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.

Bisphenol chemicals in colostrum from Shanghai, China during 2006-2019: Concentration, temporal variation, and potential influence on birth parameters.

Bisphenol A (BPA) and its alternatives bisphenol S (BPS) and bisphenol F (BPF) are identified as endocrine disruptors that have negative impacts on infant growth. Their temporal variations in human milk and potential effects on fetal growth are not well known. In this study, colostrum collecting at four time points between 2006 and 2019 and paired urine in 2019 from Shanghai, China, were analyzed for eight bisphenols. The total concentrations in colostrum in 2019 were up to 3.43 ng/mL, with BPA being dominant, followed by BPS and BPF. BPA levels in colostrum noticeably decreased from 2010 to 2013. Additionally, obvious percentage changes in bisphenols were observed in 2019. The BPA concentrations in paired colostrum and urine were not significantly correlated. High levels of BPA in colostrum were linked to a significant reduction in birth head circumference in 2019 (p = 0.031). BPA and BPS in colostrum might have similar negative effect on fetal growth in 2019, but these effects were generally non-significant. Further studies are needed to testify the potential impact. The hazard indexes for infants in the first week of life were below 1, suggesting no obvious health risks. However, the high contribution from BPA still warrants further attention.

Interaction of prenatal maternal selenium and manganese levels on child neurodevelopmental trajectories-the Shanghai birth cohort study.

OBJECTIVE: The fetal brain is particularly plastic, and may be concurrently affected by chemical exposure and malnutritional factors. Selenium is essential for the developing brain, and excess manganese exposure may exert neurotoxic effects. However, few epidemiological studies have evaluated the interaction of manganese and selenium assessed in different prenatal stages on postnatal neurodevelopmental trajectories. METHODS: This study contained 1024 mother-child pairs in the Shanghai-birth-cohort study from 2013 to 2016 recruited since early/before pregnancy with complete data on manganese and selenium levels in different prenatal stages and infant neurodevelopmental trajectories. Whole blood manganese and selenium in early pregnancy and around birth were measured by inductively-coupled-plasma-mass-spectrometry (ICP-MS), children's cognitive development was evaluated at 6, 12, and 24 months of age using Age & Stage-Questionnaire (ASQ)-3 and Bayley-III. Multiple linear regression was used to investigate the interaction of prenatal selenium and manganese on neurodevelopmental trajectories. RESULTS: The prenatal manganese and selenium levels were 1.82 ± 0.98 µg/dL and 13.53 ± 2.70 µg/dL for maternal blood in early pregnancy, and 5.06 ± 1.67 µg/dL and 11.81 ± 3.35 µg/dL for umbilical cord blood, respectively. Higher prenatal Se levels were associated with better neurocognitive performances or the consistently-high-level trajectory (P < 0.05), with more significant associations observed in early pregnancy than around birth. However, such positive relationships became non-significant or even adverse in high (vs. low) manganese status, and the effect differences between low and high manganese were more significant in early pregnancy. CONCLUSIONS: Prenatal Selenium was positively associated with child neurodevelopment, but prenatal high manganese may mitigate such favorable effects. The effects were mainly observed in earlier prenatal stage.

Prenatal exposure to selenium, mercury, and manganese during pregnancy and allergic diseases in early childhood: The Japan Environment and Children's study.

BACKGROUND: Prenatal exposure to metallic elements may adversely affect early childhood health. However, more evidence is needed as population-based cohort studies are currently limited. OBJECTIVES: We aimed to examine the associations between prenatal metallic (mercury, selenium, and manganese) exposure and the risk of allergic diseases in early childhood until three years of age. METHODS: The data from 94,794 mother-infant pairs, who participated in the Japan Environment and Children's study, were used in this study. Prenatal metallic element exposure was measured in maternal blood collected during mid-pregnancy. The incidence of atopic dermatitis, food allergies, asthma, and allergic rhinitis during the first three years of life was prospectively investigated using self-reports of physician-diagnosed allergies. A multivariable modified Poisson regression model was used to estimate the cumulative incidence ratio and their 95% confidence intervals of allergic diseases associated with prenatal exposure to mercury, selenium, and manganese. We further evaluated the interaction between mercury and selenium exposures in this association. RESULTS: We confirmed 26,238 cases of childhood allergic diseases: atopic dermatitis, food allergies, asthma, and allergic rhinitis in 9,715 (10.3%), 10,897 (11.5%), and 9,857 (10.4%), 4,630 (4.9%), respectively. No association was found between prenatal mercury or manganese exposure and the risk of allergic diseases. Prenatal selenium exposure was inversely associated with atopic dermatitis, food allergies, allergic rhinitis, and any allergic diseases, but not with asthma. These inverse associations were more pronounced for lower mercury exposures than for higher exposures. CONCLUSIONS: Our findings suggest that prenatal exposure to selenium may be beneficial for reducing the risk of atopic dermatitis, food allergies, allergic rhinitis, and any allergic diseases in early childhood, especially with lower prenatal mercury exposure.

Life Course of Asthma.

Asthma is a heterogeneous chronic airway disease that can vary over a lifetime. Although broad categories of asthma by severity and type have been constructed, there remains a tremendous opportunity to discover an approach to managing asthma with additional factors in mind. Many in the field have suggested and are pursuing a novel paradigm shift in how asthma might be better managed, considering the life course of exposures, management priorities, and predicted trajectory of lung function growth. This approach will require a more holistic view of prenatal, postnatal, adolescence, hormonal and gender aspects, and the aging process. In addition, the environment, externally and internally, including in one's genetic code and epigenetic changes, are factors that affect how asthma progresses or becomes more stable in individuals. This chapter focuses on the various influences that may, to differing degrees, affect people with asthma, which can develop at any time in their lives. Shifting the paradigm of thought and strategies for care and advocating for public policies and health delivery that focus on this philosophy is paramount to advance asthma care for all.

Vitamin D Supplementation and Vitamin D Status during Pregnancy and the Risk of Congenital Anomalies-A Systematic Review and Meta-Analysis.

Maternal dietary factors have been suggested as possible contributing influences for congenital anomalies (CAs). We aimed to assess the association between vitamin D supplementation or vitamin D status (s-25OHD) during pregnancy and CAs in the offspring. A comprehensive literature search was conducted in the three electronic databases: PubMed, Embase, and Cochrane Library. Included studies were critically appraised using appropriate tools (risk of bias 2, ROBINS-I). A protocol was registered in the International Prospective Register of Systematic Reviews (CRD42019127131). A meta-analysis of four randomised controlled trials (RCTs) including 3931 participants showed no effect of vitamin D supplementation on CAs, a relative risk of 0.76 (95% CI 0.45; 1.30), with moderate certainty in the effect estimates by GRADE assessment. Of the nine identified observational studies, six were excluded due to a critical risk of bias in accordance with ROBINS-I. Among the included observational studies, two studies found no association, whereas one case-control study identified an association between s-25OHD < 20 nmol/L and neural tube defects, with an adjusted odds ratio of 2.34 (95% CI: 1.07; 5.07). Interpretation of the results should be cautious given the low prevalence of CAs, RCTs with onset of supplementation after organogenesis, and low-quality observational studies.

Prenatal metal levels and congenital anomalies of the kidney and urinary tract: The Japan Environment and Children's Study.

BACKGROUND: Prenatal exposure to metal elements has been reported as a potential risk factor for congenital malformation. However, studies on the relationship with congenital anomalies of the kidney and urinary tract (CAKUT) are very scarce. METHODS: Participants of a prospective cohort from the Japan Environment and Children's Study, conducted at 15 research centers, were recruited between January 2011 and March 2014. The exposure factors were concentrations of lead (Pb), cadmium (Cd), mercury (Hg), selenium (Se), and manganese (Mn) measured from maternal whole blood in the second or third trimester. The primary outcome was CAKUT diagnosed during the first three years of life, which was classified into isolated cases and complicated cases accompanied by extrarenal congenital defects. To conduct a nested case-control design within the cohort, we selected 351 isolated cases with 1404 matched controls, and 79 complicated cases with 316 matched controls. RESULTS: A logistic regression model was used to examine the associations between individual metal concentrations and each subtype of CAKUT. A higher level of Se was associated with an increased risk of isolated CAKUT (adjusted odds ratio [95 % confidence interval]: 3.22 [1.33-7.77]). Meanwhile, higher levels of Pb and Mn were associated with a reduced risk of the complicated subtype (0.46 [0.24-0.90] and 0.33 [0.15-0.73], respectively). A Bayesian kernel machine regression model accounting for mixed effects of multiple metals further demonstrated that a higher level of Mn alone was significantly associated with a reduced occurrence of the complicated subtype. CONCLUSIONS: Using a stringent statistical approach, the present study demonstrated that a higher Mn concentration in the maternal blood was associated with a lower risk of complicated CAKUT in offspring. Further cohort and experimental studies are needed to verify the clinical impact of this finding.

Maternal intake of folate and folic acid during pregnancy and pubertal timing in girls and boys: A population-based cohort study.

BACKGROUND: Folate is essential for normal foetal development as it plays an important role for gene expression during different periods of foetal development. Thus, prenatal exposure to folate may have a programming effect on pubertal timing. OBJECTIVES: To study the association between maternal intake of folate during pregnancy and pubertal timing in girls and boys. METHODS: We studied 6585 girls and 6326 boys from a Danish population-based Puberty Cohort, 2000-2021. Information on maternal intake of folate from diet and folic acid from supplements was obtained from a food-frequency questionnaire in mid-pregnancy, and total folate was calculated as dietary folate equivalents. Information on age at menarche in girls, age at first ejaculation and voice break in boys, and Tanner stages, acne and axillary hair in both girls and boys was obtained every 6 months throughout puberty. We estimated mean monthly differences according to exposure groups for each pubertal milestone in addition to a combined estimate for the average age at attaining all pubertal milestones using multivariable interval-censored regression models. Total folate was analysed in quintiles, continuous and as restricted cubic splines. RESULTS: Maternal intake of total folate in mid-pregnancy was not associated with pubertal timing in girls (combined estimate for overall pubertal timing per standard deviation (SD 325 µg/day) decrease in maternal intake of total folate: -0.14 months (95% confidence interval [CI] -0.51, 0.22)). Boys had slightly later overall pubertal timing per standard deviation (SD 325 µg/day) decrease in maternal intake of total folate (combined estimate: 0.40 months, 95% CI 0.01, 0.72). Spline plots supported these findings. CONCLUSIONS: Prenatal exposure to low maternal intake of total folate in mid-pregnancy was not associated with pubertal timing in girls but associated with slightly later pubertal timing in boys. This minor delay is likely not of clinical importance.

Understanding the Chemical Exposome During Fetal Development and Early Childhood: A Review.

Early human life is considered a critical window of susceptibility to external exposures. Infants are exposed to a multitude of environmental factors, collectively referred to as the exposome. The chemical exposome can be summarized as the sum of all xenobiotics that humans are exposed to throughout a lifetime. We review different exposure classes and routes that impact fetal and infant metabolism and the potential toxicological role of mixture effects. We also discuss the progress in human biomonitoring and present possiblemodels for studying maternal-fetal transfer. Data gaps on prenatal and infant exposure to xenobiotic mixtures are identified and include natural biotoxins, in addition to commonly reported synthetic toxicants, to obtain a more holistic assessment of the chemical exposome. We highlight the lack of large-scale studies covering a broad range of xenobiotics. Several recommendations to advance our understanding of the early-life chemical exposome and the subsequent impact on health outcomes are proposed.

Pyridoxal 5'-phosphate alleviates prenatal pyridaben exposure-induced anxiety-like behaviors in offspring.

Pyridaben (PY) is a widely used organochlorine acaricide, which can be detected in the peripheral blood of pregnant women. Available evidence suggests that PY has reproductive toxicity. However, it remains uncertain whether prenatal PY exposure impacts neurobehavioral development in offspring. Here, we administered PY to pregnant mice at a dose of 0.5 and 5 mg kg-1 day-1 via gavage and observed anxiety-like behaviors in PY offspring aged five weeks. We then integrated the metabolome and transcriptome of the offspring's brain to explore the underlying mechanism. Metabolome data indicated that the vitamin B6 metabolism pathway was significantly affected, and the pyridoxal 5'-phosphate (PLP) concentration and the active form of vitamin B6 was significantly reduced. Moreover, the transcriptome data showed that both PLP generation-related Pdxk and anxiety-related Gad1 were significantly down-regulated. Meanwhile, there was a decreasing trend in the concentration of GABA in the hippocampal DG region. Next, we supplemented PLP at a dose of 20 mg kg-1 day-1 to the PY offspring via intraperitoneal injection at three weeks. We found up-regulated expression of Pdxk and Gad1 and restored anxiety-like behaviors. This study suggests that prenatal exposure to PY can disrupt vitamin B6 metabolism, reduce the concentration of PLP, down-regulate the expression levels of Pdxk and Gad1, inhibit the production of GABA, and ultimately lead to anxiety-like behaviors in offspring.

Maternal intake of folate and folic acid during pregnancy and markers of male fecundity: A population-based cohort study.

BACKGROUND: Poor male fecundity is of concern, and a prenatal origin has been proposed. Folate, a methyl donor involved in DNA methylation, is essential for normal fetal development by regulating gene expression during different periods of fetal development. Thus, prenatal exposure to low maternal folate intake might have a programing function of the developing reproductive organs. OBJECTIVES: To examine the association between maternal intake of folate from diet and folic acid from supplements during pregnancy and markers of fecundity in young men. MATERIALS AND METHODS: We conducted a follow-up study using a Danish mother-son cohort of 787 young men born 1998-2000. Percentage differences in semen characteristics, testes volume, and reproductive hormone levels were analyzed according to total folate calculated as dietary folate equivalents from diet and supplements in midpregnancy, using multivariable negative binomial regression models. Total folate was analyzed in quintiles, continuous per standard deviation decrease (SD: 318 µg/day) and as restricted cubic splines. RESULTS: Low maternal intake of total folate was associated with lower total sperm count (-5% (95% confidence intervals [CI]: -11%; 2%)), a lower proportion of non-progressive and immotile spermatozoa (-5% [95% CI: -8%; -3%]), and lower testes volume (-4% [95% CI: -6%; -2%]) per SD decrease in total folate intake. Spline plots supported these findings. DISCUSSION: The finding of a lower proportion of non-progressive and immotile spermatozoa, and hence a higher proportion of motile spermatozoa, in men of mothers with a lower intake of total folate in midpregnancy was surprising and may be a chance finding. CONCLUSION: Lower maternal intake of total folate in midpregnancy was associated with lower sperm count and lower testes volume, however, also with a lower proportion of non-progressive and immotile spermatozoa in adult men. Whether this actually affects the ability to obtain a pregnancy warrants further investigation.

Prenatal exposure to heavy metal mixtures and anthropometric birth outcomes: a cross-sectional study.

BACKGROUND: Numerous studies have suggested significant associations between prenatal exposure to heavy metals and newborn anthropometric measures. However, little is known about the effect of various heavy metal mixtures at relatively low concentrations. Hence, this study aimed to investigate associations between prenatal exposures to a wide range of individual heavy metals and heavy metal mixtures with anthropometric measures of newborns. METHODS: We recruited 975 mother-term infant pairs from two major hospitals in Israel. Associations between eight heavy metals (arsenic, cadmium, chromium, mercury, nickel, lead, selenium, and thallium) detected in maternal urine samples on the day of delivery with weight, length, and head circumference at birth were estimated using linear and Bayesian kernel machine regression (BKMR) models. RESULTS: Most heavy metals examined in our study were observed in lower concentrations than in other studies, except for selenium. In the linear as well as the BKMR models, birth weight and length were negatively associated with levels of chromium. Birth weight was found to be negatively associated with thallium and positively associated with nickel. CONCLUSION: By using a large sample size and advanced statistical models, we could examine the association between prenatal exposure to metals in relatively low concentrations and anthropometric measures of newborns. Chromium was suggested to be the most influential metal in the mixture, and its associations with birth weight and length were found negative. Head circumference was neither associated with any of the metals, yet the levels of metals detected in our sample were relatively low. The suggested associations should be further investigated and could shed light on complex biochemical processes involved in intrauterine fetal development.

Exposure to environmental contaminants and folic acid supplementation intergenerationally impact fetal skeleton development through the paternal lineage in a rat model.

Persistent organic pollutants (POPs) are ubiquitous in the environment, which is of concern since they are broadly toxic for wildlife and human health. It is generally accepted that maternal prenatal folic acid supplementation (FA) may beneficially impact offspring development, but it has been recently shown that the father's exposures also influence the health of his offspring. Bone is an endocrine organ essential for whole-body homeostasis and is susceptible to toxicants. Herein, we tested the hypotheses that prenatal paternal exposure to POPs induces developmental bone disorders in fetuses across multiple generations and that FA supplementation attenuates these disorders. We used a four-generation rat model, in which F0 founder females were divided into four treatment groups. F0 females were gavaged with corn oil or an environmentally-relevant POPs mixture and fed either a control diet (2 mg FA/kg), or FA supplemented diet (6 mg FA/kg) before mating and until parturition (four treatments in total). After the birth of the F1 litters, all F0 females and subsequent generations received the FA control diet. Staining with alcian blue and alizarin red S of male and female fetal skeletons was performed at Gestational Day 19.5. Paternal direct and ancestral exposure to POPs delayed bone ossification and decreased the length of long limb bones in fetuses. Maternal FA supplementation did not counteract the POPs-associated delayed fetal ossification and reduced long bone length. In conclusion, prenatal paternal POPs exposure causes developmental bone abnormalities over multiple generations, which were not corrected by maternal FA supplementation.

In Utero Ultrafine Particulate Exposure Yields Sex- and Dose-Specific Responses to Neonatal Respiratory Syncytial Virus Infection.

Exposure to particulate matter (PM) is associated with lower respiratory tract infections. The role of ultrafine particles (UFPs, ≤0.1 µm) in respiratory disease is not fully elucidated, especially in models of immunologically immature populations. To characterize the effects of maternal UFP exposure on neonatal infection, we exposed time-mated C57Bl/6n mice to filtered air or UFPs at a low dose (LD, ∼55 µg/m3) and high dose (HD, ∼275 µg/m3) throughout gestation. At 5 days of age, offspring were infected with a respiratory syncytial virus (RSV) strain known to mimic infant infection or sham control. Offspring body weights were significantly reduced in response to infection in the LD RSV group, particularly females. Pulmonary gene expression analysis demonstrated significantly increased levels of oxidative stress- and inflammation-related genes in HD-exposed male offspring in sham and RSV-infected groups. In males, the highest grade of inflammation was observed in the HD RSV group, whereas in females, the LD RSV group showed the most marked inflammation. Overall, findings highlight neonatal responses are dependent on offspring sex and maternal UFP dose. Importantly, infant RSV pathology may be enhanced following even low dose UFP exposure signifying the importance of preventing maternal exposure.

Reproductive disruption in adult female and male rats prenatally exposed to mesquite pod extract or daidzein.

Phytoestrogens are considered to be endocrine disruptors, since they can alter the endocrine system, thus disturbing many reproductive events. The intake of diets containing a high content of phytoestrogens has increased worldwide in human populations and in domestic animals. Phytoestrogens in maternal blood can pass through the placenta to the fetus in high amounts and can have long-term organizational effects. Mesquite (Prosopis sp) is a leguminous plant widely used to feed several livestock species, and is also used in the human diet. In this study we assessed the effects of exposure to mesquite pod extract during the periconception and pregnancy periods on the reproduction of male and female descendants. The females of three experimental groups received one of the following treatments: 1) vehicle injection; 2) mesquite pod extract or 3) the isoflavone daidzein during the periconception and pregnancy periods. Estrous cyclicity, sexual behavior and hormones, as well as uterine and vaginal epithelia were evaluated in the female descendants. In the males, sexual behavior and hormones, apoptosis in testicular cells and sperm quality were evaluated. In females the following was observed: alterations in estrous cycles, decreased sexual behavior, estradiol and progesterone levels, increased uterine and vaginal epithelia. In males, we observed a decrease in sexual behavior, testosterone and sperm quality, and apoptosis increased in testicular cells. All these effects were similar to those caused by daidzein. These results indicate that prenatal exposure to mesquite pod extract or daidzein, administered to females before and during pregnancy, can disrupt normal organizational-activational programming of reproductive physiology in female and male descendants.

Progress on association of obesity with common congenital heart diseases and its underlying mechanisms / 中华围产医学杂志

Maternal obesity is associated with an increased risk of a range of congenital malformations in offspring, including neurological malformations, congenital heart disease, congenital kidney and urinary system abnormalities, cleft lip and palate, anorectal atresia, etc. This may be related to existing metabolic abnormalities, including increased insulin resistance, chronic inflammation, and oxidative stress caused by excessive accumulation of fat, as well as the relative deficiency of nutrients such as folic acid in obese pregnant women. Therefore, it is recommended that obese women have a planned pregnancy, address folate and micronutrient supplementation and optimize their health status prior to conception.

Prenatal uranium exposure and risk for fetal neural tube defects: A case-control study in women living in a rural area of northern China.

The adverse effects of uranium exposure on human health are well-known; less is known, however, regarding its association with congenital malformations. We conducted a case-control study to examine the association between prenatal exposure to uranium and risk for fetal neural tube defects (NTDs) using the concentration of uranium in placental tissue as an exposure marker in 408 NTD cases and 593 healthy controls. Uranium concentration was quantified with an inductively coupled plasma mass spectrometer. The odds ratios of NTDs for uranium exposure levels, categorized into quartiles, were estimated using logistic regression. The median concentration of uranium in the NTD group (0.409 ng/g) was significantly higher than that in the control group (0.218 ng/g). The risk for NTDs increased 2.52-fold (95% CI, 1.85-3.45) for concentrations of uranium above the median value for all participants. After adjusting for confounders, the risk for NTDs increased 1.36-fold (95% CI, 1.25-6.17), 1.77-fold (95% CI, 1.09-2.85), and 3.60-fold (95% CI, 2.30-5.64) for the second, third, and fourth quartiles of uranium concentrations compared to the lowest quartile, respectively. Prenatal exposure to uranium is a risk factor for NTDs in this population. Prospective studies are needed to further validate this finding.

Public-health risks from tea drinking: Fluoride exposure.

AIMS: Due to new evidence on fluoride neurotoxicity during early life, this study examined maternal exposure to fluoride through tea consumption in a low-fluoride region and measured fluoride releases from commercially available teas (tea bags and loose teas) to determine the need to limit fluoride exposure. METHODS: Maternal urine fluoride (MUF) concentrations were measured in spot urine samples (N=118) from first-trimester pregnant women and in prepared tea infusions made with deionised water from 33 brand teas and 57 loose-tea products, as determined by the direct method of using a fluoride-selective electrode. RESULTS: The fluoride concentration in the local drinking water supplies ranged from 0.10 to 0.18 mg/L, and the creatinine-adjusted MUF ranged from 0.09 to 1.57 mg/L. Seventeen per cent of the women were daily tea drinkers, and their MUFs were higher than those with no consumption (p=0.002). The fluoride concentration from tea bags ranged from 0.34 to 2.67 mg/L, while loose teas showed 0.72-4.50 mg/L (black), 0.56-1.58 mg/L (oolong), 1.28-1.50 mg/L (green), and 0.33-1.17 mg/L (white tea). CONCLUSIONS: Fluoride exposure among pregnant women increases with tea consumption, with likely risks of developmental neurotoxicity to their children. As the fluoride release from tea varies widely, the fluoride concentration should be indicated on tea packages in order to allow consumers to make informed decisions on minimising their fluoride exposure.

Prenatal and Early Life Exposure to the Danish Mandatory Vitamin D Fortification Policy Might Prevent Inflammatory Bowel Disease Later in Life: A Societal Experiment.

This register-based national cohort study of 206,900 individuals investigated whether prenatal exposure to small extra doses of vitamin D from fortified margarine prevented inflammatory bowel disease (IBD) later in life; whether the risk of IBD varied according to month or season of birth; and finally, whether there was an interaction between exposure to extra D vitamin and month or season of birth. Fortification of margarine with vitamin D was mandatory in Denmark from the mid-1930s until 1st June 1985, when it was abolished. Two entire birth cohorts, each including two years, were defined: one exposed and one unexposed to the fortification policy for the entire gestation. All individuals were followed for 30 years from the day of birth for an IBD diagnosis in Danish hospital registers. Logistic regression analyses were used to estimate odds ratios (OR) and 95% confidence intervals (CI). Odds for IBD was lower among those exposed to extra D vitamin compared to those unexposed, OR = 0.87 (95% CI: 0.79; 0.95). No association with month or season of birth was found. However, estimates suggested that particularly children born during autumn may have benefitted from the effect of small extra doses of vitamin D. This is, to our knowledge, the first study to explore if prenatal exposure to vitamin D from fortification influenced the risk of IBD. Our results suggest that prenatal exposure to small amounts of extra vitamin D from food fortification may protect against the development of IBD before 30 years of age.

Male fetus susceptibility to maternal inflammation: C-reactive protein and brain development.

BACKGROUND: Maternal inflammation in early pregnancy has been identified epidemiologically as a prenatal pathogenic factor for the offspring's later mental illness. Early newborn manifestations of the effects of maternal inflammation on human fetal brain development are largely unknown. METHODS: Maternal infection, depression, obesity, and other factors associated with inflammation were assessed at 16 weeks gestation, along with maternal C-reactive protein (CRP), cytokines, and serum choline. Cerebral inhibition was assessed by inhibitory P50 sensory gating at 1 month of age, and infant behavior was assessed by maternal ratings at 3 months of age. RESULTS: Maternal CRP diminished the development of cerebral inhibition in newborn males but paradoxically increased inhibition in females. Similar sex-dependent effects were seen in mothers' assessment of their infant's self-regulatory behaviors at 3 months of age. Higher maternal choline levels partly mitigated the effect of CRP in male offspring. CONCLUSIONS: The male fetal-placental unit appears to be more sensitive to maternal inflammation than females. Effects are particularly marked on cerebral inhibition. Deficits in cerebral inhibition 1 month after birth, similar to those observed in several mental illnesses, including schizophrenia, indicate fetal developmental pathways that may lead to later mental illness. Deficits in early infant behavior follow. Early intervention before birth, including prenatal vitamins, folate, and choline supplements, may help prevent fetal development of pathophysiological deficits that can have life-long consequences for mental health.