Abortion and mental health outcomes: A systematic review and meta-analysis.

This is a protocol for a systematic review and meta-analysis of research on mental health outcomes of abortion. Does abortion increase the risk of adverse mental health outcomes? That is the central question for this review. Our review aims to inform policy and practice by locating, critically appraising, and synthesizing empirical evidence on associations between abortion and subsequent mental health outcomes. Given the controversies surrounding this topic and the complex social, political, legal, and ideological contexts in which research and reviews on abortion are conducted, it is especially important to conduct this systematic review and meta-analysis with comprehensive, rigorous, unbiased, and transparent methods. We will include a variety of study designs to enhance understanding of studies' methodological strengths and weaknesses and to identify potential explanations for conflicting results. We will follow open science principles, providing access to our methods, measures, and results, and making data available for re-analysis.

Medication and procedural abortions before 13 weeks gestation and risk of psychiatric disorders.

BACKGROUND: The proportion of abortions provided by medication in the United States and worldwide has increased greatly since the U.S. Food and Drug Administration approved mifepristone in 2000. While existing research has shown that abortion does not increase risk of mental health problems, no population-based study has examined specifically whether a procedural or medication abortion increases risk of mental health disorders. OBJECTIVE: This study examined whether mental health disorders increased in the shorter and longer-term after a medication or procedural abortion. STUDY DESIGN: Using Danish population registers' data, we conducted a prospective cohort study in which we included 72,424 females born in Denmark between 1980 and 2006, who were ages 12 to 38 during the study period and had a first first-trimester abortion before 13 weeks gestation in 2000 to 2018. Females with no previous psychiatric diagnoses were followed from 1 year before their abortion until their first psychiatric diagnosis, December 31, 2018, emigration from Demark, or death, whichever came first. Risk of any first psychiatric disorder was defined as a recorded psychiatric diagnosis at an in- or out-patient facility from the 1 year after to more than 5 years after a medication or procedural abortion relative to the year beforehand. Results were adjusted for calendar year, age, gestational age, partner status, prior mental and physical health, childbirth history, childhood environment, and parental mental health history. RESULTS: Females having medication (n=37,155) and procedural abortions (n=35,269) had the same risk of any first psychiatric diagnosis in the year after their abortion relative to the year before their abortion (medication abortion adjusted incidence rate ratio [MaIRR]=1.02, 95% confidence interval [CI]: 0.93-1.12; procedural abortion adjusted incidence rate ratio [PaIRR]=0.94, 95% CI: 0.86-1.02). Moreover, as more time from the abortion passed, the risk of a psychiatric diagnoses decreased relative to the year before their abortion for each abortion method (MaIRR 1-2 years after=0.89, 95% CI: 0.80-0.98; PaIRR 1-2 years after=0.81, 95% CI: 0.88-1.05; MaIRR 2-5 years after=0.77, 95% CI: 0.71-0.84; PaIRR 2-5 years after=0.72, 95% CI: 0.67-0.78; MaIRR 5+ years after=0.58, 95% CI: 0.53-0.63; PaIRR 5+ years after=0.54, 95% CI: 0.50-0.58). CONCLUSION: Because the risk of psychiatric diagnoses was the same in the year after relative to the year before a medication and procedural abortion and the risk did not increase as more time after the abortion increased, neither abortion method increased risk of mental health disorders in the shorter or longer-term.

Attention-Deficit Hyperactivity Disorder (ADHD) Medication Use Trajectories Among Women in the Perinatal Period.

BACKGROUND: An increasing number of women of reproductive age are treated with attention-deficit hyperactivity disorder (ADHD) medication; however, patterns of ADHD medication use for women in the perinatal period have not been well described. OBJECTIVE: This study aimed to describe ADHD medication use patterns from 1 year before pregnancy to 1 year after delivery, and to describe sociodemographic characteristics and clinical features by medication trajectories. METHODS: The population-based cohort study included pregnancies in Denmark between 1997 and 2020, from the Medical Birth Register, by women who filled at least one prescription for ADHD medication from 12 months before pregnancy until 12 months after delivery. We applied group-based trajectory modeling to classify women into subgroups based on the identification of heterogeneous ADHD medication treatment patterns, and described the characteristics associated with these groups. RESULTS: Overall, we included 4717 pregnancies leading to liveborn singletons by 4052 mothers with a mean (standard deviation) age of 27.5 (5.6) years. We identified four treatment trajectories across pregnancy and the postpartum period: continuers (23.3%), discontinuers (41.8%), interrupters who ceased filling prescriptions during pregnancy but resumed postpartum (17.2%), and postpartum initiators (17.7%). Continuers were older at the time of conception, gave birth in more recent years, were more likely to smoke during pregnancy, and used other psychotropic medications during pregnancy. A large proportion of continuers used methylphenidate (89.1%) compared with the other groups (75.9-84.1%) and had switched ADHD medication type during the whole period (16.4% vs. 7.4-14.8%). CONCLUSION: We found that approximately 60% of women discontinued or interrupted their ADHD medication around pregnancy, and those who continued differed in sociodemographic and clinical factors that may reflect more severe ADHD.

Impact of genetic, sociodemographic, and clinical features on antidepressant treatment trajectories in the perinatal period.

Pregnant women on antidepressants must balance potential fetal harm with the relapse risk. While various clinical and sociodemographic factors are known to influence treatment decisions, the impact of genetic factors remains unexplored. We conducted a cohort study among 2,316 women with diagnosed affective disorders who had redeemed antidepressant prescriptions six months before pregnancy, identified from the Danish Integrated Psychiatric Research study. We calculated polygenic risk scores (PGSs) for major depression (MDD), bipolar disorder (BD), and schizophrenia (SCZ) using individual-level genetic data and summary statistics from genome-wide association studies. We retrieved data on sociodemographic and clinical features from national registers. Applying group-based trajectory modeling, we identified four treatment trajectories across pregnancy and postpartum: Continuers (38.2 %), early discontinuers (22.7 %), late discontinuers (23.8 %), and interrupters (15.3 %). All three PGSs were not associated with treatment trajectories; for instance, the relative risk ratio for continuers versus early discontinuers was 0.93 (95 % CI: 0.81-1.06), 0.98 (0.84-1.13), 1.09 (0.95-1.27) for per 1-SD increase in PGS for MDD, BD, and SCZ, respectively. Sociodemographic factors were generally not associated with treatment trajectories, except for the association between primiparity and continuing antidepressant use. Women who received ≥2 classes or a higher dose of antidepressants had a higher probability of being late discontinuers, interrupters, and continuers. The likelihood of continuing antidepressants or restarting antidepressants postpartum increased with the previous antidepressant treatment duration. Our findings indicate that continued antidepressant use during pregnancy is influenced by the severity of the disease rather than genetic predisposition as measured by PGSs.

Association between doxycycline use and long-term functioning in patients with schizophrenia.

IMPORTANCE AND OBJECTIVE: The brain-penetrant tetracycline antibiotics, minocycline and doxycycline, have been proposed as potential candidate drugs for treatment of schizophrenia, based on preclinical studies and clinical trials. A potential long-term beneficial effect of these antibiotics for schizophrenia patients has not been investigated. This study was designed to determine if redemption of doxycycline prescription in schizophrenia is associated with decreased incidence of disability pension, a proxy for long-term functioning. DESIGN: We performed a population-based cohort study with data from schizophrenia patients available through the Danish registers. Survival analysis models with time-varying covariates were constructed to assess incidence rate ratios (IRR) of disability pension after exposure to doxycycline or a non-brain penetrant tetracycline, defined as at least one filled prescription. The analysis was adjusted for age, sex, calendar year, parental psychiatric status and educational level. RESULTS: We used data from 11,157 individuals with schizophrenia (4,945 female and 6,212 male; average age 22.4 years old, standard deviation (std) 4.50). 718 of these were exposed to brain-penetrant doxycycline, and 1,498 individuals redeemed a prescription of one or more of the non-brain-penetrant tetracyclines. The average years at risk per person in this cohort was 4.9, and 2,901 individuals received disability pension in the follow-up period. There was a significantly lower incidence rate of disability pension in schizophrenia patients who had redeemed doxycycline compared to patients who did not redeem a prescription of any tetracycline antibiotics (Incidence rate ratio (IRR) 0.68; 95 % CI 0.56, 0.83). There was also a significant lower rate of disability pension in schizophrenia patients who redeemed doxycycline compared to individuals who redeemed a prescription of one of the non-brain penetrant tetracycline antibiotics (IRR 0.69 95 % CI 0.55, 0.87). CONCLUSIONS: In this observational study, doxycycline exposure is associated with a reduced incidence of disability pension. These data support further studies on the potential long term neuroprotective effects of doxycycline and level of functioning in schizophrenia patients.

Duration and timing of depression and risk of family dissolution: A register-based cohort study of newly-formed Danish families.

BACKGROUND: Depression is detrimental to partnership stability. However, it remains unclear if and how the duration and timing of depression affect the risk of family dissolution. METHODS: We conducted a Danish register-based cohort study of newly-formed cohabiting and married couples in 2008 and 2009, who were followed from the second year after family formation. Depressive episodes were defined by individual-level prescription patterns of antidepressant drugs (ATC codes N06A) in either partner. Family dissolution was characterized by the discontinuation of a shared residential address. Using Longitudinal Targeted Minimum Loss-based Estimation, we estimated the risk of family dissolution after 5 years of follow-up under various lengths and timings of depressive episodes. RESULTS: There were 102,335 families included. The covariate-adjusted risk of family dissolution in families without depressive episodes was 30.0 % (95 % CI 29.6-30.4 %) and 35.5 % (95 % CI 29.5-41.5 %) in families with at least one depressive episode during follow-up. The risk of family dissolution increased with the duration of depressive episodes to 42.2 % (95 % CI 40.8-43.6 %) for five coherent years of depression. Depression shortly after family formation carried higher risk of family dissolution; this risk was 42.3 % (95 % CI 38.4-46.3 %) for depression experienced in the first year of family formation versus 32.9 % (95 % CI 31.8-34.0 %) in the fifth year of family formation. LIMITATIONS: Proxy measures of depression by antidepressant prescriptions fails to identify milder depression. Annual measures of family dissolution precluded more fine-grained analyses of time-intervals. CONCLUSIONS: Depression is disruptive to family stability, particularly with longer duration and early onset after family formation.

Familial risk of postpartum psychosis.

Objective: Postpartum psychosis, a mood disorder triggered by childbirth, is one of the most severe psychiatric conditions, with high risks of suicide and infanticide if untreated. While it is evident that genetic factors play a crucial role in disorder risk, the exact extent of their importance is yet to be determined. Methods: This cohort study consisted of 1,648,759 women from the Swedish nationwide registers, of whom 2,514 (0.15%) experienced postpartum psychosis within three months of their first-ever childbirth. We estimated the relative recurrence risk of postpartum psychosis for female full siblings and cousins as a measure of familial, genetic, and environmental risk. Results: Relative recurrence risk of postpartum psychosis in full siblings was 10.69 (95% CI=6.60-16.26) when adjusted for year of and age at childbirth. Although cousins showed an elevated relative recurrence risk, these results did not reach statistical significance (1.78, 95% CI=0.70-3.62). Despite the higher familial risk of postpartum psychosis among full siblings, the absolute risk for women with an affected sibling is relatively low, estimated at 1.55% within the entire population. Conclusions: The observed increased risk of postpartum psychosis in full siblings suggests both genetic and shared environmental influences. However, the lack of significant results in cousins hampers a definitive distinction between these factors. Furthermore, despite increased relative recurrence risk in siblings, their overall likelihood of developing postpartum psychosis remains low. Our study underscores the need for further research to better understand the intricate interplay of genetics and environment in the development of postpartum psychosis.

Polygenic Risk of Mental Disorders and Subject-Specific School Grades.

BACKGROUND: Education is essential for socioeconomic security and long-term mental health; however, mental disorders are often detrimental to the educational trajectory. Genetic correlations between mental disorders and educational attainment do not always align with corresponding phenotypic associations, implying heterogeneity in the genetic overlap. METHODS: We unraveled this heterogeneity by investigating associations between polygenic risk scores for 6 mental disorders and fine-grained school outcomes: school grades in language and mathematics in ninth grade and high school, as well as educational attainment by age 25, using nationwide-representative data from established cohorts (N = 79,489). RESULTS: High polygenic liability of attention-deficit/hyperactivity disorder was associated with lower grades in language and mathematics, whereas high polygenic risk of anorexia nervosa or bipolar disorder was associated with higher grades in language and mathematics. Associations between polygenic risk and school grades were mixed for schizophrenia and major depressive disorder and neutral for autism spectrum disorder. CONCLUSIONS: Polygenic risk scores for mental disorders are differentially associated with language and mathematics school grades.

Postpartum and non-postpartum depression: a population-based matched case-control study comparing polygenic risk scores for severe mental disorders.

It remains inconclusive whether postpartum depression (PPD) and depression with onset outside the postpartum period (MDD) are genetically distinct disorders. We aimed to investigate whether polygenic risk scores (PGSs) for major mental disorders differ between PPD cases and MDD cases in a nested case-control study of 50,057 women born from 1981 to 1997 in the iPSYCH2015 sample in Demark. We identified 333 women with first-onset postpartum depression (PPD group), who were matched with 993 women with first-onset depression diagnosed outside of postpartum (MDD group), and 999 female population controls. Data on genetics and depressive disorders were retrieved from neonatal biobanks and the Psychiatric Central Research Register. PGSs were calculated from both individual-level genetic data and meta-analysis summary statistics from the Psychiatric Genomics Consortium. Conditional logistic regression was used to calculate the odds ratio (OR), accounting for the selection-related reproductive behavior. After adjustment for covariates, higher PGSs for severe mental disorders were associated with increased ORs of both PPD and MDD. Compared with MDD cases, MDD PGS and attention-deficit/hyperactivity disorder PGS were marginally but not statistically higher for PPD cases, with the OR of PPD versus MDD being 1.12 (95% CI: 0 .97-1.29) and 1.11 (0.97-1.27) per-standard deviation increase, respectively. The ORs of PPD versus MDD did not statistically differ by PGSs of bipolar disorder, schizophrenia, or autism spectrum disorder. Our findings suggest that relying on PGS data, there was no clear evidence of distinct genetic make-up of women with depression occurring during or outside postpartum, after taking the selection-related reproductive behavior into account.

Prenatal antidepressant exposure and the risk of decreased gestational age and lower birthweight: A polygenic score approach to investigate confounding by indication.

INTRODUCTION: Prenatal antidepressant exposure has been associated with lower gestational age and birthweight. Yet, unmeasured residual confounding may inflate this association. We explored if maternal genetic liability for major depression explains part of the association of antidepressant use in pregnancy with lower gestational age and birthweight. MATERIAL AND METHODS: We employed the maternal polygenic score (PGS) for major depression as a measure of genetic liability. We used generalised linear models to estimate the differences in gestational age and birthweight at each PGS quintile between children whose mothers continued antidepressant use during pregnancy (continuation group), children whose mothers discontinued antidepressant use during pregnancy (discontinuation group) and unexposed children. RESULTS: After adjusting for confounders, we found significant differences in birthweight between PGS quintiles in the continuation and unexposed group. Yet, this relationship was not linear. Furthermore, at the lowest and highest PGS quintiles, the continuation group had significantly reduced mean gestational ages (adjusted ß ranges: 1.7-4.5 days, p < 0.001-0.008) and lower mean birthweights (adjusted ß ranges: 58.6-165.4 g, p = 0.001-0.008) than the discontinuation and unexposed groups. CONCLUSION: We confirmed that antidepressant use in pregnancy was associated with small reductions in gestational age and birthweight but found that genetic liability for depression was not linearly associated with this risk. The causality of the observed associations could not be established due to the observational nature of the study. Residual confounding linked to the underlying disease was likely still present.

Identification of women at high risk of postpartum psychiatric episodes: A population-based study quantifying relative and absolute risks following exposure to selected risk factors and genetic liability.

BACKGROUND: We quantified relative and absolute risks of postpartum psychiatric episodes (PPE) following risk factors: Young age, past personal or family history of psychiatric disorders, and genetic liability. METHODS: We conducted a register-based study using the iPSYCH2012 case-cohort sample. Exposures were personal history of psychiatric episodes prior to childbirth, being a young mother (giving birth before the age of 21.5 years), having a family history of psychiatric disorders, and a high (highest quartile) polygenic score (PGS) for major depression. PPE was defined within 12 months postpartum by prescription of psychotropic medication or in- and outpatient contact to a psychiatric facility. We included primiparous women born 1981-1999, giving birth before January 1st, 2016. We conducted Cox regression to calculate hazard ratios (HRs) of PPE, absolute risks were calculated using cumulative incidence functions. RESULTS: We included 8174 primiparous women, and the estimated baseline PPE risk was 6.9% (95% CI 6.0%-7.8%, number of PPE cases: 2169). For young mothers with a personal and family history of psychiatric disorders, the absolute risk of PPE was 21.6% (95% CI 15.9%-27.8%). Adding information on high genetic liability to depression, the risk increased to 29.2% (95% CI 21.3%-38.4%) for PPE. CONCLUSIONS: Information on prior personal and family psychiatric episodes as well as age may assist in estimating a personalized risk of PPE. Furthermore, additional information on genetic liability could add even further to this risk assessment.

Self-harm in pregnancy and the postnatal year: prevalence and risk factors.

BACKGROUND: Self-harm in pregnancy or the year after birth ('perinatal self-harm') is clinically important, yet prevalence rates, temporal trends and risk factors are unclear. METHODS: A cohort study of 679 881 mothers (1 172 191 pregnancies) was conducted using Danish population register data-linkage. Hospital treatment for self-harm during pregnancy and the postnatal period (12 months after live delivery) were primary outcomes. Prevalence rates 1997-2015, in women with and without psychiatric history, were calculated. Cox regression was used to identify risk factors. RESULTS: Prevalence rates of self-harm were, in pregnancy, 32.2 (95% CI 28.9-35.4)/100 000 deliveries and, postnatally, 63.3 (95% CI 58.8-67.9)/100 000 deliveries. Prevalence rates of perinatal self-harm in women without a psychiatric history remained stable but declined among women with a psychiatric history. Risk factors for perinatal self-harm: younger age, non-Danish birth, prior self-harm, psychiatric history and parental psychiatric history. Additional risk factors for postnatal self-harm: multiparity and preterm birth. Of psychiatric conditions, personality disorder was most strongly associated with pregnancy self-harm (aHR 3.15, 95% CI 1.68-5.89); psychosis was most strongly associated with postnatal self-harm (aHR 6.36, 95% CI 4.30-9.41). For psychiatric disorders, aHRs were higher postnatally, particularly for psychotic and mood disorders. CONCLUSIONS: Perinatal self-harm is more common in women with pre-existing psychiatric history and declined between 1997 and 2015, although not among women without pre-existing history. Our results suggest it may be a consequence of adversity and psychopathology, so preventative intervention research should consider both social and psychological determinants among women with and without psychiatric history.

Antidepressant treatment in pregnancy: a Danish registry linkage study in pregnant women with pre-existing obsessive-compulsive disorder.

The association between antidepressant continuation during pregnancy and postpartum mental health in women with obsessive-compulsive disorder (OCD) is uncertain. We identified 1317 women with live-birth singleton pregnancies and having outpatient/inpatient visits for OCD in the 4 years pre-pregnancy from the Danish registries. We defined three groups based on antidepressant prescriptions filled in the 2 years before pregnancy to delivery: (i) unexposed (n = 449); (ii) discontinuers (n = 346), i.e., with pre-pregnancy antidepressant fills only; (iii) continuers (n = 522), i.e., with antidepressant fills before and during pregnancy. We estimated crude and propensity score weighted hazard ratio (HRs) of postpartum visit for OCD and mood/anxiety disorders using Cox proportional hazard models. In weighted analyses, we found no difference in the probability of a postpartum visit for OCD or MADs with antidepressant continuation compared to unexposed and discontinuers. The likelihood of a postpartum OCD visit was higher in pregnancies having only one prescription fill during pregnancy compared to unexposed (HR = 3.44, 95% CI: 1.24, 9.54) or discontinuers (HR = 2.49, 95% CI: 0.91, 6.83). Continuers in pregnancy without antidepressant fill in the first three months postpartum had higher probability for postpartum visit for mood/anxiety disorders compared to discontinuers (HR = 3.84, 95% CI: 1.49, 9.92). Among pregnant women with pre-existing OCD, we found similar probabilities of a postpartum visit for OCD or mood/anxiety disorders in antidepressant continuers compared to unexposed and discontinuers. Continuers with a single prescription fill during pregnancy or no fill postpartum may have higher risks for these outcomes. Our findings highlight the importance of continuity of treatment throughout the perinatal period.

A Sex-Dependent Association Between Doxycycline Use and Development of Schizophrenia.

BACKGROUND: Doxycycline and minocycline are brain-penetrant tetracycline antibiotics, which recently gained interest because of their immunomodulatory and neuroprotective properties. Observational studies have suggested that exposure to these drugs may decrease the risk to develop schizophrenia, but results are inconsistent. The aim of this study was to investigate the potential association between doxycycline use and later onset of schizophrenia. DESIGN: We used data from 1 647 298 individuals born between 1980 and 2006 available through Danish population registers. 79 078 of those individuals were exposed to doxycycline, defined as redemption of at least 1 prescription. Survival analysis models stratified for sex with time-varying covariates were constructed to assess incidence rate ratios (IRRs) for schizophrenia (ICD-10 code F20.xx), with adjustment for age, calendar year, parental psychiatric status, and educational level. RESULTS: In the non-stratified analysis, there was no association between doxycycline exposure and schizophrenia risk. However, men who redeemed doxycycline had a significantly lower incidence rate for schizophrenia onset compared to men that did not (IRR 0.70; 95% CI 0.57-0.86). By contrast, women had a significantly higher incidence rate for schizophrenia onset, compared to women that did not redeem doxycycline prescriptions (IRR 1.23; 95% CI 1.08, 1.40). The effects were not found for other tetracycline antibiotics (IRR 1.00; 95% CI 0.91, 1.09). CONCLUSIONS: Doxycycline exposure is associated with a sex-dependent effect on schizophrenia risk. The next steps are replication of the results in independent well-characterized population cohorts, as well as preclinical studies to investigate sex-specific effects of doxycycline on biological mechanisms implicated in schizophrenia.

Timing of Antidepressant Discontinuation During Pregnancy and Postpartum Psychiatric Outcomes in Denmark and Norway.

Importance: Approximately one-half of women treated for affective disorders discontinue antidepressant use during pregnancy, yet this discontinuation could lead to relapse post partum. Objective: To investigate the associations between longitudinal antidepressant fill trajectories during pregnancy and postpartum psychiatric outcomes. Design, Setting, and Participants: This cohort study used nationwide registers in Denmark and Norway. The sample included 41 475 live-born singleton pregnancies in Denmark (1997-2016) and 16 459 in Norway (2009-2018) for women who filled at least 1 antidepressant prescription within 6 months before pregnancy. Exposures: Antidepressant prescription fills were obtained from the prescription registers. Antidepressant treatment during pregnancy was modeled using the k-means longitudinal method. Main Outcomes and Measures: Initiation of psycholeptics, psychiatric emergencies, or records of self-harm within 1 year post partum. Between April 1 and October 30, 2022, hazard ratios (HRs) for each psychiatric outcome were estimated using Cox proportional hazards regression models. Inverse probability of treatment weighting was used to control for confounding. Country-specific HRs were pooled using random-effects meta-analytic models. Results: Among 57 934 pregnancies (mean [SD] maternal age, 30.7 [5.3] years in Denmark and 29.9 [5.5] years in Norway), 4 antidepressant fill trajectories were identified: early discontinuers (31.3% and 30.4% of the included pregnancies in Denmark and Norway, respectively), late discontinuers (previously stable users) (21.5% and 27.8%), late discontinuers (short-term users) (15.9% and 18.4%), and continuers (31.3% and 23.4%). Early discontinuers and late discontinuers (short-term users) had a lower probability of initiating psycholeptics and having postpartum psychiatric emergencies vs continuers. A moderately increased probability of initiation of psycholeptics was found among late discontinuers (previously stable users) vs continuers (HR, 1.13; 95% CI, 1.03-1.24). This increase in late discontinuers (previously stable users) was more pronounced among women with previous affective disorders (HR, 1.28; 95% CI, 1.12-1.46). No association between antidepressant fill trajectories and postpartum self-harm risk was found. Conclusions and Relevance: Based on pooled data from Denmark and Norway, a moderately elevated probability of initiation of psycholeptics in late discontinuers (previously stable users) vs continuers was found. These findings suggest that women with severe mental illness who are currently on stable treatment may benefit from continuing antidepressant treatment and personalized treatment counseling during pregnancy.

In utero exposure to ADHD medication and long-term offspring outcomes.

Attention Deficit Hyperactivity Disorder (ADHD) medication is increasingly being used during pregnancy. Concerns have been raised as to whether ADHD medication has long-term adverse effects on the offspring. The authors investigated whether in utero exposure to ADHD medication was associated with adverse long-term neurodevelopmental and growth outcomes in offspring. The population-based cohort study in the Danish national registers included 1,068,073 liveborn singletons from 1998 to 2015 followed until any developmental diagnosis, death, emigration, or December 31, 2018. Children of mothers who continued ADHD medication (methylphenidate, amphetamine, dexamphetamine, lisdexamphetamine, modafinil, atomoxetine, clonidine) during pregnancy and children of mothers who discontinued ADHD medication before pregnancy were compared using Cox regression. Main outcomes were neurodevelopmental psychiatric disorders, impairments in vision or hearing, epilepsy, seizures, or growth impairment during childhood or adolescence. In total, 898 children were exposed to ADHD medication during pregnancy compared to 1270 children whose mothers discontinued ADHD medication before pregnancy. After adjustment for demographic and psychiatric characteristics of the mother, no increased risk of any offspring developmental disorders was found combined (aHR 0.97, 95% CI 0.81 to 1.17) or for separate subcategories. Similarly, no increased risk was found for any sub-categories of outcomes in the negative control or sibling controlled analyses. Neurodevelopment and growth in offspring do not differ based on antenatal exposure to ADHD medication. These findings provide reassurance for women with ADHD who depend on ADHD medication for daily functioning and who consider continuing medication in pregnancy.

Polygenic liability, stressful life events and risk for secondary-treated depression in early life: a nationwide register-based case-cohort study.

BACKGROUND: In this study, we examined the relationship between polygenic liability for depression and number of stressful life events (SLEs) as risk factors for early-onset depression treated in inpatient, outpatient or emergency room settings at psychiatric hospitals in Denmark. METHODS: Data were drawn from the iPSYCH2012 case-cohort sample, a population-based sample of individuals born in Denmark between 1981 and 2005. The sample included 18 532 individuals who were diagnosed with depression by a psychiatrist by age 31 years, and a comparison group of 20 184 individuals. Information on SLEs was obtained from nationwide registers and operationalized as a time-varying count variable. Hazard ratios and cumulative incidence rates were estimated using Cox regressions. RESULTS: Risk for depression increased by 35% with each standard deviation increase in polygenic liability (p < 0.0001), and 36% (p < 0.0001) with each additional SLE. There was a small interaction between polygenic liability and SLEs (ß = -0.04, p = 0.0009). The probability of being diagnosed with depression in a hospital-based setting between ages 15 and 31 years ranged from 1.5% among males in the lowest quartile of polygenic liability with 0 events by age 15, to 18.8% among females in the highest quartile of polygenic liability with 4+ events by age 15. CONCLUSIONS: These findings suggest that although there is minimal interaction between polygenic liability and SLEs as risk factors for hospital-treated depression, combining information on these two important risk factors could potentially be useful for identifying high-risk individuals.

Genetic liability to posttraumatic stress disorder and its association with postpartum depression.

BACKGROUND: Childbirth may be a traumatic experience and vulnerability to posttraumatic stress disorder (PTSD) may increase the risk of postpartum depression (PPD). We investigated whether genetic vulnerability to PTSD as measured by polygenic score (PGS) increases the risk of PPD and whether a predisposition to PTSD in PPD cases exceeds that of major depressive disorder (MDD) outside the postpartum period. METHODS: This case-control study included participants from the iPSYCH2015, a case-cohort of all singletons born in Denmark between 1981 and 2008. Restricting to women born between 1981 and 1997 and excluding women with a first diagnosis other than depression (N = 22 613), 333 were identified with PPD. For each PPD case, 999 representing the background population and 993 with MDD outside the postpartum were matched by calendar year at birth, cohort selection, and age. PTSD PGS was calculated from summary statistics from the Psychiatric Genomics Consortium with LDpred2-auto. Odds ratios (ORs) were estimated using conditional logistic regression adjusted for parental psychiatric history and country of origin, PGS for MDD and age at first birth, and the first 10 principal components. RESULTS: The PTSD PGS was significantly associated with PPD (OR 1.42, 95% CI 1.20-1.68 per standard deviation increase in PTSD PGS) compared to healthy female controls. Genetic PTSD vulnerability in PPD cases did not exceed that of matched female depression cases outside the postpartum period (OR 1.10, 95% CI 0.94-1.30 per standard deviation increase). CONCLUSIONS: Genetic vulnerability to PTSD increased the risk of PPD but did not differ between PPD cases and women with depression at other times.