Long-Term Effects of Intrauterine Exposure to Antidepressants on Physical, Neurodevelopmental, and Psychiatric Outcomes: A Systematic Review.

OBJECTIVE: Reviews on child outcomes following in utero antidepressant exposure have focused on short-term outcomes. However, several recent individual studies reported on adverse physical, neurodevelopmental, and psychiatric outcomes beyond infancy and early childhood. The objective of this systematic review was to establish the long-term effects of prenatal antidepressant exposure on physical, neurodevelopmental, and psychiatric outcomes in individuals aged 4 years and older. DATA SOURCES: Embase, MEDLINE Ovid, Web of Science, Cochrane Central, and Google Scholar were systematically searched for all relevant articles, written in English and published prior to November 8, 2018, using terms describing antidepressants, pregnancy, and developmental outcomes. STUDY SELECTION: All original research articles on long-term outcomes of prenatal antidepressant exposure were eligible for inclusion. After screening and removal of duplicates, a total of 34 studies were identified. DATA EXTRACTION: Included articles were qualitatively analyzed to determine inconsistency, indirectness, imprecision, and study bias. RESULTS: The identified studies demonstrated statistically significant associations between prenatal antidepressant exposure and a range of physical, neurodevelopmental, and psychiatric outcomes. Yet, the risk of confounding by indication was high. When controlling for confounders, 5 studies investigating physical outcomes (asthma, cancer, body mass index [BMI], epilepsy) found no association except conflicting outcomes for BMI. Eighteen studies examining neurodevelopmental outcomes (cognition, behavior, IQ, motor development, speech, language, and scholastic outcomes) found no consistent associations with antidepressant exposure after taking confounders into account. Eleven studies investigated psychiatric outcomes. After adjusting for confounders, prenatal antidepressant exposure was associated with affective disorders but not with childhood psychiatric outcomes (eg, autism spectrum disorders, attention-deficit/hyperactivity disorder). CONCLUSIONS: Reported associations between in utero exposure to antidepressants and physical, neurodevelopmental, and psychiatric outcomes, in large part, seem to be driven by the underlying maternal disorder. When limiting confounding by indication, prenatal exposure to antidepressants was significantly associated only with offspring BMI and affective disorders.

Postpartum psychiatric disorders.

Pregnancy is a complex and vulnerable period that presents a number of challenges to women, including the development of postpartum psychiatric disorders (PPDs). These disorders can include postpartum depression and anxiety, which are relatively common, and the rare but more severe postpartum psychosis. In addition, other PPDs can include obsessive-compulsive disorder, post-traumatic stress disorder and eating disorders. The aetiology of PPDs is a complex interaction of psychological, social and biological factors, in addition to genetic and environmental factors. The goals of treating postpartum mental illness are reducing maternal symptoms and supporting maternal-child and family functioning. Women and their families should receive psychoeducation about the illness, including evidence-based discussions about the risks and benefits of each treatment option. Developing effective strategies in global settings that allow the delivery of targeted therapies to women with different clinical phenotypes and severities of PPDs is essential.

Prescription drug use in pregnancy and variations according to prior psychiatric history.

PURPOSE: Prescription drug use during pregnancy has increased during the past decades. However, little is known about prescription drug use for high-risk pregnancies. We aimed to estimate the prevalence of redeemed prescriptions in Danish pregnant women with and without previous psychiatric history. METHODS: A Danish population-based descriptive study of 981 392 pregnancies ending in live-born singletons by 586 988 women aged 15 to 55 years between 1997 and 2012, of which 113 449 (11.6%) pregnancies were by women with a psychiatric history prior to the index pregnancy. All prescription drugs redeemed during pregnancy were identified, and dispensing patterns among the women were reported by therapeutic classes of drugs, calendar year of childbirth, and trimester. RESULTS: Overall, women with psychiatric history prior to pregnancy were more likely to fill a prescription (75.8%; 95% confidence interval [CI], 75.5-76.0%), compared with women with no psychiatric history (64.5%; 95% CI, 64.4-64.6%). The difference was observed even when psychotropic drug use was excluded and in all therapeutic classes except for antineoplastic and immunomodulating drugs. The most commonly prescribed drugs were anti-infectives. Approximately 44.7% (95% CI, 44.5-45.0%) of women with psychiatric history and 31.3% (95% CI, 31.2-31.4%) of women with no psychiatric history redeemed more than one therapeutic class of drugs. CONCLUSIONS: Women with a psychiatric history were more likely to redeem prescriptions during pregnancy across almost all drug classes, especially anti-infectives. Two thirds of all women redeemed at least one prescription drug during pregnancy and one third more than one drug class. KEY POINTS We mapped prescription drug use of almost 600 000 women during almost one million pregnancies with focus on women with a history of psychiatric disorder before conception compared with women with no such history. Pregnant women with a previous psychiatric disorder were more likely to redeem prescription drugs compared with pregnant women without a previous psychiatric disorder. The observed overall difference was not due to obvious differences in psychotropic drug use. The difference was evident across calendar years, all trimesters, and almost all drug classes, but to a large extent in anti-infectives, among those mainly antibiotics. Two thirds of pregnant women redeemed prescription drugs during pregnancy, and one third redeemed more than one drug class. Health professionals should be aware of comorbid conditions requiring multiple drug use during pregnancy with the risk of unknown fetal effects.

Antidepressant use during pregnancy and childhood cancer in the offspring.

PURPOSE: Antidepressant use during pregnancy has been increasing in recent years. We evaluated whether in utero exposure to antidepressants increased the risk of childhood cancer. METHODS: This population-based cohort study using national registers in Denmark comprised 915 128 liveborn singletons during 1998-2012. We categorised children into three mutually exclusive exposure groups according to maternal redemption of an antidepressant prescription from 2 years before pregnancy until delivery of the index child: Unexposed (N = 863 033), prior user (use before but not during pregnancy) (N = 30 607), and use during pregnancy (N = 21 488). The children were followed from birth until first diagnosis of cancer, death, emigration, or December 31, 2012, whichever came first. The children were followed maximum 14.9 years and contributed to 6.9 × 106 person-years at risk. We estimated hazard ratios (HRs) of cancer using Cox regression with 95% confidence intervals (CIs). RESULTS: In total, 1298 (0.1%) children were diagnosed with cancer. Antidepressant use during pregnancy was not associated with a significantly increased risk of childhood cancer in general; the HR was 1.03 (95% CI, 0.63-1.68), compared to children born by mothers who discontinued antidepressant use prior to pregnancy. The association between in utero exposure to antidepressants and childhood cancer did not depend on type or duration of antidepressant use. There was no strong evidence indicating a higher risk of leukaemia or nervous system tumours among children exposed to antidepressants in utero. CONCLUSION: Antidepressant use during pregnancy was not significantly associated with childhood cancer in general nor with leukaemia or nervous system tumours in specific.

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.

Life expectancy and cardiovascular mortality in persons with schizophrenia.

PURPOSE OF REVIEW: To assess the impact of cardiovascular disease on the excess mortality and shortened life expectancy in schizophrenic patients. RECENT FINDINGS: Patients with schizophrenia have two-fold to three-fold higher mortality rates compared with the general population, corresponding to a 10-25-year reduction in life expectancy. Although the mortality rate from suicide is high, natural causes of death account for a greater part of the reduction in life expectancy. The reviewed studies suggest four main reasons for the excess mortality and reduced life expectancy. First, persons with schizophrenia tend to have suboptimal lifestyles including unhealthy diets, excessive smoking and alcohol use, and lack of exercise. Second, antipsychotic drugs may have adverse effects. Third, physical illnesses in persons with schizophrenia are common, but diagnosed late and treated insufficiently. Lastly, the risk of suicide and accidents among schizophrenic patients is high. SUMMARY: Schizophrenia is associated with a substantially higher mortality and curtailed life expectancy partly caused by modifiable risk factors.

Somatic hospital contacts, invasive cardiac procedures, and mortality from heart disease in patients with severe mental disorder.

CONTEXT: Excess mortality from heart disease is observed in patients with severe mental disorder. This excess mortality may be rooted in adverse effects of pharmacological or psychotropic treatment, lifestyle factors, or inadequate somatic care. OBJECTIVES: To examine whether persons with severe mental disorder, defined as persons admitted to a psychiatric hospital with bipolar affective disorder, schizoaffective disorder, or schizophrenia, are in contact with hospitals and undergoing invasive procedures for heart disease to the same degree as the nonpsychiatric general population, and to determine whether they have higher mortality rates of heart disease. DESIGN, SETTING, AND PARTICIPANTS: A population-based cohort of 4.6 million persons born in Denmark was followed up from 1994 to 2007. Rates of mortality, somatic contacts, and invasive procedures were estimated by survival analysis. MAIN OUTCOME MEASURES: Incidence rate ratios of heart disease admissions and heart disease mortality as well as probability of invasive cardiac procedures. RESULTS: The incidence rate ratio of heart disease contacts in persons with severe mental disorder compared with the rate for the nonpsychiatric general population was only slightly increased, at 1.11 (95% confidence interval, 1.08-1.14). In contrast, their excess mortality rate ratio from heart disease was 2.90 (95% confidence interval, 2.71-3.10). Five years after the first contact for somatic heart disease, the risk of dying of heart disease was 8.26% for persons with severe mental disorder (aged <70 years) but only 2.86% in patients with heart disease who had never been admitted to a psychiatric hospital. The fraction undergoing invasive procedures within 5 years was reduced among patients with severe mental disorder as compared with the nonpsychiatric general population (7.04% vs 12.27%, respectively). CONCLUSIONS: Individuals with severe mental disorder had only negligible excess rates of contact for heart disease. Given their excess mortality from heart disease and lower rates of invasive procedures after first contact, it would seem that the treatment for heart disease offered to these individuals in Denmark is neither sufficiently efficient nor sufficiently intensive. This undertreatment may explain part of their excess mortality.