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Simple Summary: This scoping review provides an overview of the few observational studies that have investigated potential risk factors for acute lymphoblastic leukaemia in infants. It summarises some well-established associations in the literature, such as maternal exposure to pesticides and high birth weight, and outlines suggestive associations, such as heavy parental smoking, parental use of multiple medications, and maternal exposure to air pollution during pregnancy, that merit further research. The results of this review highlight the lack of research on infant acute lymphoblastic leukaemia, which contrasts with the large number of epidemiological studies investigating risk factors in childhood. Objective: Acute lymphoblastic leukaemia (ALL) is the most frequent childhood cancer. Infant ALL (<1 year) is rare, but it captures a lot of interest due to its poor prognosis, especially in patients harbouring KMT2A rearrangements, which have been demonstrated to arise prenatally. However, epidemiological studies aimed at identifying specific risk factors in such cases are scarce, mainly due to sample-size limitations. We conducted a scoping review to elucidate the prenatal or perinatal factors associated with infant ALL. Methods: Original articles, letters, or conference abstracts published up to June 2022 were identified using the PubMed, Web of Science, and Embase databases, and 33 observational studies were selected. Results: The study reveals several well-established associations across the literature, such as maternal exposure to pesticides and high birth weight, and outlines suggestive associations, such as parental heavy smoking, parental use of several medications (e.g., dipyrone), and maternal exposure to air pollution during pregnancy. Conclusions: This scoping review summarizes the few observational studies that have analysed the prenatal and perinatal risk factors for ALL in infants diagnosed before the age of 1 year. The results of this review highlight the lack of research into this specific age group, which merits further research. [ABSTRACT FROM AUTHOR]

Introduction: Preventing prenatal exposure to teratogenic medications is an important goal of regulatory risk mitigation efforts. In the USA, as of March 2024, 11 teratogenic medications have a required Risk Evaluation and Mitigation Strategy (REMS) program. It is unclear whether these programs target those medications with the most significant impact on public health and adverse pregnancy outcomes. Objectives: This study aims to develop an innovative decision support tool that uses explicit, quantifiable criteria to facilitate prioritization of teratogenic medications for risk mitigation strategies. Methods: The Teratogenic Risk Impact and Mitigation (TRIM) decision support tool will be developed by a national panel via a modified Delphi approach to define measurable criteria, and a multi-criteria decision analysis to estimate criteria weights within a discrete choice experiment. The TRIM scores will then be calculated for 12 teratogenic drugs with active or eliminated REMS programs and for 12 teratogenic drugs without REMS. These drugs will be identified based on highest prenatal exposure prevalence in claims data of privately and publicly insured individuals. Data for the TRIM criteria levels for these 24 drugs will be identified from evidence searches and ad hoc analyses of the same claims data. Conclusions: Teratogenic Risk Impact and Mitigation is intended to inform regulatory decision making about the need for risk mitigation programs for teratogenic medications by providing explicit, quantifiable, evidence-based criteria. The TRIM scores of 24 teratogenic drugs may provide benchmarks for considering REMS for marketed and new teratogenic medications. [ABSTRACT FROM AUTHOR]

Data are lacking regarding the long-term consequences of SARS-CoV-2 and COVID-19 mRNA vaccine on infants exposed in utero. We aimed to evaluate the neurodevelopment of infants exposed prenatally to SARS-CoV-2 or mRNA-COVID-19 vaccine during pregnancy at 12 months after birth. Infants born to mothers exposed to SARS-CoV-2 or mRNA-COVID-19 vaccine during pregnancy, or unexposed to either the virus or the vaccine were enrolled from 2021 to 2023. Infants with prenatal exposure to the virus or vaccine were compared with infants without prenatal exposure to the virus and/or vaccine. Parents received a neurodevelopmental questionnaire (ages and stages questionnaire third edition) at 12 months after birth assessing five subdomains: communication, gross motor, fine motor, problem-solving, and personal social development. A low score was defined as <2 standard deviations below the normative mean in at least one of the subdomains. A total of 330 infants were included (76 in the SARS-CoV-2 group, 153 in the mRNA-COVID-19 vaccine group, and 101 in the reference group). In utero exposure to the SARS-CoV-2 or mRNA-COVID-19 vaccine was not associated with an increased risk of a low score for at least one subdomain compared with the reference group. The crude ORs were 1.16 (95% CI, 0.59–2.28) and 1.04 (95% CI, 0.58–1.86), respectively. Results remained consistent in the multivariate analysis, showing no increased risk of a low score for at least one subdomain for infants exposed to the SARS-CoV-2 or mRNA-COVID-19 vaccine, compared with the reference group. The adjusted ORs were 1.74 (95% CI, 0.76–3.99) and 0.76 (95% CI, 0.39–1.49), respectively. In utero exposure to SARS-CoV-2 or mRNA-COVID-19 vaccine was not associated with an increased risk of a low score for at least one ages and stages questionnaire third edition subdomain at 12 months after birth. Additional studies are needed to confirm our results, especially longer-term evaluation of infant development. [ABSTRACT FROM AUTHOR]

Antibiotics are widely used during pregnancy. Recent epidemiological studies suggest that maternal exposure to antibiotics during pregnancy is associated with increased risks of various diseases in offspring; host-microbiome interactions are considered to be involved in pathogenesis, as antibiotic-induced perturbations (dysbiosis) of the maternal microbiome can be transmitted to offspring. We reviewed the current status of antibiotic usage during pregnancy, transmission of maternal antibiotic-induced dysbiosis to offspring, and several diseases in offspring reported to be associated with maternal antibiotic exposure. Antibiotics must be properly used when necessary. While the adverse effect of maternal antibiotic exposure during pregnancy on the health of offspring has been demonstrated by several studies, more robust clinical evidence is necessary to define the best practice for antibiotic use during pregnancy. Epidemiologic studies have limitations in establishing causal links beyond associations; animal studies provide benefits in examining these links, however, microbiomes, gestation courses, and aging vary between host species. Understanding the underlying mechanisms of epidemiologic findings as well as the healthy microbiome during pregnancy and early life in humans would contribute to developing future microbial interventions for restoring antibiotic-induced dysbiosis during pregnancy. [ABSTRACT FROM AUTHOR]

Background: The 2D:4D digit ratio (DR), representing the relative length of the index finger to the ring finger, is an anthropometric marker that shows sexual dimorphism, with males typically having a lower ratio than females. This parameter is linked to prenatal androgen exposure (PAE), which influences sexual differentiation of the brain and behavior. This study aimed to investigate the correlation between PAE and sleep among young adults. Methods: Anthropometric measurements were used to assess PAE, while sleep was evaluated using the Pittsburgh Sleep Quality Index (PSQI), Morningness-Eveningness Questionnaire (MEQ), actigraphy, and polysomnography (PSG). Data was collected from 720 participants via surveys, with 290 completing all questionnaires. Of these, 138 underwent anthropometric measurements, and 38 were further recruited for actigraphy, PSG. Results: Men exhibited a lower 2D:4D ratio than women, indicating higher PAE. The average PSQI score was 6.94 ± 2.98, and the MEQ score was 35.43 ± 19.59, with no significant gender differences in sleep quality or chronotype. Low PAE was associated with better sleep efficiency and a morning chronotype, but worse sleep quality in males. Actigraphy results showed no significant differences based on PAE. PSG data revealed that males with longer 2nd fingers and higher 2D:4D ratios were more likely to suffer from mild sleep apnea, a pattern not observed in women. PAE did not significantly impact other sleep architecture parameters. Conclusions: PAE, indicated by the 2D:4D ratio, is linked to sleep efficiency and chronotype, with significant gender differences. Men with lower PAE exhibited poorer sleep quality, and those with certain finger length patterns were more prone to mild sleep apnea. These findings underscore the potential long-term impacts of PAE on sleep health and emphasize the need for further research into gender-specific sleep regulation mechanisms. [ABSTRACT FROM AUTHOR]

Background: Prenatal maternal smoking, lower birthweight, and shorter breastfeeding duration have all been associated with an earlier age at menopause in daughters. We estimated the extent to which birthweight-for-gestational-age z-score and breastfeeding duration mediate the effect of prenatal maternal smoking on time to natural menopause in daughters. Methods: Using pooled data from two prospective birth cohort studies – the 1970 British Cohort Study (n = 3,878) followed-up to age 46 years and the 1958 National Child Development Study (n = 4,822) followed-up to age 50 years – we perform mediation analysis with inverse odds weighting implemented in Cox proportional-hazards models. Results: Prenatal maternal smoking was associated with lower birthweight z-scores [β: -0.29; 95% CI -0.34, -0.24] and reduced breastfeeding duration [RRR< 1month: 0.90; 95% CI 0.79, 1.02; RRR≥ 1 month: 0.66; 95% CI 0.59, 0.73 relative to women who were never breastfed]. Greater z-score for birthweight [HR: 0.96; 95% CI 0.91, 1.01] and longer breastfeeding duration [HR≥ 1 month: 0.84; 95% CI 0.74, 0.96] were associated with lower hazards for earlier age at natural menopause. The total effect of prenatal maternal smoking on the time to natural menopause in daughters was estimated as a HR of 1.13 [95% CI 1.02, 1.24]. Birthweight z-score and breastfeeding duration jointly explained an estimated 14% of the total effect [HRNIE: 1.02; 95% CI 0.99, 1.05]. Conclusions: The consequences of smoking during pregnancy on the earlier experience of natural menopause in daughters may partly be offset by intrauterine growth and longer breastfeeding duration to the extent that they mediate the risk of earlier menopause. However, since the extent of mediation by birthweight z-score and breastfeeding duration is small, other factors, including the direct effect of maternal smoking in utero, may play a more important role. [ABSTRACT FROM AUTHOR]

Background: Maternal stress during pregnancy may impact offspring development via changes in the intrauterine environment. However, genetic and environmental factors shared between mothers and children might skew our understanding of this pathway. This study assesses whether prenatal maternal stress has causal links to offspring outcomes: birthweight, gestational age, or emotional and behavioral difficulties, triangulating across methods that account for various measured and unmeasured confounders. Methods: We used data from the Norwegian Mother, Father, and Child Cohort Study (MoBa), including maternal reports on prenatal stress at work, at home, and via stressful life events as exposures. Outcomes were children's birthweight and gestational age, from the Medical Birth Registry of Norway, and maternal reports on early offspring emotional and behavioral difficulties. We assessed associations using four approaches: sibling control analyses, gene-environment interaction analyses, intergenerational Mendelian randomization (MR), and negative control (i.e., postnatal stress) analyses. Results: Maternal prenatal stress was observationally associated with offspring lower birthweight (e.g., βwork = − 0.01 [95%CI: − 0.02, − 0.01]), earlier birth (e.g., βwork = − 0.04 [95%CI: − 0.04, − 0.03])), and more emotional (e.g., βevents = 0.08 [95%CI: 0.07, 0.09]) and behavioral difficulties (e.g., βrelationship = 0.08 [95%CI: 0.07, 0.09]) in the full sample (N = 112,784). However, sibling control analyses (N = 36,511) revealed substantial attenuation of all associations after accounting for familial factors. Gene-environment interaction models (N = 76,288) showed no clear evidence of moderation of associations by mothers' polygenic scores for traits linked to stress sensitivity. Intergenerational MR analyses (N = 29,288) showed no clear evidence of causal effects of maternal plasma cortisol on any offspring outcomes. Negative control exposure analyses revealed similar effect sizes whether exposures were measured prenatally or postnatally. Conclusions: Our results indicate that links between prenatal maternal stress and variation in early offspring outcomes are more likely to be confounded than causal. While no observational study can rule out causality, the consistency of our findings across different approaches is striking. Other sources of prenatal stress or more extreme levels may represent intrauterine causal risk factors for offspring development. Nonetheless, our research contributes to identifying boundary conditions of the fetal programming and developmental origins of health and disease hypotheses, which may not be as universal as sometimes assumed. [ABSTRACT FROM AUTHOR]

Significance: Women are at increased risk for mood disorders, which may be partly attributed to exposure to endocrine-disrupting chemicals (EDCs) during sensitive periods such as pregnancy. Exposure during these times can impact brain development in the offspring, potentially leading to mood disorders in later life. Additionally, fluctuating levels of endogenous estrogens, as seen during pregnancy, or the use of oral contraceptives, can further elevate this risk. This study examines the cumulative effects of prenatal EDC exposure combined with chronic low-dose 17β-estradiol (E2) treatment in adulthood on neurobehavioral outcomes. Methods: Pregnant Sprague-Dawley rats were orally dosed with vehicle, bisphenol A (BPA) (5 μg/kg body weight (BW)/day), low-dose (LD) diethylhexyl phthalate (DEHP) (5 μg/kg BW/day), high-dose (HD) DEHP (7.5 mg/kg BW/day), or a combination of the two (BPA+DEHP) from gestational days 6-21. At 3 months of age, female offspring were implanted with slow-release E2 pellets or were sham-implanted. Following a 90-day treatment period, behavioral testing was conducted, and serum hormones and brain monoamine levels were analyzed. Results: Chronic E2 treatment in controls increased anxiety and reduced active coping behaviors. In DEHP- and BPA+DEHP-exposed offspring, E2 treatment reversed some of these effects. Dose-dependent alterations in circulating hormone levels and brain monoamines were observed. Dysregulation of the stress axis was particularly notable with the higher dose of DEHP. Conclusions: Overall, prenatal EDC exposure altered behavior, hormones, and brain monoamines, with adult E2 treatment further exacerbating some of these effects in female offspring. [ABSTRACT FROM AUTHOR]

Exposure to bisphenol A (BPA), one of the most widely produced plasticisers, can have a major effect on the growing embryo and the mother during pregnancy; as this is the most vulnerable period, the cutoff established in the legislation does not take this factor into account. Thus, this narrative review aims to highlight the consequences for the foetus and the pregnant woman of maternal and foetal exposure to BPA by analysing epidemiological and experimental studies on humans. Extensive research has examined the effects of BPA on several systems outcomes. Specifically, BPA exposure affects the immune system of the offspring and promotes the development of respiratory diseases, including asthma and wheezing. Moreover, BPA has been negatively associated with children's neurodevelopment, leading to behavioural changes; autism; and reproductive changes, mainly deviations in anogenital distance, sexual hormone levels and sexual maturation, which can result in infertility. Furthermore, in mothers, BPA exposure may be linked to pre-eclampsia and gestational diabetes mellitus and affects birth parameters, leading to a higher risk of preterm delivery, shorter birth lengths and lower birth weights, although the results were not always consistent. These results demonstrate the urgent need for stricter legislation banning the use of BPA during pregnancy to reduce the hazards to the health and development of the foetus and the unborn child. [ABSTRACT FROM AUTHOR]