Long-term Effects Of Prenatal Exposure Research Articles

Prenatal Exposure to the 1944-45 Dutch Famine and Risk for Dementia up to Age 75: An Analysis of Primary Care Data.

A poor prenatal environment adversely affects brain development. Studies investigating long-term consequences of prenatal exposure to the 1944-45 Dutch famine have shown that those exposed to famine in early gestation had poorer selective attention, smaller brain volumes, poorer brain perfusion, older appearing brains, and increased reporting of cognitive problems, all indicative of increased dementia risk. In the current population-based study, we investigated whether dementia incidence up to age 75 was higher among individuals who had been prenatally exposed to famine. We included men (n=6,714) and women (n=7,051) from the Nivel Primary Care Database who had been born in seven cities affected by the Dutch famine. We used Cox regression to compare dementia incidence among individuals exposed to famine during late (1,231), mid (1,083), or early gestation (601) with those unexposed (born before or conceived after the famine). We did not observe differences in dementia incidence for those exposed to famine in mid or early gestation compared to those unexposed. Men and women exposed to famine in late gestation had significantly lower dementia rates compared to unexposed individuals (HR 0.52 [95%CI 0.30-0.89]). Sex-specific analyses showed a lower dementia rate in women exposed to famine in late gestation (HR 0.39 [95%CI 0.17-0.86]) but not in men (HR 0.68 [95%CI 0.33-1.41]). Although prenatal exposure to the Dutch famine has previously been associated with measures of accelerated brain aging, the present population-based study did not show increased dementia incidence up to age 75 in those exposed to famine during gestation.

Amphetamine Exposure during Embryogenesis Alters Expression and Function of Tyrosine Hydroxylase and the Vesicular Monoamine Transporter in Adult C. elegans.

Amphetamines (Amph) are psychostimulants broadly used as physical and cognitive enhancers. However, the long-term effects of prenatal exposure to Amph have been poorly investigated. Here, we show that continuous exposure to Amph during early development induces long-lasting changes in histone methylation at the C. elegans tyrosine hydroxylase (TH) homolog cat-2 and the vesicular monoamine transporter (VMAT) homologue cat-1 genes. These Amph-induced histone modifications are correlated with enhanced expression and function of CAT-2/TH and higher levels of dopamine, but decreased expression of CAT-1/VMAT in adult animals. Moreover, while adult animals pre-exposed to Amph do not show obvious behavioral defects, when challenged with Amph they exhibit Amph hypersensitivity, which is associated with a rapid increase in cat-2/TH mRNA. Because C. elegans has helped reveal neuronal and epigenetic mechanisms that are shared among animals as diverse as roundworms and humans, and because of the evolutionary conservation of the dopaminergic response to psychostimulants, data collected in this study could help us to identify the mechanisms through which Amph induces long-lasting physiological and behavioral changes in mammals.

Treatment of depression during pregnancy: a protocol for systematic review and meta-analysis.

Major Depressive Disorder (MDD) is a chronic, recurrent, and highly prevalent disease that is associated with significant functional disability. During pregnancy, the prevalence of the disease is approximately 20%, with 12% of these, requiring treatment to avoid important negative consequences for the mother-baby binomial. Risk-benefit assessment of the use of antidepressants during pregnancy is mandatory, in addition to knowledge of the long-term effects of prenatal exposure to these drugs in the offspring. In this study, we will perform an updated systematic review and meta-analysis to explore the treatment of depression during pregnancy, along with its effectiveness, safety, and possible harm to women and children. We will search for publications in the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Web of Science, Scopus, Lilacs, and PsycINFO. The reference lists of the included studies will be manually reviewed to identify potentially relevant studies. There will be no restrictions on language or date of publication. Quality assessment of the included studies will be performed independently according to the Cochrane Risk of Bias (RoB2) instrument. To assess the certainty of the findings' body of evidence, we will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. This study aimed to ascertain the efficacy and safety of antidepressants in pregnant women and children. Ethical approval was not required as individual patient data were not collected. Dissemination: Plan to publish a systematic review in an open-access medical journal at the end of the process. PROSPERO, CRD42023447694.

Change in marijuana use from adolescence to young adulthood and its relation to gestational alcohol and marijuana exposure

IntroductionMany studies have examined changes in marijuana use across adolescence, but few have examined factors associated with transitions from adolescence to young adulthood. We examined prenatal exposures to alcohol and marijuana and adolescent risk and protective factors that best distinguished among abstinence, continuity, or cessation of marijuana use from 16 to 22 years. MethodData were from the Maternal Health Practices and Child Development Project at the prenatal and 16- and 22-year follow-up phases. The offspring were of lower socioeconomic status with an average of 12.8 years of education at 22 years. Participants' frequency and quantity of marijuana use over the past year were used to determine change in use. A discriminant analysis was applied to distinguish among the identified groups. The risk factors considered included prenatal substance exposures and age 16 demographics, behavior, and home environment. ResultFour categories of transitions were defined based on marijuana use from 16 to 22 years: non-users (n = 193), stop/decrease (n = 81), continue at same level/increase (n = 125), and initiation after the 16-year phase (n = 122). The factors that best distinguished among these groups were peers' marijuana use, delinquency, caregivers' financial strain, prenatal exposure to alcohol and marijuana, and race. ConclusionPrenatal alcohol and marijuana exposure were significantly related to transitions of marijuana use from adolescence to young adulthood, controlling for peers' use, behavior problems, and home environment. While gestational marijuana exposure was associated with early initiation/increasing use, alcohol exposure was related to later initiation. The findings emphasize the long-term effects of prenatal exposure to alcohol and marijuana.

Target analysis and suspect screening of UV filters, parabens and other chemicals used in personal care products in human cord blood: Prenatal exposure by mother-fetus transfer

Prenatal exposure to certain organic chemicals like pesticides and phenols has been lifelong associated with birth outcomes and health disorders. Many personal care product (PCP) ingredients have similar properties or structures to those chemicals. Previous studies have documented the occurrence of UV filters (UVFs) and paraben preservatives (PBs) in the placenta, but observational studies concerning PCPs chemicals and foetal exposure are particularly scarce. Thus, this work aimed to assess the presence of a wide range of PCPs chemicals using target and suspect screening in the umbilical cord blood of new born babies to evaluate their potential transfer to the fetus. To do so, we analysed 69 umbilical cord blood plasma samples from a mother–child cohort from Barcelona (Spain). We quantified 8 benzophenone-type UVFs and their metabolites, and 4 PBs using validated analytical methodologies based on target screening using liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Then, we screened for additional 3246 substances using high-resolution mass spectrometry (HRMS) and advanced suspect analysis strategies. Six UVFs and three parabens were detected in the plasma with frequencies between 1.4% and 17.4% and concentrations up to 53.3 ng/mL (benzophenone-2). Thirteen additional chemicals were tentatively identified in the suspect screening, and ten were further confirmed with the corresponding standards. Among them, we found the organic solvent N-methyl-2-pyrrolidone, the chelating agent 8-hydroxyquinoline, and the antioxidant 2,2′-methylenebis(4-methyl-6-tert-butylphenol), which have been demonstrated to display reproductive toxicity. UVFs and PBs presence in the umbilical cord blood demonstrates mother-fetus transfer through the placental barrier and prenatal exposure to these PCPs chemicals, which may lead to adverse effects in the early stages of fetal development. Considering the small cohort used in this study, the reported results should be interpreted as a preliminary reference for the background umbilical cord transfer levels of the target PCPs chemicals. Further research is needed to determine the long-term consequences of prenatal exposure to PCPs chemicals.

Binding of common organic UV-filters to the thyroid hormone transport protein transthyretin using in vitro and in silico studies: Potential implications in health.

Several anthropogenic contaminants have been identified as competing with the thyroid hormone thyroxine (T4) for binding to transport proteins as transthyretin (TTR). This binding can potentially create toxicity mechanisms posing a threat to human health. Many organic UV filters (UVFs) and paraben preservatives (PBs), widely used in personal care products, are chemicals of emerging concern due to their adverse effects as potential thyroid-disrupting compounds. Recently, organic UVFs have been found in paired maternal and fetal samples and PBs have been detected in placenta, which opens the possibility of the involvement of TTR in the transfer of these chemicals across physiological barriers. We aimed to investigate a discrete set of organic UVFs and PBs to identify novel TTR binders. The binding affinities of target UVFs towards TTR were evaluated using in vitro T4 competitive binding assays. The ligand-TTR affinities were determined by isothermal titration calorimetry (ITC) and compared with known TTR ligands. In parallel, computational studies were used to predict the 3-D structures of the binding modes of these chemicals to TTR. Some organic UVFs, compounds 2,2′,4,4′-tetrahydroxybenzophenone (BP2, Kd = 0.43 μM); 2,4-dihydroxybenzophenone (BP1, Kd = 0.60 μM); 4,4′-dihydroxybenzophenone (4DHB, Kd = 0.83 μM), and 4-hydroxybenzophenone (4HB, Kd = 0.93 μM), were found to display a high affinity to TTR, being BP2 the strongest TTR binder (ΔH = −14.93 Kcal/mol). Finally, a correlation was found between the experimental ITC data and the TTR-ligand docking scores obtained by computational studies. The approach integrating in vitro assays and in silico methods constituted a useful tool to find TTR binders among common organic UVFs. Further studies on the involvement of the transporter protein TTR in assisting the transplacental transfer of these chemicals across physiological barriers and the long-term consequences of prenatal exposure to them should be pursued.

Long-term behavioral effects of prenatal stress in the Fmr1-knock-out mouse model for fragile X syndrome.

Fragile X syndrome (FXS) is a major neurodevelopmental disorder and the most common monogenic cause of autism spectrum disorder (ASD). FXS is caused by a mutation in the X-linked FMR1 gene leading to the absence of the FMRP protein, inducing several behavioral deficits, including motor, emotional, cognitive, and social abnormalities. Beside its clear genetic origins, FXS can be modulated by environmental factors, e.g., stress exposure: indeed the behavioral phenotype of FXS, as well as of ASD patients can be exacerbated by the repeated experience of stressful events, especially early in life. Here we investigated the long-term effects of prenatal exposure to unpredictable chronic stress on the behavioral phenotype of the Fmr1-knock-out (KO) mouse model for FXS and ASD. Mice were tested for FXS- and ASD-relevant behaviors first at adulthood (3 months) and then at aging (18 months), in order to assess the persistence and the potential time-related progression of the stress effects. Stress induced the selective emergence of behavioral deficits in Fmr1-KO mice that were evident in spatial memory only at aging. Stress also exerted several age-specific behavioral effects in mice of both genotypes: at adulthood it enhanced anxiety levels and reduced social interaction, while at aging it enhanced locomotor activity and reduced the complexity of ultrasonic calls. Our findings underline the relevance of gene-environment interactions in mouse models of neurodevelopmental syndromes and highlight the long-term behavioral impact of prenatal stress in laboratory mice.

Prenatal Exposure to a Climate-Related Disaster Results in Changes of the Placental Transcriptome and Infant Temperament.

Maternal stress during pregnancy exerts long-term effects on the mental well-being of the offspring. However, the long-term effect of prenatal exposure on the offspring’s mental status is only partially understood. The placenta plays a vital role in connecting the maternal side to the fetus, thereby serving as an important interface between maternal exposure and fetal development. Here, we profiled the placental transcriptome of women who were pregnant during a hurricane (Superstorm Sandy), which struck New York City in 2012. The offspring were followed longitudinally and their temperament was assessed during the first 6–12 months of age. The data identified a significant correlation between a Superstorm Sandy stress factor score and infant temperament. Further, analysis of the placental transcriptomes identified an enrichment of functional pathways related to inflammation, extracellular matrix integrity and sensory perception in the specimen from those infants with “Slow-to-Warm-up” temperament during the first year of life. Together, these findings provide initial evidence that maternal exposure to climate-related disasters results in altered placental transcriptome, which may be related to long-term emotional and behavioral consequences in children.

Alterations in Excitatory and Inhibitory Synaptic Development Within the Mesolimbic Dopamine Pathway in a Mouse Model of Prenatal Drug Exposure.

The rise in rates of opioid abuse in recent years in the United States has led to a dramatic increase in the incidence of neonatal abstinence syndrome (NAS). Despite improved understanding of NAS and its acute symptoms, there remains a paucity of information regarding the long-term effects of prenatal exposure to drugs of abuse on neurological development. The primary goal of this study was to investigate the effects of prenatal drug exposure on synaptic connectivity within brain regions associated with the mesolimbic dopamine pathway, the primary reward pathway associated with drug abuse and addiction, in a mouse model. Our secondary goal was to examine the role of the Ca+2 channel subunit α2δ-1, known to be involved in key developmental synaptogenic pathways, in mediating these effects. Pregnant mouse dams were treated orally with either the opioid drug buprenorphine (commonly used in medication-assisted treatment for substance use patients), gabapentin (neuropathic pain drug that binds to α2δ-1 and has been increasingly co-abused with opioids), a combination of both drugs, or vehicle daily from gestational day 6 until postnatal day 11. Confocal fluorescence immunohistochemistry (IHC) imaging of the brains of the resulting wild-type (WT) pups at postnatal day 21 revealed a number of significant alterations in excitatory and inhibitory synaptic populations within the anterior cingulate cortex (ACC), nucleus accumbens (NAC), and medial prefrontal cortex (PFC), particularly in the buprenorphine or combinatorial buprenorphine/gabapentin groups. Furthermore, we observed several drug- and region-specific differences in synaptic connectivity between WT and α2δ-1 haploinsufficient mice, indicating that critical α2δ-1-associated synaptogenic pathways are disrupted with early life drug exposure.

Resveratrol prevents long-term structural hippocampal alterations and modulates interneuron organization in an animal model of ASD

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impairments in both communication and social interaction, besides repetitive or stereotyped behavior. Although the etiology is unknown, environmental factors such as valproic acid (VPA) increase the risk of ASD onset. Resveratrol (RSV), a neuroprotective molecule, has been shown to counteract the effects of intrauterine exposure to VPA. We aimed to evaluate histological parameters related to hippocampal morphology and to the distribution of parvalbumin- (PV), calbindin- (CB), and somatostatin-positive (SOM) interneurons sub-populations, in addition to evaluate the total/phosphorylation levels of PTEN, AKT, GSK3β and total CK2 in the animal model of autism induced by VPA, as well as addressing the potential protective effect of RSV. On postnatal day 120, histological analysis showed a loss in total neurons in the dentate gyrus (DG) and decreased CB+ neurons in DG and CA1 in VPA animals, both prevented by RSV. In addition, PV+ neurons were diminished in CA1, CA2, and CA3, and SOM+ were interestingly increased in DG (prevented by RSV) and decreased in CA1 and CA2. A hippocampal lesion similar to sclerosis was also observed in the samples from the VPA group. Besides that, VPA reduced AKT and PTEN immunocontent, and VPA increased CK2 immunocontent. Thus, this work demonstrated long-term effects of prenatal exposure to ASD in different sub-populations of interneurons, structural damage of hippocampus, and also alteration in proteins associated with pivotal cell signaling pathways, highlighting the role of RSV as a tool for understanding the pathophysiology of ASD.

Experiencing earthquake in the first trimester of the fetal life increases subsequent diabetes risk in the adulthood: a cross-sectional study

ObjectiveTo investigate the long-term effect of prenatal exposure to earthquake stress on diabetes risk in the adulthood.MethodsThis study included employees of Tangshan Kailuan Mining Group between July 29, 1976 and April 28, 1977. The exposure group included subjects who experienced the Tangshan Earthquake during their prenatal period and who had lived in Tangshan since birth. The non-exposure group included subjects who were born 1–1.9 years after the earthquake and who had lived in Tangshan since birth. A questionnaire was designed that included sociodemographic information, conditions during pregnancy, and earthquake experience. Anthropometric measurements including height and weight, body mass index (BMI), waist circumference were made. Fasting plasma glucose (FPG) and lipid profiles were also determined.ResultsTotally 947 subjects were included with 397 subjects in the exposed group and 550 subjects in the non-exposed group. The diabetes rate is significant different in these four groups(χ2 =8.045, P = 0.045). Moreover, 11.8, 7.5 and 8.0% of the subjects who were exposed to earthquake in the 1st, 2nd, and 3rd trimester of pregnancy had diabetes. 5.1% of the subjects had diabetes in non-exposure group. Our multivariate analysis showed that 1st trimester (OR 2.481, 95%CI 1.02, 6.034; P = 0.045) and loss of family members during earthquake (OR 2.452, 95%CI 1.293, 4.653; P = 0.006) were associated with significantly increased risk of diabetes.ConclusionsExposure to earthquake during the first trimester of pregnancy and experience of family member loss in the earthquake significantly increased the subsequent risk of diabetes in the middle age (36–39 years of age). Our data suggest that earthquake experience in the early pregnancy has a longer-term effect on diabetes risk during adulthood.

Risk of cognitive impairment in children after maternal exposure to the 1998 Yangtze River flood during pregnancy: analysis of data from China's second National Sample Survey on Disability

More research is needed to understand the long-term effects of prenatal exposure to adverse events, such as floods and other natural disasters, on cognitive outcomes in childhood. We aimed to explore the risk of cognitive impairment in children following maternal exposure to the 1998 Yangtze River flood in China during pregnancy. For this study we obtained and analysed individual-level data from the second China National Sample Survey on Disability (CNSSD), which was done in 2006. We defined the flood period as June-August, 1998. The analytical sample comprised children from four birth cohorts, defined according to their month of birth: the post-partum exposed cohort (children born between June, 1997, and May, 1998), the prenatal exposed cohort (children born between June, 1998, and May, 1999), the preconception exposed cohort (children born between June 1999, and May, 2000), and the unexposed cohort (children born between June, 2000, and May, 2001). In the CNSSD, cognitive impairment was assessed and diagnosed by validated screening tools and procedures. Difference-in-difference models were used to examine variations in the effects of maternal flood exposure on cognitive impairment in childhood across the different birth cohorts and regions. 108 175 children born between June, 1997, and May, 2001, and aged 4-8 years at the time of the survey, were included in our analysis. 1131 children had a cognitive impairment; the prevalence of cognitive impairment was 1·05% (95% CI 0·99-1·11). Maternal exposure to flood during pregnancy increased the risk of cognitive impairment among children (adjusted odds ratio [OR] 2·18 [95% CI 1·54-3·08]; p<0·0001). No significant sex-specific differences were observed, and the risk of cognitive impairment was especially high when maternal flood exposure occurred during the first trimester of pregnancy (adjusted OR 5·05 [95% CI 3·88-6·58]; p<0·0001). The risk of cognitive impairment also increased with longer durations of maternal flood exposure and with increasing severity of flooding; the risk was highest in the prenatal exposed cohort with 3 months of flood exposure in the most severely affected area (adjusted OR 5·56 [95% CI 1·58-19·54]; p=0·007). Prenatal flood exposure had a long-term negative effect on cognitive development of children. Greater maternal support and public health interventions during pregnancy and early life after a natural disaster are warranted to facilitate healthy cognitive development in later life. National Social Science Foundation of China.

Child development at 6 years after maternal cancer diagnosis and treatment during pregnancy

BackgroundData on the long-term effects of prenatal exposure to maternal cancer and its treatment on child development are scarce. MethodsIn a multicenter cohort study, the neurologic and cardiac outcomes of 6-year-old children born to women diagnosed with cancer during pregnancy were compared with the outcome of children born after an uncomplicated pregnancy. Assessment included clinical evaluation, comprehensive neuropsychological testing, electrocardiography and echocardiography. ResultsIn total, 132 study children and 132 controls were included. In the study group, 97 children (73.5%) were prenatally exposed to chemotherapy (alone or in combination with other treatments), 14 (10.6%) to radiotherapy (alone or in combination), 1 (0.8%) to trastuzumab, 12 (9.1%) to surgery alone and 16 (12.1%) to no treatment. Although within normal ranges, statistically significant differences were found in mean verbal IQ and visuospatial long-term memory, with lower scores in the study versus control group (98.1, 95% confidence interval [CI]: 94.5–101.8, versus 104.4, 95% CI: 100.4–108.4, P = 0.001, Q < 0.001 [Q refers to the false discovery rate adjusted P value], and 3.9, 95% CI: 3.6–4.3, versus 4.5, 95% CI: 4.1–4.9, P = 0.005, Q = 0.045, respectively). A significant difference in diastolic blood pressure was found, with higher values in chemotherapy-exposed (61.1, 95% CI: 59.0 to 63.2) versus control children (56.0, 95% CI 54.1 to 57.8) (P < 0.001, Q < 0.001) and in a subgroup of 59 anthracycline-exposed (61.8, 95% CI: 59.3 to 64.4) versus control children (55.9, 95% CI: 53.6 to 58.1) (P < 0.001, Q = 0.02). ConclusionsChildren prenatally exposed to maternal cancer and its treatment are at risk for lower verbal IQ and visuospatial long-term memory scores and for higher diastolic blood pressure, but other cognitive functions and cardiac outcomes were normal at the age of 6 years. Clinical trial registrationThe study is registered at ClinicalTrials.gov, NCT00330447.

The Developmental Consequences of Superfund Sites

We use population-level data on all Florida children born between 1994 and 2002 to examine the long-term effects of prenatal exposure to environmental toxicants from a Superfund (toxic waste) site....

1830P - Child development at 6 years after maternal cancer diagnosis and treatment during pregnancy

BackgroundData on the long-term effects of prenatal exposure to maternal cancer and its treatment on child development are scarce. MethodsIn a multicentre cohort study, the neurologic and cardiac outcomes of 6-year-old children born to women diagnosed with cancer during pregnancy (study group) were compared to the outcome of children born after an uncomplicated pregnancy (control group) (ClinicalTrials.gov, NCT00330447). Neurodevelopment was assessed by clinical evaluation and neuropsychological testing (including intelligence, attention and memory tests) and by general health and behaviour questionnaires. Cardiac evaluation included electro- and echocardiography. ResultsIn total, 132 study children and 132 controls (mean age 6.2 years) were included. In the study group, 97 children (73.5%) were prenatally exposed to chemotherapy (alone or in combination with other treatments), 14 (10.6%) to radiotherapy (alone or in combination), 1 (0.8%) to trastuzumab, 12 (9.1%) to surgery alone and 16 (12.1%) to no treatment. Although within normal ranges, the mean Verbal IQ score was significantly lower in the study versus control group (98.9 vs 103.0, p=0.001, q<0.001). Also, children in the study group had a significantly lower score for visuospatial long-term memory compared to the control group (3.9 vs 4.5, p=0.005, q=0.043). No significant differences were found in Full Scale IQ, Performance IQ, Processing Speed, memory span, verbal and visuospatial short-term memory, attention and behaviour problems or in cardiac dimensions and left ventricular function. ConclusionsChildren prenatally exposed to maternal cancer and its treatment may be at risk for lower Verbal IQ and visuospatial long-term memory scores, but other cognitive functions and cardiac outcomes were normal at the age of 6 years. Clinical trial identificationNCT00330447. Legal entity responsible for the studyUniversity Hospitals Leuven, Belgium. FundingEuropean Union’s Horizon 2020 research and innovation programme under grant agreement No. 647047, Research Foundation-Flanders (F.W.O)., Stichting tegen Kanker, Belgian Cancer Plan, Koningin Wilhemina Fonds (K.W.F.), Kom Op Tegen Kanker, Stichting Mitialto and Charles University grant Progres Q-34. DisclosureAll authors have declared no conflicts of interest.

Long-term effects of prenatal exposure to earthquake on adult schizophrenia.

Maternal exposure to major stressors during pregnancy has been found to increase the risk of neurodevelopmental, cognitive and psychiatric disorders in the offspring. However, the association between prenatal exposure to earthquake and the risk of adult schizophrenia has yet to be examined. To explore the potential long-term effects of prenatal exposure to maternal stress on the risk of schizophrenia in adulthood, using the Great Tangshan Earthquake in 1976 as a natural experiment. We obtained data from the Second China National Sample Survey on Disability, and analysed 94 410 Chinese individuals born between 1975 and 1979. We obtained difference-in-differences estimates of the earthquake effects on schizophrenia by exploiting temporal variation in the timing of earthquake exposure across four birth cohorts born between 1975 and 1979, along with geographical variation in earthquake severity at the prefecture level. Schizophrenia was ascertained by psychiatrists using the ICD-10 classification. Earthquake severity was measured by seismic intensity. Earthquake cohort who experienced prenatal exposure to felt earthquake had higher risk of schizophrenia (odds ratio, 3.38; 95% CI 1.43-8.00) compared with the unexposed reference cohort. After specifying the timing of exposure by the trimester of pregnancy, prenatal exposure to felt earthquake during the first trimester of pregnancy increased the risk of adulthood schizophrenia significantly (odds ratio, 7.45; 95% CI 2.83-19.59). Prenatal (particularly early pregnancy) exposure to maternal stress after a major disaster substantially affects the mental health of Chinese adults.

Long-term effects of prenatal exposure to metformin on the health of children based on follow-up studies of randomized controlled trials: a systematic review and meta-analysis.

Oral antidiabetic medication of metformin is increasingly used in pregnant women with gestational diabetes mellitus (GDM), polycystic ovary syndrome (PCOS) and obesity. The drug passes through the placenta and can potentially influence the fetus. The aim of the study is to investigate the possible long-term effects of prenatal exposure to metformin on growth and development of the offspring. A systematic review and meta-analysis was conducted to examine the longer term outcomes by the follow-up studies of the already published RCTs focusing on the body composition, metabolic parameters and neurophysiological development of the children prenatally exposed to metformin. The primary sources of the reviewed studies through August 2018, with restriction on the language of English, were Pubmed and Embase. 11 follow-up studies were included, with a maximal age of children being 13 years, comprising 823 children of mothers with GDM or PCOS who were randomized to either metformin or insulin/placebo during pregnancy. From the pooled meta-analysis we found that children prenatal exposure to metformin were associated with a significantly heavier weight (MD = 0.48kg, 95% CI 0.24kg, 0.73kg; P = 0.0001, I2 = 0). As for other parameters of body composition, metabolic parameters and neurophysiological development, the results were similar between metformin and placebo/insulin use. Increased offspring weight was more observed in children prenatal exposure to metformin. Heathcare providers and patients should be aware that metformin is increasingly prescribed in pregnancy based on the relatively limited evidences but nonetheless encouraging long-term offspring data are available.

Prenatal war exposure and schizophrenia in adulthood: evidence from the Sino-Japanese War of 1937-1945.

This study aimed to examine the long-term effect of prenatal exposure to the Sino-Japanese War during 1937-1945 on risk of schizophrenia in adulthood among Chinese wartime survivors. We obtained data from the Second National Sample Survey on Disability conducted in 31 provinces in 2006. We restricted our analysis to 369,469 adults born between 1931 and 1950. Schizophrenia was ascertained by psychiatrists based on the International Statistical Classification of Diseases 10th Revision. War intensity was assessed by the ratio of war-caused civilian casualties to the pre-war population. The effect of prenatal exposure to war on schizophrenia was estimated by difference-in-difference models, established by examining the variation of war across birth cohorts. In the male population, war cohorts of 1937-1946 had no significant higher odds of schizophrenia compared with the pre-war cohorts of 1931-1936. In the female population, war cohorts were 1.16 (95% CI 1.01, 1.33) times more likely than pre-war cohorts to have schizophrenia. Sensitive analyses show that our estimates of war effect on schizophrenia were robust and valid. Prenatal exposure to the Sino-Japanese War of 1937-1945 had long-run detrimental effect on risk of schizophrenia in the female adults. Further investigations are warranted to extend the enduring wartime impact on other health outcomes in China.

Long-Term Effects of Oral Antidiabetic Drugs During Pregnancy on Offspring: A Systematic Review and Meta-analysis of Follow-up Studies of RCTs.

IntroductionAntidiabetic drugs (OADs) are increasingly prescribed to treat hyperglycaemia during pregnancy in women with gestational diabetes mellitus (GDM) or polycystic ovary syndrome (PCOS), even though long-term effects on offspring are unknown. This systematic review summarises the evidence of follow-up studies of randomised controlled trials (RCTs) reporting on long-term effects of prenatal exposure to OADs on offspring.MethodsThe MEDLINE, EMBASE and CENTRAL databases were searched from inception to April 2018 for the concepts antidiabetic agents and prenatal exposure (or pregnancy and offspring/child) in combination with an RCT search filter. RCTs evaluating post-neonatal health effects in offspring and comparing maternal treatment with an OAD with no treatment, placebo, an alternative OAD or insulin during pregnancy were eligible for inclusion. Two independent researchers selected, extracted and assessed the data. Meta-analyses were performed using a random effects model and the Cochrane Collaboration’s risk of bias tool was used for quality assessment.ResultsTen studies were included, with a maximal follow-up duration of 9 years, comprising 778 children of mothers with GDM or PCOS who were randomised to either metformin or insulin/placebo during pregnancy. Meta-analysis showed that children prenatally exposed to metformin were heavier compared to controls (standardised mean difference (SMD) 0.26 [95% CI 0.11–0.41]), but not taller (SMD 0.10 [95% CI −0.14–0.33]). Additionally, offspring body mass index (BMI) z scores did not differ according to metformin exposure (mean difference 0.30 [95% CI −0.01–0.61]). Individual small studies reported that prenatal exposure to metformin was associated with greater mid-upper arm, head and waist circumferences, biceps skinfolds, waist-to-height ratio, more arm fat, higher fasting glucose, ferritin and lower LDL cholesterol in offspring.ConclusionPrenatal exposure to metformin is associated with increased offspring weight, but not with height or BMI. Larger follow-up studies are needed to confirm and look into the implications of these findings.Plain Language SummaryPlain language summary available for this article.Electronic supplementary materialThe online version of this article (10.1007/s13300-018-0479-0) contains supplementary material, which is available to authorized users.

Long-term effect of prenatal exposure to malnutrition on risk of schizophrenia in adulthood: Evidence from the Chinese famine of 1959–1961

BackgroundSchizophrenia is a common major mental disorder and prenatal nutritional deficiency may increase its risk. We aimed to investigate long-term impact of prenatal exposure to malnutrition on risk of schizophrenia in adulthood using the Chinese famine of 1959–1961 as a natural experiment. MethodsWe obtained data from the Second National Sample Survey on Disability implemented in 31 provinces in 2006, and restricted our analysis to 387,093 individuals born from 1956 to 1965. Schizophrenia was ascertained by psychiatrists based on the International Statistical Classification of Diseases, Tenth Revision. Famine severity was defined as cohort size shrinkage index. The famine effect on adult schizophrenia was estimated by difference-in-difference models, established by examining the variations of famine exposure across birth cohorts. ResultsCompared with the reference cohort of 1965, famine cohorts (1959–1962) had significantly higher odds (OR: 1.84; 95% CI: 1.13, 3.00; P = 0.014) of schizophrenia in the rural population. After adjusting for multiple covariates, this association remained significant (OR: 1.82; 95% CI: 1.11, 2.98; P = 0.018). We did not observe statistically significant differences in odds of schizophrenia among famine cohorts compared with the reference cohort in the urban population. ConclusionsPrenatal malnutrition exposure has a detrimental impact on risk of schizophrenia in adulthood in the rural population. Further studies were needed to investigate corresponding mechanisms on this topic.