Novel Interventions on Comorbidities in Patients with Fetal Alcohol Spectrum Disorder (FASD): An Integrative Review.

Prenatal exposure to alcohol can cause Fetal Alcohol Spectrum Disorders (FASDs) after birth, encompassing a spectrum of physical, cognitive, and behavioral abnormalities. FASD represents a severe non-genetic disability avoidable through alcohol abstinence during pregnancy and when planning it. Clinical severity depends on alcohol impact, symptomatology, and resulting disabilities. FASD is a permanent disability with no recognized specific medical care. Conversely, secondary FASD-related disabilities can be symptomatically treated. This integrative review aims to provide information about the novel pharmacological treatments of FASD-associated comorbidities by selecting the last ten years of studies carried out on animals and humans. PRISMA guidelines were followed to search human/animal model studies of pharmacological interventions on FASD comorbidities, using different databases (PubMed, Cochrane, etc.). From 1348 articles, 44 met the criteria after full-text analysis. Firstly, all the reported studies point out that early diagnosis and tailored interventions are the principal tools to reduce FASD-related secondary disabilities, due to the fact that there is currently no approved pharmacological treatment for the tissue damage which produces FASD. Despite limitations in study designs and small sample sizes, these review results highlight how the treatment strategies of children with FASD have changed. In the past, studies focused on treating symptoms, but in the last years, researchers have turned their attention to the prevention targeting central nervous system embryogenesis. Novel treatments like choline and natural antioxidants and nutritional supplements are the most investigated treatments in humans with promising results. More follow-up studies need to be performed, to confirm and generalize reported efficacy to a wide sample size.

Prenatal caffeine consumption and neurobehavioral disorders - A systematic review.

Studies have suggested associations between gestational exposure to caffeine and adverse outcomes, however the evidence is still limited. Therefore, a systematic review was conducted to investigate the association between prenatal caffeine exposure and neurobehavioral disorders. The MEDLINE (PubMed), EMBASE, Scopus, Web of Science, and LILACS databases were searched. Observational studies involving women with documented caffeine consumption during pregnancy were eligible for inclusion. The outcomes evaluated were behavioral and intellectual development, Attention Deficit Hyperactivity Disorder, and related behaviors. The data were analyzed by qualitative synthesis. The ROBINS-I tool was employed to assess the risk of bias, and the certainty of evidence was evaluated using GRADE (PROSPERO: CRD42023421164). The search yielded fourteen studies that met the inclusion/exclusion criteria. The sample size among pregnant women ranged from 173 to 64,189, and among children ranged from 88 to 49,190. Maternal caffeine consumption during pregnancy ranged from 0 to 1000 mg/day, with the highest levels observed during mid-pregnancy. Seven studies indicated a potential association between prenatal caffeine exposure and neurobehavioral/neurodevelopment deficits, one study showed that prenatal caffeine exposure improved peer problems, and six studies did not show a significant effect of prenatal caffeine consumption on neurobehavioral disorders. The included studies were classified as moderate for the risk of bias and with very low certainty of evidence. Thus, the evidence is insufficient to confirm with certainty that the prenatal caffeine exposure leads to neurobehavioral disorders. Studies heterogenicity, as well as their variable quality and the presence of several confounding factors, generate uncertainty.

Neonatal outcomes and follow-up of children born to women with pregnancy-associated cancer: a prospective observational study.

BACKGROUND: During the last decade, there has been a growing number of cases of children born from pregnancy-associated cancer (PAC), however there are currently insufficient data on the follow up to be observed in this category of newborns. Objective of the study was to evaluate the neonatal outcomes of infants born to mother with PAC, the potential adverse effect of chemotherapy during pregnancy and the risk of metastasis to the fetus. METHODS: Maternal clinical data and neonatal outcomes of child born to mothers diagnosed with PAC were collected; infants were divided into those were and were not exposed to chemotherapy during fetal life and their outcomes were compered. RESULTS: A total of 37 newborn infants from 36 women with PAC were analyzed. Preterm delivery occurred in 83.8% of the cases. No significant differences in neonatal outcomes were found between infants who were and were not exposed to chemotherapy during pregnancy. The median follow-up period was 12 months. CONCLUSIONS: PAC treatment during the second or third trimester does not seem to be dangerous for the fetus, however infants born from PAC must be carefully evaluated for to rule out the consequences of chemotherapy and exclude the presence of metastasis. Long-term follow-up, especially in children exposed to chemotherapy, should be encouraged to obtain relevant data on long-term toxicity.

Maternal Thyroid Dysfunction During Pregnancy as an Etiologic Factor in Autism Spectrum Disorder: Challenges and Opportunities for Research.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition with unknown etiology. Both genetic and environmental factors have been associated with ASD. Environmental exposures during the prenatal period may play an important role in ASD development. This narrative review critically examines the evidence for a relationship between maternal thyroid dysfunction during pregnancy and ASD in the child. Summary: Studies that assessed the associations of hypothyroidism, hyperthyroidism, hypothyroxinemia, thyroid hormone concentrations, or autoimmune thyroid disease with ASD outcomes were included. Most research focused on the relationship between hypothyroidism and ASD. Multiple population-based studies found that maternal hypothyroidism was associated with higher likelihood of an ASD diagnosis in offspring. Associations with other forms of maternal thyroid dysfunction were less consistent. Findings may have been affected by misclassification bias, survival bias, or publication bias. Studies using medical records may have misclassified subclinical thyroid dysfunction as euthyroidism. Two studies that assessed children at early ages may have misclassified those with ASD as typically developing. Most studies adjusted for maternal body mass index (BMI) and/or mental illness, but not interpregnancy interval or pesticide exposure, all factors associated with fetal survival and ASD. Most studies reported a combination of null and statistically significant findings, although publication bias is still possible. Conclusions: Overall, evidence supported a positive association between maternal thyroid dysfunction during pregnancy and ASD outcomes in the child, especially for hypothyroidism. Future studies could reduce misclassification bias by using laboratory measures instead of medical records to ascertain thyroid dysfunction and evaluating children for ASD at an age when it can be reliably detected. Survival bias could be further mitigated by adjusting models for more factors associated with fetal survival and ASD. Additional research is needed to comprehensively understand the roles of maternal levothyroxine treatment, iodine deficiency, or exposure to thyroid-disrupting compounds in the relationship between maternal thyroid dysfunction and child ASD outcomes.

Association between cumulative maternal exposures related to inflammation and child attention-deficit/hyperactivity disorder: A cohort study.

BACKGROUND: Preclinical studies suggest synergistic effects of maternal inflammatory exposures on offspring neurodevelopment, but human studies have been limited. OBJECTIVES: To examine the cumulative association and potential interactions between seven maternal exposures related to inflammation and child attention-deficit/hyperactivity disorder (ADHD). METHODS: We conducted a population-based cohort study of children born from July 2001 to December 2011 in New South Wales, Australia, and followed up until December 2014. Seven maternal exposures were identified from birth data and hospital admissions during pregnancy: autoimmune disease, asthma, hospitalization for infection, mood or anxiety disorder, smoking, hypertension, and diabetes. Child ADHD was identified from stimulant prescription records. Multivariable Cox regression assessed the association between individual and cumulative exposures and ADHD and potential interaction between exposures, controlling for potential confounders. RESULTS: The cohort included 908,770 children, one-third (281,724) with one or more maternal exposures. ADHD was identified in 16,297 children (incidence 3.5 per 1000 person-years) with median age of 7 (interquartile range 2) years at first treatment. Each exposure was independently associated with ADHD, and risk increased with additional exposures: one exposure (hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.54, 1.65), two exposures (HR 2.25, 95% CI 2.13, 2.37), and three or more exposures (HR 3.28, 95% CI 2.95, 3.64). Positive interaction was found between smoking and infection. The largest effect size was found for cumulative exposure of asthma, infection, mood or anxiety disorder, and smoking (HR 6.12, 95% CI 3.47, 10.70). CONCLUSIONS: This study identifies cumulative effects of multiple maternal exposures related to inflammation on ADHD, most potentially preventable or modifiable. Future studies should incorporate biomarkers of maternal inflammation and consider gene-environment interactions.

Associations of prenatal maternal depressive symptoms with cord blood glucocorticoids and child hair cortisol levels in the project viva and the generation R cohorts: a prospective cohort study.

BACKGROUND: Prior studies have reported conflicting results regarding the association of prenatal maternal depression with offspring cortisol levels. We examined associations of high levels of prenatal depressive symptoms with child cortisol biomarkers. METHODS: In Project Viva (n = 925, Massachusetts USA), mothers reported their depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS) during pregnancy, cord blood glucocorticoids were measured at delivery, and child hair cortisol levels were measured in mid-childhood (mean (SD) age: 7.8 (0.8) years) and early adolescence (mean (SD) age: 13.2 (0.9) years). In the Generation R Study (n = 1644, Rotterdam, The Netherlands), mothers reported depressive symptoms using the Brief Symptom Inventory (BSI) during pregnancy, and child hair cortisol was measured at a mean (SD) age of 6.0 (0.5) years. We used cutoffs of ≥ 13 for the EPDS and > 0.75 for the BSI to indicate high levels of prenatal depressive symptoms. We used multivariable linear regression models adjusted for child sex and age (at outcome), and maternal pre-pregnancy BMI, education, social support from friends/family, pregnancy smoking status, marital status, and household income to assess associations separately in each cohort. We also meta-analyzed childhood hair cortisol results from both cohorts. RESULTS: 8.0% and 5.1% of women respectively experienced high levels of prenatal depressive symptoms in Project Viva and the Generation R Study. We found no associations between high levels of maternal depressive symptoms during pregnancy and child cortisol biomarkers in either cohort. CONCLUSIONS: The present study does not find support for the direct link between high levels of maternal depressive symptoms and offspring cortisol levels.

Associations between Birth Weight and Adult Sleep Characteristics: A Cross-Sectional Analysis from the UAEHFS.

Abnormal birth weight, particularly low birth weight (LBW), is known to have long-term adverse health consequences in adulthood, with disrupted sleep being suggested as a mediator or modifier of this link. We thus aimed to assess the associations between birth weight and self-reported adult sleep characteristics: sleep duration, difficulty waking up in the morning, daily nap frequency, sleep problems at night, snoring, daytime tiredness or sleepiness, and ever-stop breathing during sleep. This cross-sectional analysis used the United Arab Emirates Healthy Future Study data collected from February 2016 to March 2023 involving 2124 Emiratis aged 18-61 years. We performed a Poisson regression under unadjusted and age-sex-and-BMI-adjusted models to obtain the risk ratio and its 95% confidence interval for our analysis of the association between birth weight and each adult sleep characteristics, compared to individuals with normal birth weight (≥2.5 kg). Those with LBW had significantly a 17% increased risk of difficulty waking up in the morning, compared to those with normal birth weight. In addition, females with LBW history were also at an increased risk of reporting difficulty waking up in the morning. Studies with objective sleep assessments that include measurements of more confounding factors are recommended to confirm these risks.

Lipid Profile Variations in Pregnancies with and without Cardiovascular Risk: Consequences for Both Mother and Newborn.

Background: Maternal cardiovascular risk and its implications can have significant repercussions for both the mother and the child. This study compares the lipid profiles of two distinct groups of pregnant women, those with and without cardiovascular risk, to shed light on its effects on maternal and outcomes for newborns. Materials and Methods: This study enrolled 86 pregnant women, dividing them into two groups: Group 1 (n = 46, healthy pregnancies) and Group 2 (n = 40, pregnancies with cardiovascular risk factors). The data collected included maternal demographics, smoking history, pre-existing pathologies, and a range of laboratory measures. Neonatal outcomes were also recorded. Results: Group 2 showed a significant increase in the percentage of newborns with abnormal APGAR scores (p-value < 0.0001), congenital abnormalities (p-value < 0.0001), severe prematurity (p-value < 0.0001), and neonatal mortality rates (p-value < 0.0001), as well as differences in birth weight (p-value = 0.0392) and therapy usage (surfactant: p-value < 0.001, steroids p-value = 0.004, and antibiotics p-value < 0.001). Regarding laboratory measures, Group 2 exhibited significantly elevated levels of total cholesterol, LDL-C (p-value < 0.0001), ApoB (p-value < 0.0001), Lp(A) (p-value = 0.0486), triglycerides (p-value < 0.0001), and hs-CRP (p-value = 0.0300). Discussion: These results underscore the elevated risk associated with pregnancies complicated by cardiovascular risk factors. Group 2 demonstrated a more concerning clinical profile, with a higher prevalence of detrimental neonatal outcomes and different lipid and inflammatory profiles, signifying a potential pathophysiological link. Conclusions: The differential lipid profiles and adverse neonatal outcomes in pregnancies with cardiovascular risks highlight the urgency of effective risk stratification and management strategies in this population.

Identifying Prenatal Alcohol Exposure and Children Affected by It: A Review of Biomarkers and Screening Tools.

PURPOSE: Early identification of prenatal alcohol exposure (PAE) and of those in need of services resulting from this exposure is an important public health concern. This study reviewed the existing literature on potential biomarkers and screening tools of PAE and its impact. SEARCH METHODS: Electronic databases were searched for articles published between January 1, 1996, and November 30, 2021, using the following search terms: ("fetal alcohol" or "prenatal alcohol" or "FASD" or "alcohol-related neurodevelopmental disorder" or "ARND" or "ND-PAE") and ("screening" or "identification" or "biomarker"). Duplicate articles were electronically eliminated. Titles and abstracts were reviewed for appropriateness, and selected articles were retrieved for further analysis. Additional articles were added that were referenced in the reviewed articles or identified from expert knowledge. Information about the characteristics of the sample, the biomarker or screening tool, and the predictive validity outcome data were abstracted. A narrative analysis of the studies was then performed on the data. SEARCH RESULTS: A total of 3,813 articles were initially identified, and 1,215 were removed as duplicates. Of the remaining articles, 182 were identified as being within the scope of the review based on title and abstract inspection, and 181 articles were successfully retrieved. Of these, additional articles were removed because they were preclinical (3), were descriptive only (13), included only self-report of PAE (42), included only mean group comparison (17), were additional duplicates (2), focused on cost analysis (9), missed predictive validity data (24), or for other reasons (23). The remaining articles (n = 48) were abstracted. An additional 13 manuscripts were identified from these articles, and two more from expert knowledge. A total of 63 articles contributed to the review. DISCUSSION AND CONCLUSIONS: Biomarkers and screening tools of PAE and its impact fall short of ideal predictive validity characteristics. Higher specificity than sensitivity was found for many of the biomarkers and screening tools used to identify PAE and its impact, suggesting that current methods continue to under-identify the full range of individuals impacted by PAE. Exceptions to this were found in recent investigations using microRNAs related to growth and vascular development, proteomic changes associated with PAE, and combinations of markers estimating levels of various cytokines. Replications of these findings are needed across other samples to confirm the limited data available. Future research on biomarkers and screening tools should attend to feasibility and scalability of implementation. This article also recommends a systematic process of evaluation to improve early identification of individuals impacted by PAE so that harm reduction and habilitative care efforts can be implemented.

Carryover effects from environmental change in early life: An overlooked driver of the amphibian extinction crisis?

Ecological carryover effects, or delayed effects of the environment on an organism's phenotype, are central predictors of individual fitness and a key issue in conservation biology. Climate change imposes increasingly variable environmental conditions that may be challenging to early life-history stages in animals with complex life histories, leading to detrimental physiological and fitness effects in later life. Yet, the latent nature of carryover effects, combined with the long temporal scales over which they can manifest, means that this phenomenon remains understudied and is often overlooked in short-term studies limited to single life-history stages. Herein, we review evidence for the physiological carryover effects induced by elevated ultraviolet radiation (UVR; 280-400 nm) as a potential contributor to recent amphibian population declines. UVR exposure causes a suite of molecular, cellular and physiological consequences known to underpin carryover effects in other taxa, but there is a lack of research linking embryonic and larval UVR exposures to fitness consequences post-metamorphosis in amphibians. We propose that the key impacts of UVR on disease-related amphibian declines are facilitated through carryover effects that bridge embryonic and larval UVR exposure with potential increased disease susceptibility post-metamorphosis. We conclude by identifying a practical direction for the study of ecological carryover effects in amphibians that could guide future ecological research in the broader field of conservation physiology. Only by addressing carryover effects can many of the mechanistic links between environmental change and population declines be elucidated.

Delayed fatal intracranial hemorrhage in a pediatric patient following resection and adjuvant cranial radiotherapy for ependymoma: illustrative case.

BACKGROUND: Cranial radiotherapy (CRT) is an important treatment modality for malignancies of the central nervous system. CRT has deleterious effects that are commonly classified into acute, early delayed, and late delayed. Late-delayed effects include weakening of the cerebral vasculature and the development of structurally abnormal vasculature, potentially leading to ischemic or hemorrhagic events within the brain parenchyma. Such events are not well reported in the pediatric population. OBSERVATIONS: The authors present the case of a 14-year-old patient 8.2 years after CRT who experienced intracerebral hemorrhage. Autopsy demonstrated minimal pathological change without evidence of vascular malformation or aneurysm. These findings were unexpected given the degree of hemorrhage in this case. However, in the absence of other etiologies, it was believed that late-delayed radiation effect was the cause of this patient's fatal hemorrhage. LESSONS: Although not all cases of pediatric spontaneous intracerebral hemorrhage will have a determined etiology, the authors' patient's previous CRT may represent a poorly defined risk for late-delayed hemorrhage. This correlation has not been previously reported and should be considered in pediatric patients presenting with spontaneous hemorrhage in a delayed fashion after CRT. Neurosurgeons must not be dismissive of unexpected events in the remote postoperative period.

The estimated effect of season and vitamin D in the first trimester on pubertal timing in girls and boys: a cohort study and an instrumental variable analysis.

BACKGROUND: Season of birth has been associated with age at menarche. Maternal vitamin D levels in pregnancy may explain this effect. We investigated whether the season of first trimester or maternal 25-hydroxyvitamin D3 [25(OH)D3] levels were associated with pubertal timing in children. METHODS: We conducted a follow-up study of 15 819 children born in 2000-03 from the Puberty Cohort, nested in the Danish National Birth Cohort (DNBC). Mean differences in attaining numerous pubertal markers, including a combined estimate for the average age at attaining all pubertal markers, were estimated for low (November-April) relative to high (May-October) sunshine exposure season in the first trimester using multivariable interval-censored regression models. Moreover, we conducted a two-sample instrumental variable analysis using season as an instrument for maternal first-trimester 25(OH)D3 plasma levels obtained from a non-overlapping subset (n = 827) in the DNBC. RESULTS: For the combined estimate, girls and boys of mothers who had their first trimester during November-April had earlier pubertal timing than girls and boys of mothers whose first trimester occurred during May-October: -1.0 months (95% CI: -1.7 to -0.3) and -0.7 months (95% CI: -1.4 to -0.1), respectively. In the instrumental variable analysis, girls and boys also had earlier pubertal timing: respectively, -1.3 months (95% CI: -2.1 to -0.4) and -1.0 months (95% CI: -1.8 to -0.2) per SD (22 nmol/L) decrease in 25(OH)D3. CONCLUSIONS: Both first pregnancy trimester during November-April and lower 25(OH)D3 were associated with earlier pubertal timing in girls and boys.

Examining the Effect of Time-From-Treatment on Activities of Daily Living Kinematics in Breast Cancer Survivors.

Breast cancer affects one in 8 females with a 5-year survival rate of 89%. Up to 72% of breast cancer survivors have trouble with activities of daily living (ADL) following treatment. Increased time-from-treatment improves some measures of function, yet ADL limitations persist. Therefore, this study assessed the effect of time-from-treatment on upper extremity kinematics during ADLs in breast cancer survivors. Twenty-nine female breast cancer survivors were divided into 2 groups: <1 year (n = 12) and 1-2 years (n = 17) from treatment. Kinematics were collected during 6 ADL tasks, and humerothoracic joint angles were quantified. A 2-way mixed analysis of variance assessed the effects of time-from-treatment and arm on maximum angles for each ADL. Decreased maximum angle existed for breast cancer survivors with increased time-from-treatment during all ADLs. Breast cancer survivors in the 1-2 years group used ∼28° to 32° lower elevation, ∼14° to 28° lower axial rotation, and ∼10° to 14° lower plane of elevation range across tasks. Decreased ranges of arm movement during ADLs with increased time-from-treatment may reflect compensatory movement strategies. Recognizing this shift in strategies and accompanying underlying disease progression can help inform responses to functional performance limitations in breast cancer survivors as delayed effects are present posttreatment.

Lag-time effects of vaccination on SARS-CoV-2 dynamics in German hospitals and intensive-care units.

Background: The Efficacy and effectiveness of vaccination against SARS-CoV-2 have clearly been shown by randomized trials and observational studies. Despite these successes on the individual level, vaccination of the population is essential to relieving hospitals and intensive care units. In this context, understanding the effects of vaccination and its lag-time on the population-level dynamics becomes necessary to adapt the vaccination campaigns and prepare for future pandemics. Methods: This work applied a quasi-Poisson regression with a distributed lag linear model on German data from a scientific data platform to quantify the effects of vaccination and its lag times on the number of hospital and intensive care patients, adjusting for the influences of non-pharmaceutical interventions and their time trends. We separately evaluated the effects of the first, second and third doses administered in Germany. Results: The results revealed a decrease in the number of hospital and intensive care patients for high vaccine coverage. The vaccination provides a significant protective effect when at least approximately 40% of people are vaccinated, whatever the dose considered. We also found a time-delayed effect of the vaccination. Indeed, the effect on the number of hospital patients is immediate for the first and second doses while for the third dose about 15 days are necessary to have a strong protective effect. Concerning the effect on the number of intensive care patients, a significant protective response was obtained after a lag time of about 15-20 days for the three doses. However, complex time trends, e.g. due to new variants, which are independent of vaccination make the detection of these findings challenging. Conclusion: Our results provide additional information about the protective effects of vaccines against SARS-CoV-2; they are in line with previous findings and complement the individual-level evidence of clinical trials. Findings from this work could help public health authorities efficiently direct their actions against SARS-CoV-2 and be well-prepared for future pandemics.

Synergistic survival-related effects of larval exposure to an aquatic pollutant and food stress get stronger during and especially after metamorphosis and shape fitness of terrestrial adults.

To improve the ecological risk assessment of aquatic pollutants it is needed to study their effects not only in the aquatic larval stage, but also in the terrestrial adult stage of the many animals with a complex life cycle. This remains understudied, especially with regard to interactive effects between aquatic pollutants and natural abiotic stressors. We studied effects of exposure to the pesticide DNP (2,4-Dinitrophenol) and how these were modulated by limited food availability in the aquatic larvae, and the possible delayed effects in the terrestrial adults of the damselfly Lestes viridis. Our results revealed that DNP and low food each had large negative effects on the life history, behaviour and to a lesser extent on the physiology of not only the larvae, but also the adults. Food limitation magnified the negative effects of DNP as seen by a strong decline in larval survival, metamorphosis success and adult lifespan. Notably, the synergism between the aquatic pollutant and food limitation for survival-related traits was stronger in the non-exposed adults than in the exposed larvae, likely because metamorphosis is stressful itself. Our results highlight that identifying effects of aquatic pollutants and synergisms with natural abiotic stressors, not only in the aquatic larval but also in the terrestrial adult stage, is crucial to fully assess the ecological impact of aquatic pollutants and to reveal the impact on the receiving terrestrial ecosystem through a changed aquatic-terrestrial subsidy.

The delayed effects of acute radiation exposure (DEARE): characteristics, mechanisms, animal models, and promising medical countermeasures.

PURPOSE: Terrorist use of nuclear weapons and radiation accidents put the human population at risk for exposure to life-threatening levels of radiation. Victims of lethal radiation exposure face potentially lethal acute injury, while survivors of the acute phase are plagued with chronic debilitating multi-organ injuries for years after exposure. Developing effective medical countermeasures (MCM) for the treatment of radiation exposure is an urgent need that relies heavily on studies conducted in reliable and well-characterized animal models according to the FDA Animal Rule. Although relevant animal models have been developed in several species and four MCM for treatment of the acute radiation syndrome are now FDA-approved, animal models for the delayed effects of acute radiation exposure (DEARE) have only recently been developed, and there are no licensed MCM for DEARE. Herein, we provide a review of the DEARE including key characteristics of the DEARE gleaned from human data as well as animal, mechanisms common to multi-organ DEARE, small and large animal models used to study the DEARE, and promising new or repurposed MCM under development for alleviation of the DEARE. CONCLUSIONS: Intensification of research efforts and support focused on better understanding of mechanisms and natural history of DEARE are urgently needed. Such knowledge provides the necessary first steps toward the design and development of MCM that effectively alleviate the life-debilitating consequences of the DEARE for the benefit of humankind worldwide.

Prenatal exposure to opioids and neurodevelopment in infancy and childhood: A systematic review.

Aim: This systematic review aims to estimate the relationship between prenatal exposure to opioids and neurodevelopmental outcomes and examines potential sources of heterogeneity between the studies. Methods: We searched four databases through May 21st, 2022: PubMed, Embase, PsycInfo and the Web of Science according to a specified search strings. Study inclusion criteria include: (1) cohort and case-control peer-reviewed studies published in English; (2) studies comparing neurodevelopmental outcomes among children with prenatal opioid-exposure (prescribed or used non-medically) vs. an unexposed group. Studies investigating fetal alcohol syndrome or a different primary prenatal exposure other than opioids were excluded. Two main performed data extraction using "Covidence" systematic review platform. This systematic review was conducted in accordance with PRISMA guidelines. The Newcastle-Ottawa-Scale was used for quality assessment of the studies. Studies were synthesized based on the type of neurodevelopmental outcome and the instrument used to assess neurodevelopment. Results: Data were extracted from 79 studies. We found significant heterogeneity between studies due to their use of different instruments to explore cognitive skills, motor, and behavioral outcomes among children of different ages. The other sources of heterogeneity included: procedures to assess prenatal exposure to opioids; period of pregnancy in which exposure was assessed; type of opioids assessed (non-medical, medication used for opioid use dis-order, prescribed by health professional), types of co-exposure; source of selection of prenatally exposed study participants and comparison groups; and methods to address lack of comparability between exposed and unexposed groups. Cognitive and motor skills as well as behavior were generally negatively affected by prenatal opioid exposure, but the significant heterogeneity precluded a meta-analysis. Conclusion: We explored sources of heterogeneity in the studies assessing the association between prenatal exposure to opioids and neurodevelopmental outcomes. Sources of heterogeneity included different approaches to participant recruitment as well as exposure and outcome ascertainment methods. Nonetheless, overall negative trends were observed between prenatal opioid exposure and neuro-developmental outcomes.

Early-life exposure to methylmercury induces reversible behavioral impairments and gene expression modifications in one isogenic lineage of mangrove rivulus fish Kryptolebias marmoratus.

Methylmercury (MeHg) is a ubiquitous bioaccumulative neurotoxicant present in aquatic ecosystems. It is known to alter behaviors, sensory functions and learning abilities in fish and other vertebrates. Developmental and early-life stages exposure to MeHg can lead to brain damage with immediate consequences on larvae behavior, but may also induce long term effects in adults after a detoxification period. However, very little is known about developmental origin of behavioral impairment in adults due to early exposure to MeHg. The aim of this study is to assess whether early-life MeHg exposure induces immediate and/or delayed effects on behaviors, related genes expression and DNA methylation (one of epigenetic mechanisms). To reach this goal, newly hatched larvae of mangrove rivulus fish, Kryptolebias marmoratus, were exposed to two sub-lethal concentrations of MeHg (90 µg/L and 135 µg/L) for 7 days, and immediate and delayed effects were assessed respectively in 7 dph (days post-hatching) and 90 dph fish. This species naturally produces isogenic lineages due to its self-fertilizing reproduction system, which is unique among vertebrates. It allows to study how environment stressors can influence organism's phenotype while minimizing genetic variability. As results, both MeHg exposures are associated with a decreased foraging efficiency and thigmotaxis, and a dose-dependent reduction in larvae locomotor activity. Regarding molecular analysis in larvae whole bodies, both MeHg exposures induced significant decreased expression of DNMT3a, MAOA, MeCP2 and NIPBL, and significant increase of GSS, but none of those genes underwent methylation changes in targeted CpGs. None of significant behavioral and molecular impairments observed in 7-dph larvae were found in 90-dph adults, which highlight a distinction between immediate and delayed effects of developmental MeHg exposure. Our results suggest implications of aminergic system and its neurotransmitters, redox/methylation trade-off and possibly other epigenetic mechanisms in MeHg neurotoxicity underlying behavioral alterations in rivulus.

Gestational lead exposure and its effects on fetal/infant development - A systematic review.

Studies suggest that gestational exposure to lead (Pb) is related to spontaneous abortions, preterm birth, lower infant birth weight and length, and neurological dysfunctions. However, the evidence about its effects during pregnancy exposure on fetal and child development is still poor. Thus, the aim of this systematic review was to verify the association between prenatal exposure to Pb and the occurrence of neurobehavioral deficits, miscarriages, and child mortality. Observational studies with pregnant women exposed to Pb during pregnancy were included, without gender or ethnicity restrictions. The MEDLINE, Cochrane Library, EMBASE, Scopus, Web of Science, and LILACS databases were searched. The reading of titles and abstracts was conducted, followed by reading in full format and data extraction, that were performed independently by two reviewers. The included studies were evaluated by Downs and Black tool and qualitatively synthesized. Certainty of evidence was assessed by Grading of Recommendations Assessment, Development, and Evaluations (GRADE). The study protocol was registered with the Prospective Registry of Systematic Reviews (PROSPERO; CRD42022296750). Among twenty-one studies included, sixteen were classified as prospective cohort, two case-control, one nested case-control, one cohort, and one longitudinal study. No study that evaluated child mortality associated with gestational Pb exposure was found. There is a very low certainty of evidence in the association of gestational Pb exposure and neurobehavioral deficits or miscarriages. This systematic review reflects the poor evidence and the challenges of human toxicology studies, since it was not possible to associate gestational Pb exposure to neurobehavioral deficits, miscarriages, and child mortality.

The Pregnancy, Arsenic, and Immune Response (PAIR) Study in rural northern Bangladesh.

BACKGROUND: Arsenic exposure and micronutrient deficiencies may alter immune reactivity to influenza vaccination in pregnant women, transplacental transfer of maternal antibodies to the foetus, and maternal and infant acute morbidity. OBJECTIVES: The Pregnancy, Arsenic, and Immune Response (PAIR) Study was designed to assess whether arsenic exposure and micronutrient deficiencies alter maternal and newborn immunity and acute morbidity following maternal seasonal influenza vaccination during pregnancy. POPULATION: The PAIR Study recruited pregnant women across a large rural study area in Gaibandha District, northern Bangladesh, 2018-2019. DESIGN: Prospective, longitudinal pregnancy and birth cohort. METHODS: We conducted home visits to enrol pregnant women in the late first or early second trimester (11-17 weeks of gestational age). Women received a quadrivalent seasonal inactivated influenza vaccine at enrolment. Follow-up included up to 13 visits between enrolment and 3 months postpartum. Arsenic was measured in drinking water and maternal urine. Micronutrient deficiencies were assessed using plasma biomarkers. Vaccine-specific antibody titres were measured in maternal and infant serum. Weekly telephone surveillance ascertained acute morbidity symptoms in women and infants. PRELIMINARY RESULTS: We enrolled 784 pregnant women between October 2018 and March 2019. Of 784 women who enrolled, 736 (93.9%) delivered live births and 551 (70.3%) completed follow-up visits to 3 months postpartum. Arsenic was detected (≥0.02 µg/L) in 99.7% of water specimens collected from participants at enrolment. The medians (interquartile ranges) of water and urinary arsenic at enrolment were 5.1 (0.5, 25.1) µg/L and 33.1 (19.6, 56.5) µg/L, respectively. Water and urinary arsenic were strongly correlated (Spearman's ⍴ = 0.72) among women with water arsenic ≥ median but weakly correlated (⍴ = 0.17) among women with water arsenic < median. CONCLUSIONS: The PAIR Study is well positioned to examine the effects of low-moderate arsenic exposure and micronutrient deficiencies on immune outcomes in women and infants. REGISTRATION: NCT03930017.