Evaluating the epidemiology of clozapine-associated neutropenia among people on clozapine across Australia and Aotearoa New Zealand: a retrospective cohort study.

BACKGROUND: Clozapine is associated with the risk of serious neutropenia. However, this risk might decrease over time, meaning that indefinite absolute neutrophil count (ANC) monitoring could be unnecessary. We aimed to determine the epidemiology and timing of clozapine-associated neutropenia outcomes, to investigate variables that might contribute to the odds of neutropenia, and to determine risk of competing neutropenic events during clozapine treatment. METHODS: We performed a retrospective analysis of the Australian and New Zealand Viatris Pharmacovigilance system (one of two monitoring databases for these two countries) between June 6, 1990, and Oct 25, 2022. Patients were excluded from analysis if they commenced clozapine before 1990, did not have a haematology test within 2 weeks of commencement date, or had no follow-up. We measured minor neutropenia (ANC 1·0-1·5 × 109 per L) and serious neutropenia (ANC <1·0 × 109 per L) leading to cessation of clozapine within 6 weeks of the neutropenic event. We determined the rates of minor and serious neutropenia and calculated odds ratios (ORs) for the likelihood of neutropenia leading to cessation. For serious neutropenia leading to cessation, we used time-to-event to calculate rolling weekly averages and to perform competing risk analysis of outcomes using Cox proportional hazards models and a Fine-Gray subdistribution hazards regression model. For the subset of data where information on previous clozapine use was available, we did an analysis for participants who did and did not have previous clozapine exposure. FINDINGS: We included 26 630 people, with 2·6 million ANC values. Within the total cohort, 17 585 people (66%) were male, 9025 (33·9%) female, and 20 (0·1%) other gender, and the mean age was 36·1 years (SD 13·7). We did not have data on race or ethnicity. Of the 26 630 people taking clozapine, 1146 (4·3%) had minor neutropenia, 313 (1·2%) had serious neutropenia leading to cessation, and 223 (0·8%) had serious neutropenia unrelated to clozapine without cessation. In people with no previous exposure to clozapine (n=15 973), the cumulative incidence of serious neutropenia leading to cessation was 0·9% at 18 weeks and 1·4% at 2 years; the weekly incidence rate for serious neutropenia leading to cessation peaked at 9 weeks (0·128%) and fell to a rolling average weekly incidence of 0·001% by 2 years. For minor neutropenia, the cumulative incidence was 1·7% at 18 weeks and 3·5% at 2 years; the weekly incidence rate peaked at 9 weeks (0·218%) and fell to a stable rolling average of 0·01%. The median time to a serious neutropenic event leading to cessation was 17 weeks (IQR 9·96-102). Previous clozapine exposure reduced the risk of serious neutropenia leading to cessation (OR 0·19, 95% CI 0·12-0·31; p <0·0001). INTERPRETATION: Most serious neutropenia leading to clozapine cessation occurs within 18 weeks of treatment and becomes negligible after 2 years. Weekly haematological monitoring after the first 18 weeks could be safely reduced to once every 4 weeks and ceased after 2 years unless clinically indicated. Clozapine retrial after interruption with 2 cumulative years of unremarkable testing might not require further haematological monitoring. A serious neutropenia ANC threshold of ≤1·0 × 109 per L could be used in more jurisdictions. FUNDING: None.

A classic case of Capnocytophaga induced septic shock with multi-organ failure after a dog bite in an asplenic patient.

We hereby report a case of a 40-year-old male with a recent dog bite, a past history of immune thrombocytopenic purpura (ITP) and therapeutic splenectomy. He presented to the hospital with abdominal pain and shortness of breath, which progressed to sepsis and disseminated intravascular coagulation (DIC). Based on clinical presentation, Capnocytophaga-induced sepsis was suspected, and the diagnosis was confirmed through blood culture. Upon confirmation of the diagnosis, the patient was started on IV ampicillin/sulbactam which improved his condition and led to complete recovery without any long-term effects. Capnocytophaga is a genus of Gram-negative bacteria that are commensal to the oral cavity of common household pets such as dogs and cats. This case highlights the importance of considering Capnocytophaga as a potential pathogen in asplenic patients with recent pet-bites and emphasizes how early recognition and intervention can significantly improve outcomes in these critically-ill patients. It also warrants the need for healthcare providers to consider Capnocytophaga infections from minor pet-bites as a differential diagnosis in immunocompromised as well as immunocompetent individuals.

Hematological and Other Cancers in People Using Clozapine: Analysis of Australian Spontaneous Reports Between 1995 and 2020.

BACKGROUND: Recent observational study evidence suggests that clozapine, unlike other antipsychotics, may be associated with a small increased risk of hematological malignancy. This study described characteristics of hematological and other cancers in those taking clozapine reported to the Australian Therapeutic Goods Administration. METHODS: We analyzed public case reports for "clozapine," "Clozaril," or "Clopine" from January 1995 to December 2020 classified as "neoplasm benign, malignant and unspecified" by the Australian Therapeutic Goods Administration. Data on age, sex, dose, clozapine start and cessation dates, Medical Dictionary for Regulatory Activities reaction terms, and date of cancer were extracted. RESULTS: Overall, 384 spontaneous reports of cancers in people taking clozapine were analyzed. The mean age of patients was 53.9 years (SD, 11.4 years), and 224 (58.3%) were male. The most frequent cancers were hematological (n = 104 [27.1%]), lung (n = 50 [13.0%]), breast (n = 37 [9.6%]), and colorectal (n = 28 [7.3%]). The outcome was fatal for 33.9% of cancer reports. Lymphoma comprised 72.1% of all hematological cancers (mean patient age, 52.1 years; SD, 11.6 years). The median daily dose of clozapine at the time of hematological cancer report was 400 mg (interquartile range, 300-543.8 mg), and the median duration of clozapine use before hematological cancer diagnosis was 7.0 years (interquartile range, 2.8-13.2 years). CONCLUSIONS: Lymphoma and other hematological cancers are overrepresented in spontaneous adverse event reports compared with other cancer types. Clinicians should be aware of the possible association with hematological cancers and monitor for and report any hematological cancers identified. Future studies should examine histology of lymphomas in people using clozapine and corresponding blood level of clozapine.

Neutrophil-lymphocyte ratio - a simple, accessible measure of inflammation, morbidity and prognosis in psychiatric disorders?

OBJECTIVE: A narrative review to describe the utility of the neutrophil-lymphocyte ratio (NLR) as an inflammatory marker in psychiatric and non-psychiatric disorders and to discuss the potential role of NLR in psychiatric research. CONCLUSIONS: NLR is inexpensive and readily available using division of two measures obtained on routine blood testing. NLR is elevated in a number of psychiatric disorders. It can predict morbidity and mortality in a wide range of non-psychiatric conditions, but this has not been confirmed in psychiatric conditions. It can be calculated in large, pre-existing datasets to investigate clinical correlates of inflammatory processes. NLR may have a future role in identifying patients with an inflammatory phenotype who could benefit from adjunctive anti-inflammatory medications.

Systematic review and meta-analysis of rates of clozapine-associated myocarditis and cardiomyopathy.

BACKGROUND: Clozapine is the most effective medication for treatment refractory schizophrenia, but is associated with cardiac adverse drug reactions. Myocarditis and cardiomyopathy are the most serious cardiac adverse drug reactions although reported rates of these conditions vary in the literature. We systematically reviewed and meta-analysed the event rates, the absolute death rates and case fatality rates of myocarditis and cardiomyopathy associated with clozapine. METHODS: PubMed, EMBASE and PsycINFO were searched for studies that reported on the incidence of cardiomyopathy or myocarditis in people exposed to clozapine. Data were meta-analysed using a random effects model, with subgroup analysis on study size, time frame, region, quality, retrospective vs prospective, and diagnostic criteria of myocarditis or cardiomyopathy. RESULTS: 28 studies of 258,961 people exposed to clozapine were included. The event rate of myocarditis was 0.007 (95% confidence interval [CI] = [0.003, 0.016]), absolute death rate was 0.0004 (95% CI = [0.0002, 0.0009]) and case fatality rate was 0.127 (95% CI = [0.034, 0.377]). The cardiomyopathy event rate was 0.006 (95% CI = [0.002, 0.023]), absolute death rate was 0.0003 (95% CI = [0.0001, 0.0012]) and case fatality rate was 0.078 (95% CI = [0.018, 0.285]). Few included studies provided information on criteria for diagnosis of myocarditis and cardiomyopathy. Event rates of cardiomyopathy and myocarditis were higher in Australia. CONCLUSION: Clarity of diagnostic criteria for myocarditis remains a challenge. Observation bias may, in part, influence higher reported rates in Australia. Monitoring for myocarditis is warranted in the first 4 weeks, and treatment of comorbid metabolic syndrome and diabetes may reduce the risk of cardiomyopathy. The risks of myocarditis and cardiomyopathy are low and should not present a barrier to people with treatment refractory schizophrenia being offered a monitored trial of clozapine.

A meta-analysis of controlled studies comparing the association between clozapine and other antipsychotic medications and the development of neutropenia.

BACKGROUND: In most countries, clozapine can only be prescribed with regular monitoring of white blood cell counts because of concerns that clozapine has a stronger association with neutropenia than other antipsychotics. However, this has not been previously demonstrated conclusively with meta-analysis of controlled studies. METHODS: The aim of this study was to assess the strength of the association between clozapine and neutropenia when compared to other antipsychotic medications by a meta-analysis of controlled studies. An electronic search of Medline (1948-2018), PsycINFO (1967-2018) and Embase (1947-2018) using search terms (clozapine OR clopine OR clozaril OR zaponex) AND (neutropenia OR agranulocytosis) was undertaken. Random-effects meta-analysis using Mantel-Haenszel risk ratio was used to assess the strength of the effect size. RESULTS: We located 20 studies that reported rates of neutropenia associated with clozapine and other antipsychotic medications. The risk ratio was not significantly increased in clozapine-exposed groups compared to exposure to other antipsychotic medications (Mantel-Haenszel risk ratio = 1.45, 95% confidence interval = [0.87, 2.42]). This also applied to severe neutropenia (absolute neutrophil count < 500 per µL) when compared to other antipsychotics (Mantel-Haenszel risk ratio = 1.65, 95% confidence interval = [0.58, 4.71]). The relative risk of neutropenia associated with clozapine exposure was not significantly associated with any individual antipsychotic medication. CONCLUSION: Data from controlled trials do not support the belief that clozapine has a stronger association with neutropenia than other antipsychotic medications. This implies that either all antipsychotic drugs should be subjected to haematological monitoring or monitoring isolated to clozapine is not justified.

Cognition in schizophrenia improves with treatment of severe obstructive sleep apnoea: A pilot study.

Previous studies have shown that people with schizophrenia have high rates of Obstructive Sleep Apnoea (OSA). Despite this, intervention studies to treat OSA in this population have not been undertaken. The ASSET (Assessing Sleep in Schizophrenia and Evaluating Treatment) pilot study investigated Continuous Positive Airway Pressure (CPAP) treatment of severe OSA in participants recruited from a clozapine clinic in Adelaide. Participants with severe untreated OSA (Apnoea-Hypopnoea Index (AHI) > 30), were provided with CPAP treatment, and assessed at baseline and six months across the following domains: physical health, quality of sleep, sleepiness, cognition, psychiatric symptoms and CPAP adherence. Six of the eight ASSET participants with severe OSA accepted CPAP. At baseline, half of the cohort had hypertension, all were obese with a mean BMI of 45, and they scored on average 1.47 standard deviations below the normal population in cognitive testing. The mean AHI was 76.8 and sleep architecture was markedly impaired with mean rapid eye movement (REM) sleep 4.1% and mean slow wave sleep (SWS) 4.8%. After six months of treatment there were improvements in cognition (BACS Z score improved by an average of 0.59) and weight loss (mean weight loss 7.3 ±â€¯9 kg). Half of the participants no longer had hypertension and sleep architecture improved with mean REM sleep 31.4% of the night and mean SWS 24% of the night. Our data suggests CPAP may offer novel benefits to address cognitive impairment and sleep disturbance in people with schizophrenia.

Obstructive sleep apnoea is more prevalent in men with schizophrenia compared to general population controls: results of a matched cohort study.

OBJECTIVES:: Obstructive sleep apnoea (OSA) may be more common in people with schizophrenia compared to the general population, but the relative prevalence is unknown. Here, we determine the relative prevalence of severe OSA in a cohort of men with schizophrenia compared to representative general population controls, and investigate the contribution of age and body mass index (BMI) to differences in prevalence. METHODS:: Rates of severe OSA (apnoea-hypopnoea index > 30) were compared between male patients with schizophrenia and controls from a representative general population study of OSA. RESULTS:: The prevalence of severe OSA was 25% in the schizophrenia group and 12.3% in the general population group. In subgroups matched by age, the relative risk of severe OSA was 2.9 ( p = 0.05) in the schizophrenia subjects, but when adjusted for age and BMI, the relative risk dropped to 1.7 and became non-significant ( p = 0.17). CONCLUSIONS:: OSA is prevalent in men with schizophrenia. Obesity may be an important contributing factor to the increased rate of OSA.

Correction to: Clozapine-related neutropenia, myocarditis and cardiomyopathy adverse event reports in Australia 1993-2014.

The authors would like to change the statement found in the results section of the abstract from "There were five reported deaths from neutropenia and cardiomyopathy." to "There were five, 13, and two reported deaths from neutropenia, myocarditis, and cardiomyopathy, respectively."

Clozapine-related neutropenia, myocarditis and cardiomyopathy adverse event reports in Australia 1993-2014.

RATIONALE: Clozapine is the gold-standard medicine for treating refractory schizophrenia but there are some notable serious adverse events (AE). We aimed to analyse reported rates of clozapine cardiac and haematological AEs in Australia. METHODS: Using data from the Therapeutic Goods Administration, we examined all reported clozapine AEs (1993-2014) with a specific focus on neutropenia, myocarditis and cardiomyopathy. We related AEs to clozapine-dispensing data in Queensland, scaled up to Australia. RESULTS: There were 8561 AEs reported: neutropenia (13.7%), myocarditis (9.3%) and cardiomyopathy (3.8%). Reported rates of myocarditis and cardiomyopathy increased after 1999 following a myocarditis case series from Sydney. Cardiomyopathy AE rates have remained stable since then but myocarditis AEs have increased steadily. Neutropenia was more common in women, while cardiomyopathy and myocarditis were more common in men. There were five, 13, and two reported deaths from neutropenia, myocarditis, and cardiomyopathy, respectively. CONCLUSIONS: The rates of serious AEs (including deaths) are low and likely an underestimate of true rates and need to be considered by clinicians in balancing the risks and benefits. Continued education on the monitoring and treatment of these AEs for consumers, carers and health professionals is essential and reporting these to the relevant national reporting agency is crucial.

A cohort study assessing the impact of small volume blood tubes on diagnostic test quality and iatrogenic blood loss in a cohort of adult haematology patients.

BACKGROUND/AIM: To estimate the reduction in blood volume loss and impact on diagnostic test quality associated with introduction of small volume blood tubes in a cohort of haematology inpatients compared to a historical comparator group. METHODS: Prospective cohort study of haematology inpatients admitted to a tertiary referral hospital in Adelaide. Small volume blood tubes were used in an intervention cohort admitted between 2012 and 2013 and compared to a control cohort admitted between 2009 and 2010 where standard volume blood tubes had been used. The diagnostic test quality, specimen integrity and total reduction in blood loss associated with small volume blood tubes were estimated. RESULTS: Small volume blood tubes demonstrated acceptable collinearity on commonly assayed haematological and biochemical parameters. Small volume tubes were associated with a 42% reduction in blood volume loss equating to a saving of 8.5 mL per patient per day or 180 mL of blood loss over a 3-week admission. Small volume blood tubes were associated with a slight but significantly increased rate of fibrin contamination of ethylenediaminetetraacetic acid samples (0.2-0.5% of specimens). CONCLUSION: Small volume blood tubes are associated with a substantial reduction in total blood volume collected per day in haematology inpatients. They have similar diagnostic validity and sample integrity to that of standard volume containers.

Use of granulocyte-colony stimulating factor to prevent recurrent clozapine-induced neutropenia on drug rechallenge: A systematic review of the literature and clinical recommendations.

BACKGROUND: Clozapine is the most effective medication for treatment-refractory schizophrenia; however, its use is contraindicated in people who have had previous clozapine-induced neutropenia. Co-prescription of granulocyte-colony stimulating factor may prevent recurrent neutropenia and allow continuation or rechallenge of clozapine. OBJECTIVE AND METHODS: Systematic review of literature reporting the use of granulocyte-colony stimulating factor to allow rechallenge or continuation of clozapine in people with previous episodes of clozapine-induced neutropenia. The efficacy of granulocyte-colony stimulating factor and predictors of successful rechallenge will be determined to elucidate whether evidence-based recommendations can be made regarding the use of granulocyte-colony stimulating factor in this context. RESULTS: A total of 17 articles were identified that reported on clozapine rechallenge with granulocyte-colony stimulating factor support. In all, 76% of cases were able to continue clozapine at median follow-up of 12 months. There were no clear clinical or laboratory predictors of successful rechallenge; however, initial neutropenia was more severe in successful cases compared to unsuccessful cases. Cases co-prescribed lithium had lower success rates of rechallenge (60%) compared to those who were not prescribed lithium (81%). The most commonly reported rechallenge strategy was use of filgrastim 150-480 µg between daily to three times a week. There were no medication-specific side effects of granulocyte-colony stimulating factor reported apart from euphoria in one case. Three cases who failed granulocyte-colony stimulating factor had bacterial infection at time of recurrent neutropenia. No deaths were reported. CONCLUSION: Preliminary data suggest granulocyte-colony stimulating factor is safe and effective in facilitating rechallenge with clozapine. Clinical recommendations for use are discussed.

Known unknowns and unknown unknowns in suicide risk assessment: evidence from meta-analyses of aleatory and epistemic uncertainty.

Suicide risk assessment aims to reduce uncertainty in order to focus treatment and supervision on those who are judged to be more likely to die by suicide. In this article we consider recent meta-analytic research that highlights the difference between uncertainty about suicide due to chance factors (aleatory uncertainty) and uncertainty that results from lack of knowledge (epistemic uncertainty). We conclude that much of the uncertainty about suicide is aleatory rather than epistemic, and discuss the implications for clinicians.

Australia's economic transition, unemployment, suicide and mental health needs.

OBJECTIVE: There have been substantial changes in workforce and employment patterns in Australia over the past 50 years as a result of economic globalisation. This has resulted in substantial reduction in employment in the manufacturing industry often with large-scale job losses in concentrated sectors and communities. Large-scale job loss events receive significant community attention. To what extent these mass unemployment events contribute to increased psychological distress, mental illness and suicide in affected individuals warrants further consideration. METHODS: Here we undertake a narrative review of published job loss literature. We discuss the impact that large-scale job loss events in the manufacturing sector may have on population mental health, with particular reference to contemporary trends in the Australian economy. We also provide a commentary on the expected outcomes of future job loss events in this context and the implications for Australian public mental health care services. RESULTS AND CONCLUSION: Job loss due to plant closure results in a doubling of psychological distress that peaks 9 months following the unemployment event. The link between job loss and increased rates of mental illness and suicide is less clear. The threat of impending job loss and the social context in which job loss occurs has a significant bearing on psychological outcomes. The implications for Australian public mental health services are discussed.

Meta-Analysis of Longitudinal Cohort Studies of Suicide Risk Assessment among Psychiatric Patients: Heterogeneity in Results and Lack of Improvement over Time.

OBJECTIVE: It is widely assumed that the clinical care of psychiatric patients can be guided by estimates of suicide risk and by using patient characteristics to define a group of high-risk patients. However, the statistical strength and reliability of suicide risk categorization is unknown. Our objective was to investigate the odds of suicide in high-risk compared to lower-risk categories and the suicide rates in high-risk and lower-risk groups. METHOD: We located longitudinal cohort studies where psychiatric patients or people who had made suicide attempts were stratified into high-risk and lower-risk groups for suicide with suicide mortality as the outcome by searching for peer reviewed publications indexed in PubMed or PsychINFO. Electronic searches were supplemented by hand searching of included studies and relevant review articles. Two authors independently extracted data regarding effect size, study population and study design from 53 samples of risk-assessed patients reported in 37 studies. RESULTS: The pooled odds of suicide among high-risk patients compared to lower-risk patients calculated by random effects meta-analysis was of 4.84 (95% Confidence Interval (CI) 3.79-6.20). Between-study heterogeneity was very high (I2 = 93.3). There was no evidence that more recent studies had greater statistical strength than older studies. Over an average follow up period of 63 months the proportion of suicides among the high-risk patients was 5.5% and was 0.9% among lower-risk patients. The meta-analytically derived sensitivity and specificity of a high-risk categorization were 56% and 79% respectively. There was evidence of publication bias in favour of studies that inflated the pooled odds of suicide in high-risk patients. CONCLUSIONS: The strength of suicide risk categorizations based on the presence of multiple risk factors does not greatly exceed the association between individual suicide risk factors and suicide. A statistically strong and reliable method to usefully distinguish patients with a high-risk of suicide remains elusive.

Cannabis use in first episode psychosis: Meta-analysis of prevalence, and the time course of initiation and continued use.

OBJECTIVES: Cannabis use is prevalent among people with first episode psychosis and the epidemiology of its use in early psychosis is unclear. We performed a meta-analysis of observational studies to determine; (1) the interval between age at initiation of cannabis use and age at onset of first episode psychosis, (2) the prevalence of cannabis use at time of first episode psychosis, and (3) the odds of continuing cannabis following treatment for first episode psychosis. DATA SOURCES: Search of electronic databases MEDLINE, EMBASE, PsycINFO, Web of Science and CINAHL for English-language papers using search terms (psychosis OR schizophrenia) AND (cannabis OR marijuana) IN (title OR keyword OR abstract), current to October 2014. STUDY SELECTION: Studies were included if they reported on prevalence of current cannabis use in first episode psychosis cohorts. A total of 37 samples were included for meta-analysis. DATA EXTRACTION: Rates of cannabis use in each sample were extracted to determine prevalence estimates. The age at initiation of regular cannabis and age at onset of psychosis were used to determine the length of cannabis use preceding psychosis. Prevalence estimates at first episode psychosis and various time points of follow-up following first episode psychosis were analysed to determine odds ratio of continuing cannabis use. Data synthesis was performed using random-effects meta-analyses. RESULTS: The pooled estimate for the interval between initiation of regular cannabis use and age at onset of psychosis was 6.3 years (10 samples, standardised mean difference = 1.56, 95% confidence interval = [1.40, 1.72]). The estimated prevalence of cannabis use at first episode psychosis was 33.7% (35 samples, 95% confidence interval = [31%, 39%]). Odds of continued cannabis use between 6 months and 10 years following first episode psychosis was 0.56 (19 samples, 95% confidence interval = [0.40, 0.79]).

Obstructive sleep apnea and schizophrenia: A systematic review to inform clinical practice.

BACKGROUND: Risk factors for obstructive sleep apnea (OSA) are common in people with schizophrenia. Identification and treatment of OSA may improve physical health in this population; however there are no guidelines to inform screening and management. OBJECTIVES: Systematic review to determine, in people with schizophrenia and related disorders: the prevalence of OSA; the prevalence of OSA compared to general population controls; the physical and psychiatric correlates of OSA, associations between antipsychotic medications and OSA; the impact of treatment of OSA on psychiatric and physical health; and the diagnostic validity of OSA screening tools. DATA SOURCES: Medline, EMBASE, ISI Web of Science and PsycINFO electronic databases. Cohort, case-control and cross-sectional studies and RCTs reporting on prevalence of OSA in subjects with schizophrenia and related disorders were reviewed. RESULTS: The prevalence of OSA varied between 1.6% and 52%. The prevalence of OSA was similar between people with schizophrenia and population controls in two studies. Diagnosis of OSA was associated with larger neck circumference, BMI>25, male sex and age>50years. There were no data on physical or psychiatric outcomes following treatment of OSA. The diagnostic utility of OSA screening tools had not been investigated. CONCLUSION: OSA may be prevalent and potentially under-recognized in people with schizophrenia. Further research is required to determine utility of OSA screening tools, the relationships between antipsychotic medications and OSA and any benefits of treating OSA. We propose a strategy for the identification of OSA in people with schizophrenia and related disorders.

Systematic meta-analysis of individual selective serotonin reuptake inhibitor medications and congenital malformations.

CONTEXT: It has been suggested that the commonly prescribed class of antidepressants selective serotonin reuptake inhibitors (SSRIs) are associated with birth defects. However, the teratogenic effect of individual SSRIs has not been previously compared using meta-analysis. OBJECTIVE: To determine the strength of the association between individual SSRIs and major, minor, and cardiac malformation among infants born to women taking these medications. DATA SOURCES: Electronic search of CINAHL, EMBASE, Medline, PsycINFO, and ISI Web of Science using the search terms (SSRI OR antidepressant) AND (obstetric outcome OR malformation OR birth outcome OR teratogen), supplemented by manual searching of published references and requests of primary researchers for unpublished data. STUDY SELECTION: There were 115 studies identified by electronic search and reviewed in full text, which yielded 16 papers reporting 36 data samples for major malformations, nine papers reporting 26 data samples for cardiac malformations, and four papers reporting seven data samples for minor malformations. DATA SYNTHESIS: Fluoxetine (OR 1.14, 95% CI 1.01-1.30) and paroxetine (OR 1.29, 95% CI 1.11-1.49) were associated with increased risk of major malformations. Paroxetine was associated with increased risk of cardiac malformations (OR 1.44, 95% CI 1.12-1.86). Sertraline and citalopram were not significantly associated with congenital malformation. Between-sample heterogeneity was low and a range of methodological considerations had no significant impact on effect size. There was little evidence of publication bias. CONCLUSIONS: Fluoxetine and paroxetine should be avoided in the first trimester and among those at risk of an unplanned pregnancy.