acid intake of 3.51 to 4.50 g/kg/d at 7 days after birth, 938 infants were exposed, and 851 infants were not; 717 infants from each group could be paired. The primary outcome was known in 396 of 646 exposed infants and 379 of 644 nonexposed infants who were alive at age 5 years and was observed more frequently among exposed vs nonexposed infants (243 infants [61.4%] vs 206 infants [54.4%], respectively; odds ratio [OR], 1.33 [95% CI, 1.00-1.71]; absolute risk increase in events [ie, the likelihood of having an FSIQ score >-1 SD at age 5 years] per 100 infants, 7.01 [95% CI, 0.06-13.87]; P = .048). In the matched cohort, correlation was found between amino acid intake per 1.00 g/kg/d at day 7 and FSIQ score at age 5 years (n = 775; ß = 2.43 per 1-point increase in FSIQ; 95% CI, 0.27-4.59; P = .03), white matter area (n = 134; ß = 144 per mm2; 95% CI, 3-285 per mm2; P = .045), anisotropy of the corpus callosum (n = 50; ß = 0.018; 95% CI, 0.016-0.021; P < .001), left superior longitudinal fasciculus (n = 42; ß = 0.018; 95% CI, 0.010-0.025; P < .001), and right superior longitudinal fasciculus (n = 42; ß = 0.014 [95% CI, 0.005-0.024; P = .003) based on magnetic resonance imaging at term. Confirmatory and sensitivity analyses confirmed these results. For example, the adjusted OR for the association between the exposure and the primary outcome was 1.30 (95% CI, 1.16-1.46) using the instrumental variable approach among 978 participants in the overall cohort, and the adjusted OR was 1.35 (95% CI, 1.05-1.75) using multiple imputations among 1290 participants in the matched cohort. Conclusions and Relevance: In this cohort study, high amino acid intake at 7 days after birth was associated with an increased likelihood of an FSIQ score greater than -1 SD at age 5 years. Well-designed randomized studies with long-term follow-up are needed to confirm the benefit of this nutritional approach.

Effects of cyproheptadine on body weight gain in children with nonorganic failure to thrive in Taiwan: A hospital-based retrospective study.

Failure to thrive (FTT) impairs the expected normal physical growth of children. This study aimed to evaluate the effects of cyproheptadine hydrochloride on growth parameters in prepubertal children with FTT. The medical records of prepubertal children who were newly diagnosed with FTT at China Medical University Hospital between 2007 and 2016 were retrospectively examined. The patients were divided into two groups depending on whether they had (T-group) or had not (NT-group) received cyproheptadine hydrochloride (0.3 mg/kg daily) for at least 14 days. The mean length of the treatment period was 97.22 days (range: 14-532 days). Weight, height, and body mass index were adjusted for age using the median values in the growth charts for Taiwanese boys and girls as the reference. A total of 788 patients aged 3-11 years were enrolled, 50 in the T-group and 738 in the NT-group. No statistically significant difference in the median age-adjusted weight value was noted between the T-group and NT-group during the follow up period. In the T-group, age-adjusted weight and body mass index were inversely associated with age (P <0.001, P <0.001) and positively associated with medication duration (P = 0.026, P = 0.04). Our findings underscore the positive association between cyproheptadine hydrochloride treatment and weight gain among prepubertal children. Further prospective clinical studies with a. longer and consistent treatment course is warranted.

Impact of prenatal exposure characterization on early risk detection: Methodologic insights for the HEALthy Brain and Child Development (HBCD) study.

BACKGROUND: A major challenge in prenatal drug exposure research concerns the balance of measurement quality with sample sizes necessary to address confounders. To inform the selection of optimal exposure measures for the HEALthy Brain and Child Development (HBCD) Study, we employed integrated analysis to determine how different methods used to characterize prenatal tobacco exposure influence the detection of exposure-related risk, as reflected in normal variations in birth weight. METHODS: Participants were N = 2323 mother-infant dyads derived from 7 independent developmental cohorts harmonized on measures of exposure, outcome (birthweight), and covariates. We compared estimates of PTE-related effects on birthweight derived from linear regression models when PTE was categorized dichotomously based on any fetal exposure (30% exposed; 69% not exposed); versus categorically, based on common patterns of maternal smoking during pregnancy (never smoked 69%; quit smoking 16%; smoked intermittently 2%; smoked persistently 13%). We secondarily explored sex differences in PTE-birthweight associations across these categorization methods. RESULTS: When PTE was categorized dichotomously, exposure was associated with a - 125-g difference in birthweight (95% C.I. -173.7 - -76.6, p < .0001). When PTE was characterized categorically based on maternal smoking patterns, however, exposure was associated with either no difference in birthweight if mothers quit smoking by the end of the first trimester (B = -30.6, 95% C.I. -88.7-27.4, p = .30); or a - 221.8 g difference in birthweight if mothers did not [95% C.I. (-161.7 to -282.0); p < .001]. Qualitative sex differences were also detected though PTE x sex interactions did not reach statistical significance. Maternal smoking cessation during pregnancy was associated with a 239.3 g increase in birthweight for male infants, and a 114.0 g increase in birthweight for females infants (p = .07). CONCLUSIONS: Categorization of PTE based on patterns of maternal smoking rather than the presence or absence of exposure alone revealed striking nuances in estimates of exposure-related risk. The described method that captures both between-individual and within-individual variability in prenatal drug exposure is optimal and recommended for future developmental investigations such as the HBCD Study.

Co-occurrence of preconception maternal childhood adversity and opioid use during pregnancy: Implications for offspring brain development.

Understanding of the effects of in utero opioid exposure on neurodevelopment is a priority given the recent dramatic increase in opioid use among pregnant individuals. However, opioid abuse does not occur in isolation-pregnant individuals abusing opioids often have a significant history of adverse experiences in childhood, among other co-occurring factors. Understanding the specific pathways in which these frequently co-occurring factors may interact and cumulatively influence offspring brain development in utero represents a priority for future research in this area. We highlight maternal history of childhood adversity (CA) as one such co-occurring factor that is more prevalent among individuals using opioids during pregnancy and which is increasingly shown to affect offspring neurodevelopment through mechanisms beginning in utero. Despite the high incidence of CA history in pregnant individuals using opioids, we understand very little about the effects of comorbid prenatal opioid exposure and maternal CA history on fetal brain development. Here, we first provide an overview of current knowledge regarding effects of opioid exposure and maternal CA on offspring neurodevelopment that may occur during gestation. We then outline potential mechanistic pathways through which these factors might have interactive and cumulative influences on offspring neurodevelopment as a foundation for future research in this area.