Prenatal exposure to phthalates and emotional/behavioral development in young children.

INTRODUCTION: Endocrine disrupting chemicals (EDCs) such as phthalates, found in our daily environment, are nowadays suggested to be associated with adverse outcomes. Prenatal exposure was found associated with neurodevelopmental complications such as behavioral difficulties in school age children. AIM: To explore the association between intrauterine exposure to phthalates and emotional/behavioral development of 24 months old toddlers. METHODS: Women were recruited at 11-18 weeks of gestation and provided spot urine samples, analyzed for phthalate metabolites (DEHP, DiNP, MBzBP). Offspring were examined at 24 months of age, using standard maternal report, regarding developmental and behavioral problems (CBCL, ASQ-3, HOME questionnaires) (N = 158). To explore the associations between metabolite levels and developmental outcomes, multivariate GLM analysis (General Linear Model) was used according to tertiles and developmental scores on each developmental outcome. RESULTS: Associations of Di-(2-ethylhexyl) phthalate (DEHP) maternal exposure with behavioral-developmental outcomes were found only in boys. Compared with boys with lower DEHP maternal exposure, boys with high DEHP maternal exposure had lower developmental score in personal social abilities in the ASQ-3 questionnaire (50.68 + 8.06 and 44.14 + 11.02, high and low DEHP, respectively, p = 0.03), and more internalizing problems (for example, emotionally reactive score in high and low DEHP: 53.77 + 7.41 and 50.50 + 1.19, respectively, p = 0.029; anxious or depressed score: 53.38 + 5.01 and 50.75 + 1.34, respectively, p = 0.009; and somatic complaints scores 64.03 + 10.1 and 55.84 + 7.84, respectively, p = 0.003), and externalizing problems (49.28 + 8.59 and 43.33 + 9.11, respectively, p = 0.039). No differences were found in the development and behavior problems between high and low DEHP maternal exposure level in girls. CONCLUSION: Maternal DEHP metabolite concentrations measured in first trimester urine was associated with children's emotional/behavioral developmental problems in 24-months old boys, supporting accumulating evidence of DEHP as a potentially harming chemical and call for environmental attention.

Prenatal SAMe Treatment Changes via Epigenetic Mechanism/s USVs in Young Mice and Hippocampal Monoamines Turnover at Adulthood in a Mouse Model of Social Hierarchy and Depression.

The role of hippocampal monoamines and their related genes in the etiology and pathogenesis of depression-like behavior, particularly in impaired sociability traits and the meaning of changes in USVs emitted by pups, remains unknown. We assessed the effects of prenatal administration of S-adenosyl-methionine (SAMe) in Sub mice that exhibit depressive-like behavior on serotonergic, dopaminergic and noradrenergic metabolism and the activity of related genes in the hippocampus (HPC) in adulthood in comparison to saline-treated control Sub mice. During postnatal days 4 and 8, we recorded and analyzed the stress-induced USVs emitted by the pups and tried to understand how the changes in the USVs' calls may be related to the changes in the monoamines and the activity of related genes. The recordings of the USVs showed that SAMe induced a reduction in the emitted flat and one-frequency step-up call numbers in PND4 pups, whereas step-down type calls were significantly increased by SAMe in PND8 pups. The reduction in the number of calls induced by SAMe following separation from the mothers implies a reduction in anxiety, which is an additional sign of decreased depressive-like behavior. Prenatal SAMe increased the concentrations of serotonin in the HPC in both male and female mice without any change in the levels of 5HIAA. It also decreased the level of the dopamine metabolite DOPAC in females. There were no changes in the levels of norepinephrine and metabolites. Several changes in the expression of genes associated with monoamine metabolism were also induced by prenatal SAMe. The molecular and biochemical data obtained from the HPC studies are generally in accordance with our previously obtained data from the prefrontal cortex of similarly treated Sub mice on postnatal day 90. The changes in both monoamines and their gene expression observed 2-3 months after SAMe treatment are associated with the previously recorded behavioral improvement and seem to demonstrate that SAMe is effective via an epigenetic mechanism.

Relationships of the gut microbiome with cognitive development among healthy school-age children.

Background: The gut microbiome might play a role in neurodevelopment, however, evidence remains elusive. We aimed to examine the relationship between the intestinal microbiome and cognitive development of school-age children. Methods: This cross-sectional study included healthy Israeli Arab children from different socioeconomic status (SES). The microbiome was characterized in fecal samples by implementing 16S rRNA gene sequencing. Cognitive function was measured using Stanford-Binet test, yielding full-scale Intelligence Quotient (FSIQ) score. Sociodemographics and anthropometric and hemoglobin measurements were obtained. Multivariate models were implemented to assess adjusted associations between the gut microbiome and FSIQ score, while controlling for age, sex, SES, physical growth, and hemoglobin levels. Results: Overall, 165 children (41.2% females) aged 6-9 years were enrolled. SES score was strongly related to both FSIQ score and the gut microbiome. Measures of α-diversity were significantly associated with FSIQ score, demonstrating a more diverse, even, and rich microbiome with increased FSIQ score. Significant differences in fecal bacterial composition were found; FSIQ score explained the highest variance in bacterial ß-diversity, followed by SES score. Several taxonomic differences were significantly associated with FSIQ score, including Prevotella, Dialister, Sutterella, Ruminococcus callidus, and Bacteroides uniformis. Conclusions: We demonstrated significant independent associations between the gut microbiome and cognitive development in school-age children.

Yolk sac development, function and role in rodent pregnancy.

During the early phases of embryonic development, the yolk sac serves as an initial placenta in many animal species. While in some, this role subsides around the end of active organogenesis, it continues to have important functions in rodents, alongside the chorio-allantoic placenta. The yolk sac is the initial site of hematopoiesis in many animal species including primates. Cells of epiblastic origin form blood islands that are the forerunners of hematopoietic cells and of the primitive endothelial cells that form the vitelline circulation. The yolk sac is also a major route of embryonic and fetal nutrition apparently as long as it functions. In mammals and especially rodents, macro and micronutrients are absorbed by active pinocytosis into the visceral yolk sac, degraded and the degradation products (i.e., amino acids) are then transferred to the embryo. Interference with the yolk sac function may directly reflect on embryonic growth and development, inducing congenital malformations or in extreme damage, causing embryonic and fetal death. In rodents, many agents were found to damage the yolk sac (i.e., anti-yolk sac antibodies or toxic substances interfering with yolk sac pinocytosis) subsequently affecting the embryo/fetus. Often, the damage to the yolk sac is transient while embryonic damage persists. In humans, decreased yolk sac diameter was associated with diabetic pregnancies and increased diameter was associated with pregnancy loss. In addition, culture of rat yolk sacs in serum obtained from pregnant diabetic women or from women with autoimmune diseases induced severe damage to the visceral yolk sac epithelium and embryonic malformations. It can be concluded that as a result of the crucial role of the yolk sac in the well-being of the early embryo, any damage to its normal function may severely and irreversibly affect further development of the embryo/fetus.

Sex-Related Changes in the Clinical, Genetic, Electrophysiological, Connectivity, and Molecular Presentations of ASD: A Comparison between Human and Animal Models of ASD with Reference to Our Data.

The etiology of autism spectrum disorder (ASD) is genetic, environmental, and epigenetic. In addition to sex differences in the prevalence of ASD, which is 3-4 times more common in males, there are also distinct clinical, molecular, electrophysiological, and pathophysiological differences between sexes. In human, males with ASD have more externalizing problems (i.e., attention-deficit hyperactivity disorder), more severe communication and social problems, as well as repetitive movements. Females with ASD generally exhibit fewer severe communication problems, less repetitive and stereotyped behavior, but more internalizing problems, such as depression and anxiety. Females need a higher load of genetic changes related to ASD compared to males. There are also sex differences in brain structure, connectivity, and electrophysiology. Genetic or non-genetic experimental animal models of ASD-like behavior, when studied for sex differences, showed some neurobehavioral and electrophysiological differences between male and female animals depending on the specific model. We previously carried out studies on behavioral and molecular differences between male and female mice treated with valproic acid, either prenatally or early postnatally, that exhibited ASD-like behavior and found distinct differences between the sexes, the female mice performing better on tests measuring social interaction and undergoing changes in the expression of more genes in the brain compared to males. Interestingly, co-administration of S-adenosylmethionine alleviated the ASD-like behavioral symptoms and the gene-expression changes to the same extent in both sexes. The mechanisms underlying the sex differences are not yet fully understood.

Associations of early-life exposures and socioeconomic status with cognitive development at preadolescence.

BACKGROUND: The long-term relations of socioeconomic status (SES) and early-life exposures with cognitive development at preadolescence are not fully understood, especially in low SES populations. We examined associations of SES and early-life exposures including feeding practices, physical growth and infections with cognitive development among preadolescents from underprivileged communities. METHODS: A prospective study was conducted among 146 healthy children from two relatively low SES Arab villages in Israel, who were recruited at age 1-9 weeks and followed until age 18 months. Information was obtained on their feeding practices, health status and growth indicators. Cognitive development at age 10-12 years was assessed using the Wechsler Intelligence Scale, including the full-scale intelligence quotient (FSIQ) and scores of four cognitive domains. Multiple linear regression models were performed. RESULTS: Nearly all the children (98%) were breastfed in infancy. Bivariate correlations were found of SES, growth indices and rates of diarrheal and respiratory illnesses in infancy, but not of feeding practices, with cognitive scores. In multivariable models, SES was positively (p < 0.001) associated with all the cognitive domains (beta coefficient ranges 4.3 to 8.2). Birthweight was positively associated with FSIQ (p = 0.039) and the perceptual reasoning index (p = 0.002). Weight for age Z score at age 10-14 months was positively associated with the verbal comprehension index (p = 0.003). The rate of respiratory illnesses was negatively associated with the perceptual reasoning index (p = 0.05). CONCLUSION: SES is strongly associated with cognitive development even in relatively low SES communities. Birthweight, weight indicators and respiratory illness in infancy might affect cognitive development through preadolescence.

Valproic Acid in Pregnancy Revisited: Neurobehavioral, Biochemical and Molecular Changes Affecting the Embryo and Fetus in Humans and in Animals: A Narrative Review.

Valproic acid (VPA) is a very effective anticonvulsant and mood stabilizer with relatively few side effects. Being an epigenetic modulator, it undergoes clinical trials for the treatment of advanced prostatic and breast cancer. However, in pregnancy, it seems to be the most teratogenic antiepileptic drug. Among the proven effects are congenital malformations in about 10%. The more common congenital malformations are neural tube defects, cardiac anomalies, urogenital malformations including hypospadias, skeletal malformations and orofacial clefts. These effects are dose related; daily doses below 600 mg have a limited teratogenic potential. VPA, when added to other anti-seizure medications, increases the malformations rate. It induces malformations even when taken for indications other than epilepsy, adding to the data that epilepsy is not responsible for the teratogenic effects. VPA increases the rate of neurodevelopmental problems causing reduced cognitive abilities and language impairment. It also increases the prevalence of specific neurodevelopmental syndromes like autism (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). High doses of folic acid administered prior to and during pregnancy might alleviate some of the teratogenic effect of VPA and other AEDs. Several teratogenic mechanisms are proposed for VPA, but the most important mechanisms seem to be its effects on the metabolism of folate, SAMe and histones, thus affecting DNA methylation. VPA crosses the human placenta and was found at higher concentrations in fetal blood. Its concentrations in milk are low, therefore nursing is permitted. Animal studies generally recapitulate human data.

Comparison between School-Age Children with and without Obesity in Nutritional and Inflammation Biomarkers.

Childhood obesity is a major health problem. We examined differences between children with obesity and normal weight in nutritional and inflammation biomarkers. A cross-sectional study was conducted among healthy children aged 10-12 years from Arab villages in Israel. Parents were interviewed regarding sociodemographic and children's health status. Body weight and height measurements were performed and weight categories were defined using the 2007 WHO growth curves. Blood samples were tested for complete blood count, levels of iron, ferritin, lipids, uric acid, and C-reactive protein (CRP). Overall, 146 children (59.0% males, mean age = 11.3 [SD = 0.5]) were enrolled. In total 43.8%, 14.1% and 42.3% of the participants had normal weight, overweight and obesity, respectively. A multivariable logistic regression model showed that children with overweight and obesity had lower iron, and HDL-C levels than children with normal weight. Levels of CRP, uric acid, LDL-C and lymphocytes were higher among children with overweight and obesity. In conclusion, our findings highlight the worse metabolic and nutritional status in overweight and obese children. Such markers play a role in metabolic syndrome, thus suggesting that metabolic syndrome might start in childhood.

Prenatal SAMe Treatment Induces Changes in Brain Monoamines and in the Expression of Genes Related to Monoamine Metabolism in a Mouse Model of Social Hierarchy and Depression, Probably via an Epigenetic Mechanism.

Reduction in the levels of monoamines, such as serotonin and dopamine in the brain, were reported in patients and animals with depression. SAMe, a universal methyl donor and an epigenetic modulator, is successfully used as an adjunct treatment of depression. We previously found that prenatal treatment with SAMe of Submissive (Sub) mice that serve as a model for depression alleviated many of the behavioral depressive symptoms. In the present study, we treated pregnant Sub mice with 20 mg/kg of SAMe on days 12-15 of gestation and studied the levels of monoamines and the expression of genes related to monoamines metabolism in their prefrontal cortex (PFC) at the age of 3 months. The data were compared to normal saline-treated Sub mice that exhibit depressive-like symptoms. SAMe increased the levels of serotonin in the PFC of female Sub mice but not in males. The levels of 5-HIAA were not changed. SAMe increased the levels of dopamine and of DOPAC in males and females but increased the levels of HVA only in females. The levels of norepinephrine and its metabolite MHPG were unchanged. SAMe treatment changed the expression of several genes involved in the metabolism of these monoamines, also in a sex-related manner. The increase in several monoamines induced by SAMe in the PFC may explain the alleviation of depressive-like symptoms. Moreover, these changes in gene expression more than 3 months after treatment probably reflect the beneficial effects of SAMe as an epigenetic modulator in the treatment of depression.

S-Adenosyl-Methionine alleviates sociability aversion and reduces changes in gene expression in a mouse model of social hierarchy.

Epigenetic changes are an important pathogenic mechanism in many diseases, including a variety of psychiatric disorders such as Autism Spectrum Disorder (ASD) and depression. Methyl donors such as S-Adenosyl-Methionine (SAMe) may cause epigenetic modifications, especially during embryonic development when the epigenetic memory is established. We treated pregnant submissive (Sub) mice exhibiting depressive-like phenotype with SAMe during days 12-14 of gestation aiming to alleviate the depressive - like symptoms in their offspring and normalize the expression in their prefrontal cortex of several genes possibly involved in depression. We also aimed to define possible gender differences of the effects of SAMe on the measured parameters. Treatment of the Dams with SAMe did not affect the early neurodevelopmental milestones in males or females. The results of the behavioral tests showed improvement in some behavioral parameters compared to saline treated Sub mice. Several of these improvements were gender related. Prenatal SAMe treatment mainly improved sociability, as observed in the three chambers social interaction test, in both genders. It also improved the increased locomotion (as observed by the open field test) in the female mice, but not in males. Prenatal SAMe increased the expression of Vegfa and Flt1 in males, but not in females. The expression of IgfII and SynIIb increased in males and decreased in females and the expression of serotonin receptor Htr2A did not change in both genders. In our mouse model of depression, prenatal treatment with SAMe significantly improved some parameters of depressive like behavior and normalized the expression of several genes related to depression. The gender differences observed in our studies may explain the sex related differences in the clinical presentation of depression and the different gender related response to treatment.

SAMe, Choline, and Valproic Acid as Possible Epigenetic Drugs: Their Effects in Pregnancy with a Special Emphasis on Animal Studies.

In this review, we discuss the functions and main effects on pregnancy outcomes of three agents that have the ability to induce epigenetic modifications: valproic acid (VPA), a well-known teratogen that is a histone deacetylase inhibitor; S-adenosylmethionine (SAMe), the most effective methyl donor; and choline, an important micronutrient involved in the one methyl group cycle and in the synthesis of SAMe. Our aim was to describe the possible effects of these compounds when administered during pregnancy on the developing embryo and fetus or, if administered postnatally, their effects on the developing child. These substances are able to modify gene expression and possibly alleviate neurobehavioral changes in disturbances that have epigenetic origins, such as autism spectrum disorder (ASD), depression, Rett syndrome, and fetal alcohol spectrum disorder (FASD). Valproic acid and SAMe are antagonistic epigenetic modulators whether administered in utero or postnatally. However, VPA is a major human teratogen and, whenever possible, should not be used by pregnant women. Most currently relevant data come from experimental animal studies that aimed to explore the possibility of using these substances as epigenetic modifiers and possible therapeutic agents. In experimental animals, each of these substances was able to alleviate the severity of several well-known diseases by inducing changes in the expression of affected genes or by other yet unknown mechanisms. We believe that additional studies are needed to further explore the possibility of using these substances, and similar compounds, for the treatment of "epigenetic human diseases".

Participation of soldiers with DCD in the military.

Developmental coordination disorder (DCD) is a disorder affecting motor coordination which negatively impacts academic and daily activities in various environments. The military is a highly structured environment with limited freedom, placing high demand on motor coordination, organizational ability, time management, and social skills. All these present challenges to young adults with DCD. Our study aimed to describe and assess the functioning of young adults with DCD in the Israel Defense Forces. Participants included three groups of young adults recruited via the Israel Army Health Survey upon discharge from active service: probable DCD (135), suspected borderline DCD (149), and control (145). Participants completed the Adolescents & Adults Coordination Questionnaire and the Army Questionnaire. The probable-DCD group reported significantly more difficulties in their military service than did the other groups: more unit reassignments, more accidents during field operations, and more complaints related to discipline and professional behavior. Significant differences emerged between both DCD groups and the control group in "understanding of learning materials," "forgetting belongings," and "success in the army." The participants with probable DCD and suspected borderline DCD were able to integrate into the army, but the probable-DCD group performed significantly worse than the others and reported more difficulties participating in the army. These results highlight the importance of being aware of soldiers with probable DCD, in order to assign them duties that fit their abilities.

The Associations between Diet and Socioeconomic Disparities and the Intestinal Microbiome in Preadolescence.

The intestinal microbiome continues to shift and develop throughout youth and could play a pivotal role in health and wellbeing throughout adulthood. Environmental and interpersonal determinants are strong mediators of the intestinal microbiome during the rapid growth period of preadolescence. We aim to delineate associations between the gut microbiome composition, body mass index (BMI), dietary intake and socioeconomic status (SES) in a cohort of ethnically homogenous preadolescents. This cohort included 139 Arab children aged 10-12 years, from varying socioeconomic strata. Dietary intake was assessed using the 24-h recall method. The intestinal microbiome was analyzed using 16S rRNA gene amplicon sequencing. Microbial composition was associated with SES, showing an overrepresentation of Prevotella and Eubacterium in children with lower SES. Higher BMI was associated with lower microbial diversity and altered taxonomic composition, including higher levels of Collinsella, especially among participants from lower SES. Intake of polyunsaturated fatty acids was the strongest predictor of bacterial alterations, including an independent association with Lachnobacterium and Lactobacillus. This study demonstrates that the intestinal microbiome in preadolescents is associated with socioeconomic determinants, BMI and dietary intake, specifically with higher consumption of polyunsaturated fatty acids. Thus, tailored interventions during these crucial years have the potential to improve health disparities throughout the lifespan.

Associations of Feeding Practices in Early Life and Dietary Intake at School Age with Obesity in 10- to 12-Year-Old Arab Children.

Understanding the role in pediatric obesity of early life feeding practices and dietary intake at school age is essential for early prevention. The study aimed to examine associations of early life feeding practices, environmental and health-related exposures, and dietary intake at school age as determinants of obesity in children aged 10-12 years. In an earlier study of 233 healthy infants in two Arab towns in northern Israel, neonatal history, feeding practices, and health information were obtained up to age 18 months. This follow-up study assessed dietary intake and anthropometric measurements at age 10-12 years using the 24 h recall method. Overall, 174 children participated in this study. Almost all (98%) the children were breastfed. The prevalence of obesity at school age was 42%. A multivariable model adjusted for energy intake and socioeconomic status showed positive associations of total fat intake and of weight-for-height z score, but not feeding practices in infancy, with obesity. Higher gestational age at birth was associated with lower odds of obesity at age 10-12 years. In conclusion, in a population with near universal breastfeeding, gestational age at birth, weight indicators but not feeding practices in infancy, and total fat intake at school age were associated with increased likelihood of obesity.

Paternal and/or maternal preconception-induced neurobehavioral teratogenicity in animal and human models.

Prenatal insult exposure effects on the offspring, have and are still considered the main interest of most teratological studies, while paternal and maternal preconception effects have received relatively little interest. Once thought to be a myth, paternal exposure to insults leading to numerous detrimental effects in the offspring, has been confirmed on several occasions and is gaining increased attention. These effects could be demonstrated molecularly, biochemically and/or behaviorally. Different epigenetic mechanisms have been proposed for these effects to occur, including DNA methylation, histone modification and sperm RNA transmission. Paternal insult exposure has been shown to cause several neurobehavioral and developmental defects in the offspring. Findings on parental insult exposure effects on the progeny will be discussed in this review, with the main focus being on neurobehavioral effects after parental preconceptional exposure. The exposure to the insults induced long-lasting, mostly marked, defects. A few pioneering, prevention and reversal studies were published. Interestingly, most studies were conducted on paternal exposure and, at the present state of this field, on animal models. Clinical translation remains the subsequent challenge.

Diabetes during Pregnancy: A Maternal Disease Complicating the Course of Pregnancy with Long-Term Deleterious Effects on the Offspring. A Clinical Review.

In spite of the huge progress in the treatment of diabetes mellitus, we are still in the situation that both pregestational (PGDM) and gestational diabetes (GDM) impose an additional risk to the embryo, fetus, and course of pregnancy. PGDM may increase the rate of congenital malformations, especially cardiac, nervous system, musculoskeletal system, and limbs. PGDM may interfere with fetal growth, often causing macrosomia, but in the presence of severe maternal complications, especially nephropathy, it may inhibit fetal growth. PGDM may also induce a variety of perinatal complications such as stillbirth and perinatal death, cardiomyopathy, respiratory morbidity, and perinatal asphyxia. GDM that generally develops in the second half of pregnancy induces similar but generally less severe complications. Their severity is higher with earlier onset of GDM and inversely correlated with the degree of glycemic control. Early initiation of GDM might even cause some increase in the rate of congenital malformations. Both PGDM and GDM may cause various motor and behavioral neurodevelopmental problems, including an increased incidence of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Most complications are reduced in incidence and severity with the improvement in diabetic control. Mechanisms of diabetic-induced damage in pregnancy are related to maternal and fetal hyperglycemia, enhanced oxidative stress, epigenetic changes, and other, less defined, pathogenic mechanisms.

Institutionalized Children and the Risk of Fetal Alcohol Spectrum Disorder (FASD); A Primer for Clinicians, Adoption Staff and Parents.

OBJECTIVES: Our objective was to estimate the likelihood of abnormal development among institutionalized children, addressing either the risk in general, or the risk for fetal alcohol spectrum disorder (FASD). METHODS: Narrative review of studies measuring developmental effects of these populations. We identified all systematic reviews and meta analyses dealing with the associations between institutionalization of children and their neurodevelopment in general, or between institunalization of children and their likelihood of suffering from FASD. RESULTS: a) In a published meta-analysis the mean IQ/DQ was 84 among institutionalized children, as compared to 104 among children raised in families. Favorable caregiver-child ratios appeared to have a protective effect, whereas longer stays in institutions had a detrimental effect on IQ/DQ.b) A further meta- analysis has shown a positive impact of adoption on children's cognitive development with adopted children's displaying remarkably normal cognitive competence as compared to their non-adopted peers.c) The overall pooled prevalence was 6% (60 per 1,000, 95% CI 38-85) for full blown fetal alcohol syndrome (FAS), and 16.9% (95% CI 109-238 per 1,000) for the whole range of FASD.d) The estimated prevalence of FASD was 10-40 fold higher than the 7.7 per 1000 in the general population. CONCLUSIONS: A large proportion of adopted institutionalized children may not follow a normal developmental trajectory. If not afflicted by FASD, there is a positive impact of adoption on children's cognitive development and in general they are comparable to their non- adopted peers.

Animal Models of Depression: What Can They Teach Us about the Human Disease?

Depression is apparently the most common psychiatric disease among the mood disorders affecting about 10% of the adult population. The etiology and pathogenesis of depression are still poorly understood. Hence, as for most human diseases, animal models can help us understand the pathogenesis of depression and, more importantly, may facilitate the search for therapy. In this review we first describe the more common tests used for the evaluation of depressive-like symptoms in rodents. Then we describe different models of depression and discuss their strengths and weaknesses. These models can be divided into several categories: genetic models, models induced by mental acute and chronic stressful situations caused by environmental manipulations (i.e., learned helplessness in rats/mice), models induced by changes in brain neuro-transmitters or by specific brain injuries and models induced by pharmacological tools. In spite of the fact that none of the models completely resembles human depression, most animal models are relevant since they mimic many of the features observed in the human situation and may serve as a powerful tool for the study of the etiology, pathogenesis and treatment of depression, especially since only few patients respond to acute treatment. Relevance increases by the fact that human depression also has different facets and many possible etiologies and therapies.

Gestational Exposure to Serotonin Reuptake Inhibitors and Pregnancy Outcome; Exploring the Role of Bias and Confounders.

There is no other example in human teratology where, after more than 40 epidemiological studies, repeated meta-analyses and thousands of pregnancies, the fetal safety or risk of an agent has not been verified and settled. The objectives of the present review were to identify and discuss sources of bias that may lead clinicians and scientists to believe that SRIs cause malformation or other adverse outcomes, where, in fact, they may not. The present study highlights sources of bias that may explain why children exposed in utero to SRI exhibit higher rates of congenital malformations, mostly cardiovascular and other complications. It appears that pregnant women treated for depression and anxiety are distinctively different from healthy women in numerous covariates, which may confound pregnancy outcomes. Acknowledging and adjusting for these sources of bias are critical before one selects to withhold therapy for moderate or severe cases of depression and anxiety in pregnancy.