Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression.

OBJECTIVE: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD. METHOD: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)-based heritability ([Formula: see text]), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system. RESULTS: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The [Formula: see text] of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD. CONCLUSIONS: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone).

Depression and anxiety disorders during the postpartum period in women diagnosed with attention deficit hyperactivity disorder.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is associated with an increased risk of poor mental health. However, the understanding of ADHD-related burden and impairments in women during the postpartum period is limited. The aim with the present study was to examine the risk of depression and anxiety disorders during the postpartum period among women with and without an ADHD diagnosis. METHODS: We used register-based data to identify women who gave birth to their first and/or second child between 2005 and 2013 in Sweden (n = 773,047), of which 0.5 % (n = 3515) had a diagnosis of ADHD prior to pregnancy. Diagnoses of depression and anxiety disorders up to one year after delivery were collected from the national patient register. RESULTS: A total of 16.76 % of the women with an ADHD diagnosis were also diagnosed with depression disorders in the postpartum period, prevalence ratio (PR) 5.09 (95 % confidence interval (CI), 4.68-5.54). A total of 24.92 % of the women with an ADHD diagnosis were also diagnosed with anxiety disorders in the postpartum period, PR 5.41 (5.06-5.78). Stratified results revealed that having a diagnosis of ADHD increased the risk for both depression and anxiety disorders postpartum, beyond other well-known risk factors. LIMITATIONS: There is a potential risk of surveillance bias as women diagnosed with ADHD are more likely to have repeated visits to psychiatric care and might have an enhanced likelihood of also being diagnosed with depression and anxiety disorders postpartum, compared to women without ADHD. CONCLUSIONS: ADHD is an important risk factor for both depression and anxiety disorders postpartum. Therefore, ADHD needs to be considered in the maternal care, regardless of sociodemographic factors and the presence of other psychiatric disorders.

Effect of CYP2C19 polymorphisms on antidepressant prescription patterns and treatment emergent mania in bipolar disorder.

Antidepressant medication is used extensively to treat bipolar depression despite uncertain efficacy. The cytochrome P450 (CYP) 2C19 enzyme metabolize several antidepressants, and polymorphisms in the corresponding gene CYP2C19 influence plasma concentration and hence treatment outcomes in major depressive disorder. Here, we investigate if CYP2C19 polymorphisms are associated with antidepressant treatment patterns and the risk of mania when antidepressants are used in bipolar disorder. Two single nucleotide polymorphisms (rs4244285 and rs12248560) were used to classify 5019 bipolar disorder patients into CYP2C19 metabolic phenotypes ranging from poor to ultra-rapid metabolizers. We used Swedish national registry data 2005-2017 on dispensed medications and inpatient care to estimate risks for early-treatment persistence, treatment discontinuation, switching to a new antidepressant medication, and mania within 3 months of treatment initiation in patients treated with citalopram, escitalopram, sertraline, amitriptyline, and clomipramine. Metabolic phenotypes of CYP2C19 were not robustly associated with the investigated treatment outcomes based on dispense patterns. Slower metabolism was associated with an increased risk of treatment emergent mania for sertraline (hazard ratio [HR] = 1.3, 95% CI = 1.04-1.62, p = 0.02) and the tricyclic antidepressants amitriptyline and clomipramine (HR = 1.46, 95% CI = 1.05-2.02, p = 0.024). In a large study of the impact of CYP2C19 metabolic phenotypes on antidepressant treatment of bipolar depression, we found an association between slower CYP2C19 metabolism and higher risk of treatment emergent mania, which is a step towards personalized risk assessments. There were, however, no clear associations with early treatment persistence, treatment discontinuation, and switching to a new antidepressant.

Heritability of nervous system tumors: a sibling-based design.

Background: The contribution of genetic and environmental factors to susceptibility to nervous system tumors remains unclear. We performed a quantitative genetic study using a sibling design to estimate the heritability of nervous system tumors, as well as the proportion of the risk of these tumors, which is attributable to environmental factors. Methods: We conducted a population-based cohort study using Swedish National Register data. All individuals born in Sweden during 1950-2010 with available information on both biological parents were included. A Multi-Generation Register was used to identify family clusters, including both full- and half-siblings. Initially, one index person was randomly selected from each cluster containing only full siblings and one sibling was randomly assigned to this index person. Subsequently, within each of the remaining clusters of full- and half-siblings, an index person was randomly selected, and a half-sibling was randomly assigned to this index person. Among the randomly selected siblings, cases of nervous system tumors were identified using the cancer registry. Quantitative genetic models were used to estimate the proportion of the variance in nervous system tumors attributable to additive genetic factors, shared environment, and individual-specific environment. Results: The heritability of nervous system tumors was estimated to be 29% (95% confidence interval (CI) = 19%-39%), while the contribution of the non-shared environment to the variance of nervous system tumors was estimated to be 71% (95% CI = 61%-81%). The shared environmental parameter was estimated as zero in the full model. Conclusion: The variation in susceptibility to nervous system tumors is predominantly attributable to non-shared environmental factors, followed by genetic factors.

Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits.

Immunoglobulin A (IgA) mediates mucosal responses to food antigens and the intestinal microbiome and is involved in susceptibility to mucosal pathogens, celiac disease, inflammatory bowel disease, and IgA nephropathy. We performed a genome-wide association study of serum IgA levels in 41,263 individuals of diverse ancestries and identified 20 genome-wide significant loci, including 9 known and 11 novel loci. Co-localization analyses with expression QTLs prioritized candidate genes for 14 of 20 significant loci. Most loci encoded genes that produced immune defects and IgA abnormalities when genetically manipulated in mice. We also observed positive genetic correlations of serum IgA levels with IgA nephropathy, type 2 diabetes, and body mass index, and negative correlations with celiac disease, inflammatory bowel disease, and several infections. Mendelian randomization supported elevated serum IgA as a causal factor in IgA nephropathy. African ancestry was consistently associated with higher serum IgA levels and greater frequency of IgA-increasing alleles compared to other ancestries. Our findings provide novel insights into the genetic regulation of IgA levels and its potential role in human disease.

Clinical indications of premenstrual disorders and subsequent risk of injury: a population-based cohort study in Sweden.

BACKGROUND: Premenstrual disorders, including premenstrual syndrome and premenstrual dysphoric disorder, are suggested to be correlated with suicidal behavior and accidents in cross-sectional and retrospective studies. However, prospective data are still lacking. METHODS: We performed a population-based cohort study including 1,472,379 Swedish women of reproductive age who were followed from 2001 to 2012. Within the cohort, we also performed a sibling analysis where we compared the rates of injury between full sisters. By linking to the Patient and the Prescribed Drug Registers, we identified 18,628 women with any clinical indications for premenstrual disorders in the cohort (population analysis) and 7674 women in the sibling analysis. Any injury, primarily suicidal behavior (completed suicide and suicide attempt) or accidents (e.g., fall and transportation accidents), was identified through the Patient and Causes of Death Registers as the primary outcome. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) of these outcomes among women with premenstrual disorders in both population and sibling analyses using multivariable Cox proportional hazards regression. RESULTS: During a maximal follow-up of 12 years (mean 9.55 years), we identified 2390 women with premenstrual disorders with any injury; 216 through suicidal behavior and 2191 through accidents. Compared to women without premenstrual disorders, women with premenstrual disorders were at increased risk of any injury (HR 1.37, 95% CI 1.31-1.42), particularly suicidal behavior (HR 2.26, 95% CI 1.97-2.59) and accidents (HR 1.32, 95% CI 1.27-1.38). Such associations somewhat attenuated yet remained significant in the sibling analysis (HRs: 1.31 for any injury, 1.86 for suicidal behavior, and 1.29 for accidents). Additional adjustment for psychiatric comorbidities minimally altered the associations with any injury and accidents in both population and sibling analyses, whereas the association with suicidal behavior was considerably attenuated to non-significance in the sibling analysis. Such risks were particularly strong within 2 years after receiving the diagnosis of premenstrual disorders and were evident among women with premenstrual disorders with and without psychiatric comorbidities. CONCLUSIONS: Our findings suggest that women with a clinical indication of premenstrual disorders are at increased subsequent risk of injury, particularly accidents within the first 2 years after diagnosis.

Prediction of treatment dosage and duration from free-text prescriptions: an application to ADHD medications in the Swedish prescribed drug register.

BACKGROUND: Accurate estimation of daily dosage and duration of medication use is essential to pharmacoepidemiological studies using electronic healthcare databases. However, such information is not directly available in many prescription databases, including the Swedish Prescribed Drug Register. OBJECTIVE: To develop and validate an algorithm for predicting prescribed daily dosage and treatment duration from free-text prescriptions, and apply the algorithm to ADHD medication prescriptions. METHODS: We developed an algorithm to predict daily dosage from free-text prescriptions using 8000 ADHD medication prescriptions as the training sample, and estimated treatment periods while taking into account several features including titration, stockpiling and non-perfect adherence. The algorithm was implemented to all ADHD medication prescriptions from the Swedish Prescribed Drug Register in 2013. A validation sample of 1000 ADHD medication prescriptions, independent of the training sample, was used to assess the accuracy for predicted daily dosage. FINDINGS: In the validation sample, the overall accuracy for predicting daily dosage was 96.8%. Specifically, the natural language processing model (NLP1 and NLP2) have an accuracy of 99.2% and 96.3%, respectively. In an application to ADHD medication prescriptions in 2013, young adult ADHD medication users had the highest probability of discontinuing treatments as compared with other age groups. The daily dose of methylphenidate use increased with age substantially. CONCLUSIONS: The algorithm provides a flexible approach to estimate prescribed daily dosage and treatment duration from free-text prescriptions using register data. The algorithm showed a good performance for predicting daily dosage in external validation. CLINICAL IMPLICATIONS: The structured output of the algorithm could serve as basis for future pharmacoepidemiological studies evaluating utilization, effectiveness, and safety of medication use, which would facilitate evidence-based treatment decision-making.

Associations of Prescribed ADHD Medication in Pregnancy with Pregnancy-Related and Offspring Outcomes: A Systematic Review.

BACKGROUND: Increasing numbers of reproductive-aged women are using attention-deficit/hyperactivity disorder (ADHD) medications. Findings from studies exploring the safety of these medications during pregnancy are mixed, and it is unclear whether associations reflect causal effects or could be partially or fully explained by other factors that differ between exposed and unexposed offspring. OBJECTIVES: The aim of this systematic review was to evaluate the adverse pregnancy-related and offspring outcomes associated with exposure to prescribed ADHD medication during pregnancy with a focus on how studies to date have handled the influence of confounding. METHODS: We searched PubMed, Embase, PsycINFO, and Web of Science up to 1 July 2019 without any restrictions on language or date of publication. We included all observational studies (e.g., cohort studies, case-control studies, case-crossover studies, cross-sectional studies, and registry-based studies) with pregnant women of any age or from any setting who were prescribed ADHD medications and evaluated any outcome, including both short- and long-term maternal and offspring outcomes. Two independent authors then used the Newcastle-Ottawa Scale to rate the quality of the included studies. RESULTS: Eight cohort studies that estimated adverse pregnancy-related and offspring outcomes associated with exposure to ADHD medication during pregnancy were included in the qualitative review. The included studies had substantial methodological differences in data sources, type of medications examined, definitions of studied pregnancy-related and offspring outcomes, types of control groups, and confounding adjustment. There was no convincing evidence for teratogenic effects according to the relative risk of pregnancy-related and offspring outcomes, and the observed differences in absolute risks were overall small in magnitude. Adjustment for confounding was inadequate in most studies, and none of the included studies adjusted for ADHD severity in the mothers. CONCLUSION: The current evidence does not suggest that the use of ADHD medication during pregnancy results in significant adverse consequences for mother or offspring. However, the data are too limited to make an unequivocal recommendation. Therefore, physicians should consider whether the advantages of using ADHD medication outweigh the potential risks for the developing fetus according to each woman's specific circumstances. Future research should attempt to triangulate research findings based on a combination of different designs that differ in their underlying strengths and limitations and should investigate specific confounding factors, the potential impact of timing of exposure, and potential long-term outcomes in the offspring.

Minimal phenotyping yields genome-wide association signals of low specificity for major depression.

Minimal phenotyping refers to the reliance on the use of a small number of self-reported items for disease case identification, increasingly used in genome-wide association studies (GWAS). Here we report differences in genetic architecture between depression defined by minimal phenotyping and strictly defined major depressive disorder (MDD): the former has a lower genotype-derived heritability that cannot be explained by inclusion of milder cases and a higher proportion of the genome contributing to this shared genetic liability with other conditions than for strictly defined MDD. GWAS based on minimal phenotyping definitions preferentially identifies loci that are not specific to MDD, and, although it generates highly predictive polygenic risk scores, the predictive power can be explained entirely by large sample sizes rather than by specificity for MDD. Our results show that reliance on results from minimal phenotyping may bias views of the genetic architecture of MDD and impede the ability to identify pathways specific to MDD.

Methylphenidate and the risk of psychosis in adolescents and young adults: a population-based cohort study.

BACKGROUND: There is a clinical concern that prescribing methylphenidate, the most common pharmacological treatment for attention-deficit hyperactivity disorder (ADHD), might increase the risk of psychotic events, particularly in young people with a history of psychosis. We aimed to determine whether the risk of psychotic events increases immediately after initiation of methylphenidate treatment or, in the longer term, 1 year after treatment initiation in adolescents and young adults with and without a previously diagnosed psychotic disorder. METHODS: In this cohort study, we used population-based observational data from the Swedish Prescribed Drug Register, the National Patient Register, and the Total Population Register, three population-based registers containing data on all individuals in Sweden, to attain data on sex, birth, death, migration, medication use, and psychotic events for all eligible participants. We screened individuals on these registers to identify those receiving methylphenidate treatment, and who were aged 12-30 years at the start of treatment, for their inclusion in the study. We used a within-individual design to compare the incidence of psychotic events in these individuals during the 12-week periods immediately before and after methylphenidate initiation. Longer term risk was assessed by comparing the incidence of psychotic events 12 weeks before methylphenidate initiation and during a 12-week period one calendar year before the initiation of methylphenidate with the incidence of these events during the 12-week period one calendar year after methylphenidate initiation. We estimated the incidence rate ratios (IRR) and 95% CIs of psychotic events after the initation of methylphenidate treatment, relative to the events before treatment, which were defined as any hospital visit (inpatient admission or outpatient attendance, based on data from the National Patient Register) because of psychosis, using the International Classification of Diseases version 10 definition. Analyses were stratified by whether the individual had a history of psychosis. FINDINGS: We searched the Swedish Prescribed Drug Register to find eligible individuals who had received methylphenidate between Jan 1, 2007 and June 30, 2012. 61 814 individuals were screened, of whom 23 898 (38·7%) individuals were assessed and 37 916 (61·3%) were excluded from the study because they were outside of the age criteria at the start of treatment, they had immigrated, emigrated, or died during the study period, or because they were administered other ADHD medications. The median age at methylphenidate initiation was 17 years, and a history of psychosis was reported in 479 (2·0%) participants. The IRR of psychotic events in the 12-week period after initiation of methylphenidate treatment relative to that in the 12-week period before treatment start was 1·04 (95% CI 0·80-1·34) in adolescents and young adults without a history of psychosis and 0·95 (0·69-1·30) among those with a history of psychosis. INTERPRETATION: Contrary to clinical concerns, we found no evidence that initiation of methylphenidate treatment increases the risk of psychotic events in adolescents and young adults, including in those individuals with a history of psychosis. Our study should reassure clinicians considering initiating methylphenidate treatment for ADHD in adolescents and young adults, and it challenges the widely held view in clinical practice that methylphenidate should be avoided, or its use restricted, in individuals with a history of psychosis. FUNDING: Swedish Research Council, National Institute of Mental Health, UK National Institute of Health Research Nottingham Biomedical Research Centre.

Association of Autism Spectrum Disorder With Prenatal Exposure to Medication Affecting Neurotransmitter Systems.

Importance: Prenatal exposure to certain medications has been hypothesized to influence the risk of autism spectrum disorders (ASD). However, the underlying effects on the neurotransmitter systems have not been comprehensively assessed. Objective: To investigate the association of early-life interference with different neurotransmitter systems by prenatal medication exposure on the risk of ASD in offspring. Design, Setting, and Participants: This case-control study included children born from January 1, 1997, through December 31, 2007, and followed up for ASD until January 26, 2015, within a single Israeli health maintenance organization. Using publicly available data, 55 groups of medications affecting neurotransmitter systems and prescribed to pregnant women in this sample were identified. Children prenatally exposed to medications were compared with nonexposed children. Data were analyzed from March 1, 2017, through June 20, 2018. Main Outcome and Measures: Hazard ratios (HRs) and 95% CIs of ASD risk associated with exposure to medication groups using Cox proportional hazards regression, adjusted for the relevant confounders (eg, birth year, maternal age, maternal history of psychiatric and neurologic disorders, or maternal number of all medical diagnoses 1 year before pregnancy). Results: The analytic sample consisted of 96 249 individuals (1405 cases; 94 844 controls; mean [SD] age at the end of follow-up, 11.6 [3.1] years; 48.8% female), including 1405 with ASD and 94 844 controls. Of 34 groups of medications, 5 showed nominally statistically significant association with ASD in fully adjusted models. Evidence of confounding effects of the number of maternal diagnoses on the association between offspring exposure to medication and ASD was found. Adjusting for this factor, lower estimates of ASD risk among children exposed to cannabinoid receptor agonists (HR, 0.72; 95% CI, 0.55-0.95; P = .02), muscarinic receptor 2 agonists (HR, 0.49; 95% CI, 0.24-0.98; P = .04), opioid receptor κ and ε agonists (HR, 0.67; 95% CI, 0.45-0.99; P = .045), or α2C-adrenergic receptor agonists (HR, 0.43; 95% CI, 0.19-0.96; P = .04) were observed. Exposure to antagonists of neuronal nicotinic acetylcholine receptor α was associated with higher estimates of ASD risk (HR, 12.94; 95% CI, 1.35-124.25; P = .03). Conclusions and Relevance: Most of the medications affecting neurotransmitter systems in this sample had no association with the estimates of ASD risk. Replication and/or validation using experimental techniques are required.

Paternal use of antidepressants and offspring outcomes in Sweden: nationwide prospective cohort study.

OBJECTIVE: To examine the association between paternal antidepressant use at conception and offspring preterm birth, malformations, autism spectrum disorder, and intellectual disability. DESIGN: Observational prospective cohort study with regression methods, and negative control comparison. SETTING: Sweden nationwide. PARTICIPANTS: 170 508 children conceived from 29 July 2005 and born in 2006-07, followed up to 2014 at age 8-9 years. This cohort included 3983 children born to fathers receiving antidepressant treatment during the conception period (that is, from four weeks before conception to four weeks after), a control group of 164 492 children not exposed to paternal antidepressant use, and a negative control comparison group of 2033 children born to fathers who did not use antidepressants during the conception period but began antidepressant treatment later during the pregnancy period (that is, from four weeks after conception to childbirth). MAIN OUTCOME MEASURE: Offspring preterm birth, malformation diagnosed at birth, diagnosis of autism spectrum disorder, and diagnosis of intellectual disability. RESULTS: Paternal antidepressant use during conception was not associated with preterm birth (adjusted odds ratio 0.91 (95% confidence interval 0.79 to 1.04)) or malformations (1.06 (0.90 to 1.26)) using logistic regression, compared with offspring born to unexposed fathers. No association was seen between antidepressant use during conception and autism (adjusted hazard ratio 1.13 (0.84 to 1.53)) or intellectual disability (0.82 (0.51 to 1.31)) using Cox regression. In children whose fathers initiated antidepressant treatment during pregnancy, results were similar for all outcomes apart from intellectual disability, which had an increased adjusted hazard ratio (1.66 (1.06 to 2.59)). Compared with the 2033 children whose fathers initiated antidepressant treatment during pregnancy, the 3983 children exposed to paternal use of antidepressants at conception had no differences in preterm birth, malformation, and autism, but a reduced risk of intellectual disability (adjusted hazard ratio 0.49 (0.26 to 0.93)). CONCLUSION: Paternal intake of antidepressants during the period around conception is safe with respect to the risk of the four major adverse outcomes in offspring-preterm birth, malformation, autism, or intellectual disability.

Maternal and infant outcomes associated with lithium use in pregnancy: an international collaborative meta-analysis of six cohort studies.

BACKGROUND: Concerns about teratogenicity and maternal and offspring complications restrict the use of lithium during pregnancy for the treatment of mood disorders. We aimed to investigate the association between in-utero lithium exposure and risk of pregnancy complications, delivery outcomes, neonatal morbidity, and congenital malformations. METHODS: In this meta-analysis, primary data from pregnant women and their children from six international cohorts based in the community (Denmark, Sweden, and Ontario, Canada) and in clinics (the Netherlands, UK, and USA) were analysed. Pregnancies were eligible for analysis if the pregnancy resulted in a liveborn singleton between 1997 and 2015, if health-related information was available for both mother and infant, and if the mother had a mood disorder (bipolar disorder or major depressive disorder) or if she had been given lithium during pregnancy (at least two dispensations of lithium during pregnancy that were dispensed any time from 1 month before conception until the delivery, or a single lithium dispensation during pregnancy when there was at least one other lithium dispensation within 6 months before or after this date). Pregnancies during which the mother had been prescribed known teratogenic drugs were excluded. Pregnancies were grouped into a lithium-exposed group and a mood disorder reference group. The main outcome measures were pregnancy complications, delivery outcomes, neonatal readmission to hospital within 28 days of birth, and congenital malformations (major malformations and major cardiac malformations). Analyses were done at each site by use of a shared protocol. Adjusted odds ratios (aORs) and 95% CIs were calculated by use of logistic regression models, and site-specific prevalence rates and ORs were pooled by use of random-effects meta-analytical models. FINDINGS: 22   124 eligible pregnancies were identified across the six cohorts, of which 727 pregnancies were eligible for inclusion in the lithium-exposed group (557 [77%] from register-based cohorts and 170 [23%] from clinical cohorts). Lithium exposure was not associated with any of the predefined pregnancy complications or delivery outcomes. An increased risk for neonatal readmission within 28 days of birth was seen in the lithium-exposed group compared with the reference group (pooled prevalence 27·5% [95% CI 15·8-39·1] vs 14·3% [10·4-18·2]; pooled aOR 1·62, 95% CI 1·12-2·33). Lithium exposure during the first trimester was associated with an increased risk of major malformations (pooled prevalence 7·4% [95% CI 4·0-10·7] vs 4·3% [3·7-4·8]; pooled aOR 1·71, 95% CI 1·07-2·72) but for major cardiac malformations the difference was not significant (2·1% [0·5-3·7] vs 1·6% [1·0-2·1]; pooled aOR 1·54, 95% CI 0·64-3·70). INTERPRETATION: Considering both the effect sizes and the precision of the estimates in this meta-analysis, treatment decisions for pregnant women with mood disorders must weigh the potential for increased risks of lithium during pregnancy-in particular those associated with use of lithium during the first trimester-against its effectiveness at reducing relapse. FUNDING: None.

Association of Maternal Use of Folic Acid and Multivitamin Supplements in the Periods Before and During Pregnancy With the Risk of Autism Spectrum Disorder in Offspring.

Importance: The association of maternal use of folic acid and multivitamin supplements before and during pregnancy with the risk of autism spectrum disorder (ASD) in offspring is unclear. Objective: To examine the associations between the use of maternal folic acid and multivitamin supplements before and during pregnancy and the risk of ASD in offspring. Design, Setting, and Participants: A case-control cohort study of 45 300 Israeli children born between January 1, 2003, and December 31, 2007, were followed up from birth to January 26, 2015, for the risk of ASD. The cases were all children diagnosed with ASD and the controls were a random sample of 33% of all live-born children. Exposures: Maternal vitamin supplements were classified for folic acid (vitamin B9), multivitamin supplements (Anatomical Therapeutic Chemical A11 codes vitamins A, B, C, and D), and any combination thereof exposed in the intervals before and during pregnancy. Main Outcomes and Measures: The association between maternal vitamin supplementation and the risk of ASD in offspring was quantified with relative risks (RRs) and their 95% CIs fitting Cox proportional hazards regression models adjusted for confounders. Sensitivity analyses were performed to test the robustness of the results. Results: Of the 45 300 children in the study (22 090 girls and 23 210 boys; mean [SD] age, 10.0 [1.4] years at the end of follow-up), 572 (1.3%) received a diagnosis of ASD. Maternal exposure to folic acid and/or multivitamin supplements before pregnancy was statistically significantly associated with a lower likelihood of ASD in the offspring compared with no exposure before pregnancy (RR, 0.39; 95% CI, 0.30-0.50; P < .001). Maternal exposure to folic acid and/or multivitamin supplements during pregnancy was statistically significantly associated with a lower likelihood of ASD in offspring compared with no exposure during pregnancy (RR, 0.27; 95% CI, 0.22-0.33; P < .001). Corresponding RRs were estimated for maternal exposure to folic acid before pregnancy (RR, 0.56; 95% CI, 0.42-0.74; P = .001), maternal exposure to folic acid during pregnancy (RR, 0.32; 95% CI, 0.26-0.41; P < .001), maternal exposure to multivitamin supplements before pregnancy (RR, 0.36; 95% CI, 0.24-0.52; P < .001), and maternal exposure to multivitamin supplements during pregnancy (RR, 0.35; 95% CI, 0.28-0.44; P < .001). The results generally remained statistically significant across sensitivity analyses. Conclusions and Relevance: Maternal exposure to folic acid and multivitamin supplements before and during pregnancy is associated with a reduced risk of ASD in the offspring compared with the offspring of mothers without such exposure.

Maternal suicide - Register based study of all suicides occurring after delivery in Sweden 1974-2009.

BACKGROUND: Recent research suggests that having a newborn child is associated with substantially reduced risk for maternal suicide. We studied postpartum suicides in a national cohort of mothers and the role of mental disorder, self-harm and delivery related factors. METHODS: We used a nested case-control design with data from Swedish registries. The cohort consisted of all women given birth in Sweden 1974-2009. Mothers who died by suicide during follow-up were considered cases (n = 1,786) and risk of suicide was estimated with proximity to delivery as the explanatory variable. In a second step, association between suicide during the first year following delivery (n = 145) and mental disorder, self-harm and delivery related variables risk factors were analyzed. RESULTS: The first postpartum year was associated with a lower risk of suicide, compared to later (RR 0.80, 95%CI 0.66-0.96), which was unaltered after adjustment for socio-economic status and history of self-harm (aRR 0.82, 95%CI 0.68-0.99). Compared to living mothers, suicide victims of the postpartum year more often had affective disorders (aRR 133.94, 95%CI 45.93-390.61), psychotic disorders (aRR 83.69, 95%CI 36.99-189.31) and history of self-harm (aRR 47.56, 95%CI 18.24-124.02). The aRR of stillbirth was 2.66 (95%CI 0.63-11.30). CONCLUSIONS: We found only a weak negative association between childbirth during the preceding year and suicide, when using mothers as controls. A severe mental disorder after delivery and a history of self-harm was strongly associated with increased risk of suicide in the postpartum year and may inform the clinical assessment postpartum.

Longitudinal depression or anxiety in mothers and offspring asthma: a Swedish population-based study.

Background: Previous research has found that maternal stress during pregnancy increases the risk of offspring asthma. However, whether this association is consistent with a causal interpretation has never been tested. The objective is to determine whether there is a critical exposure period for maternal depression or anxiety on offspring asthma or whether cumulative exposure is most important, and to investigate evidence of confounding. Methods: The study population included all children born in Sweden from July 2006 to December 2009 (n = 360 526). Information about childhood asthma, maternal depression or anxiety (diagnosis or medication) and covariates was obtained from the Swedish national health registers. The associations between exposure periods (pre-conception, pregnancy, postnatal or current) and childhood asthma were estimated using structured life course approach hypothesis testing. Paternal and cousin analyses were used to test for evidence of confounding from shared genes and environment. Results: For childhood asthma, cumulative exposure best described the effect of exposure to maternal depression or anxiety up to a maximum of any two exposure periods [adjusted odds ratio 1.44, 95% confidence interval (CI) 1.38, 1.52]. The hypotheses of a critical period were not supported. The paternal and cousin analyses indicated minimal influence from familial confounding. Conclusions: These findings support an association between cumulative exposure to maternal depression or anxiety and asthma development in offspring. This association is unique for maternal depression or anxiety and not due to familial confounding. The clinical implication is that effective psychological management of women with chronic distress may reduce offspring asthma risk.

Association of Antidepressant Medication Use During Pregnancy With Intellectual Disability in Offspring.

Importance: Maternal antidepressant medication use during pregnancy has previously been associated with adverse outcomes in offspring, but to our knowledge, the association with intellectual disability (ID) has not been investigated. Objectives: To examine the association of maternal antidepressant medication use during pregnancy with ID in offspring and investigate the importance of parental mental illness for such an association. Design, Setting, and Participants: A population-based cohort study of 179 007 children born from January 1, 2006, through December 31, 2007, with complete parental information from national registers who were followed up from birth throughout 2014. Main Outcomes and Measures: We estimated relative risks (RRs) and 95% CIs of ID in children exposed during pregnancy to any antidepressant medication or specifically to selective serotonin reuptake inhibitor (SSRI) antidepressants, all other non-SSRI antidepressants, or other nonantidepressant psychotropic medications. Analyses were adjusted for potential confounders. In addition to full population analyses, we used a subsample to compare mothers who used antidepressants during pregnancy with mothers who had at least one diagnosis of depression or anxiety before childbirth but did not use antidepressants during pregnancy. Results: Of the 179 007 children included in the study (mean [SD] age at end of follow-up, 7.9 [0.6] years; 92 133 [51.5%] male and 86 874 [48.5%] female), ID was diagnosed in 37 children (0.9%) exposed to antidepressants and in 819 children (0.5%) unexposed to antidepressants. With adjustment for potential confounders, the RR of ID after antidepressant exposure was estimated at 1.33 (95% CI, 0.90-1.98) in the full population sample and 1.64 (95% CI, 0.95-2.83) in the subsample of women with depression. Results from analyses of SSRI antidepressants, non-SSRI antidepressants, and nonantidepressant psychotropic medications and analyses in the clinically relevant subsample did not deviate from the full-sample results. Conclusions and Relevance: The unadjusted RR of ID was increased in offspring born to mothers treated with antidepressants during pregnancy. After adjustment for confounding factors, however, the current study did not find evidence of an association between ID and maternal antidepressant medication use during pregnancy. Instead, the association may be attributable to a mechanism integral to other factors, such as parental age and mother's psychiatric disorder.

Clinical phenotypes of perinatal depression and time of symptom onset: analysis of data from an international consortium.

BACKGROUND: The perinatal period is a time of high risk for onset of depressive disorders and is associated with substantial morbidity and mortality, including maternal suicide. Perinatal depression comprises a heterogeneous group of clinical subtypes, and further refinement is needed to improve treatment outcomes. We sought to empirically identify and describe clinically relevant phenotypic subtypes of perinatal depression, and further characterise subtypes by time of symptom onset within pregnancy and three post-partum periods. METHODS: Data were assembled from a subset of seven of 19 international sites in the Postpartum Depression: Action Towards Causes and Treatment (PACT) Consortium. In this analysis, the cohort was restricted to women aged 19-40 years with information about onset of depressive symptoms in the perinatal period and complete prospective data for the ten-item Edinburgh postnatal depression scale (EPDS). Principal components and common factor analysis were used to identify symptom dimensions in the EPDS. The National Institute of Mental Health research domain criteria functional constructs of negative valence and arousal were applied to the EPDS dimensions that reflect states of depressed mood, anhedonia, and anxiety. We used k-means clustering to identify subtypes of women sharing symptom patterns. Univariate and bivariate statistics were used to describe the subtypes. FINDINGS: Data for 663 women were included in these analyses. We found evidence for three underlying dimensions measured by the EPDS: depressed mood, anxiety, and anhedonia. On the basis of these dimensions, we identified five distinct subtypes of perinatal depression: severe anxious depression, moderate anxious depression, anxious anhedonia, pure anhedonia, and resolved depression. These subtypes have clear differences in symptom quality and time of onset. Anxiety and anhedonia emerged as prominent symptom dimensions with post-partum onset and were notably severe. INTERPRETATION: Our findings show that there might be different types and severity of perinatal depression with varying time of onset throughout pregnancy and post partum. These findings support the need for tailored treatments that improve outcomes for women with perinatal depression. FUNDING: Janssen Research & Development.