Management of Lithium Dosing Around Delivery: An Observational Study.

Objectives: Recommendations on lithium dosing around delivery vary, with several guidelines suggesting that lithium should be discontinued prior to delivery. We aimed to evaluate the validity of these recommendations by investigating 1) maternal lithium blood level changes following delivery, and 2) the association between neonatal lithium blood levels at delivery and neonatal outcomes. Methods: In this retrospective observational cohort study, we included women with at least one lithium blood level measurement during the final week of pregnancy and the first postpartum week. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels (obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery) were available. Results: There were a total of 233 maternal lithium blood level measurements; 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. There was no association between time and lithium blood level/dose ratio (Pearson correlation coefficient -0.03, P = .63). Additionally, we included a total of 29 neonates for whom a lithium measurement was performed within 24 hours postpartum. Maternal and neonatal lithium blood levels were strongly correlated. We observed no associations between neonatal lithium blood levels at delivery and neonatal outcomes. Conclusion: Based on our findings, we do not recommend lowering the dosage or discontinuation of lithium prior to delivery. Stable dosing can prevent subtherapeutic lithium serum levels, which is especially important in the postpartum period when relapse risks are highest.Appeared originally in Bipolar Disord 2021; 23:49-54.

Outcomes at the Motherhood Center: A Comparison of Virtual and On-Site Versions of a Specialized Perinatal Partial Hospitalization Program.

OBJECTIVES: Remotely administered mental health care is becoming increasingly common for treatment of a range of psychiatric disorders; however, there is a dearth of literature overviewing direct comparisons between remote and in-person interventions for treatment of Perinatal Mood and Anxiety Disorders (PMADs). The sudden advent of the Covid-19 pandemic in New York City forced an abrupt conversion for an intensive day treatment program for new mothers with PMADs, from an on-site to a remote program. METHODS: The current report compares outcomes of 81 women who completed the program in-person to those of 60 women who completed the program remotely. RESULTS: Improvement in depression scores was statistically superior in the remote program, and improvement in mother-infant bonding was statistically equivalent between the on-site and remote programs. DISCUSSION: These findings indicate that specialized partial hospitalization treatment for individuals with moderate to severe psychiatric illness can be effectively provided via telehealth, thus offering improved convenience, accessibility, and safety without compromising care. We conclude that remotely administered group psychotherapy is an effective intervention for women with moderate to severe PMADs.

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.

Risks and benefits of pre-delivery taper in pregnant women taking antidepressants.

BACKGROUND: Serotonin reuptake inhibitors are commonly used for treatment of mental health problems in pregnancy but may cause neonatal adaptation syndrome. It is unknown whether reduction or discontinuation of medication prior to delivery may mitigate this effect. METHODS: We present a case series of 38 women who either tapered their medication prior to delivery or maintained or increased their dose. RESULTS: Greater reductions in maternal antidepressant dose just prior to delivery were associated with fewer admissions to the neonatal intensive care unit (NICU) for infants. There was a slightly greater increase in depressive symptoms across delivery for women who tapered, which was not statistically significant. CONCLUSIONS: NICU admissions may be less frequent among neonates whose mothers tapered their medication prior to delivery. Large prospective randomized trials are needed to further study this practice.

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.

Insulin resistance and accelerated cognitive aging.

Insulin resistance may be an early sign of metabolic dysfunction with the potential to lead to neuropsychiatric sequelae in the long term. In order to identify whether insulin resistance in otherwise healthy young and middle-aged adults is associated with preclinical signs of neuropsychiatric impairment, we recruited 126 overweight but nondiabetic, nondepressed individuals who completed an insulin suppression test for direct measurement of insulin resistance as well as a battery of cognitive and neuropsychiatric measures. Insulin resistance was associated with weaker performance on a fine motor task (Purdue Pegboard) as well as increases in subclinical symptoms of depression. We submit that insulin resistance in early to mid-adulthood may be an important predictor of long-term risk for metabolic, psychiatric, and neurobehavioral dysfunction.

Neurodevelopment in school-aged children after intrauterine exposure to antipsychotics.

OBJECTIVE: Antipsychotics are increasingly prescribed in pregnancy, yet little is known about potential long-term developmental effects on children. In this study, we investigated the effect of prenatal antipsychotic exposure on neurodevelopmental functioning in school-aged children. METHODS: We performed a cross-sectional neurodevelopmental assessment of 91 children aged 6-14 years whose mothers had severe mental illness and were either exposed or unexposed to antipsychotic medication during pregnancy. Neurodevelopmental outcomes were assessed using validated neurodevelopmental assessment instruments to examine the child's IQ and global cognitive functioning, and the presence of any psychiatric disorders and/or learning problems in the child was assessed by parental report. RESULTS: No statistically significant associations were found between antipsychotic exposure during pregnancy and either adverse neurodevelopmental outcomes (IQ, neuropsychological function), likelihood of psychiatric diagnosis, or learning problems based on parental report. Analyses were likely limited in power to detect subtler differences in neurodevelopmental functioning because of small sample size and heterogeneity of the sample. CONCLUSIONS: In this exploratory cohort study, intrauterine exposure to antipsychotics was not associated with any adverse effect on IQ or neurodevelopmental functioning in a cohort of school-aged children (6-14 years).

Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder with peripartum onset: A multicenter, open-label, controlled proof-of-concept clinical trial (DELOS-1).

BACKGROUND: Postpartum depression has a high prevalence in the United States (~13 %) and often goes undertreated/untreated. We conducted a multicenter, open-label, proof-of-concept trial to assess the Nesos wearable, non-invasive, transcutaneous auricular vagus nerve stimulation (taVNS) system for the treatment of major depressive disorder with peripartum onset (PPD). METHODS: Women (n = 25), ages 18 to 45, within 9 months postpartum, and diagnosed with PPD were enrolled at 3 sites. The study included 6 weeks open-label therapy and 2 weeks observation. Efficacy outcomes included change from baseline (CFB) in Hamilton Rating Scale for Depression (HAMD17) total scores, HAM-D17 response and remission, and patient and clinician global impression of change (PGIC, CGIC) scores. Analysis included descriptive statistics and mixed-effects models for repeated measures. RESULTS: The most common AEs (≥5 %) were discomfort (n = 5), headache (n = 3), and dizziness (n = 2); all resolved without intervention. No serious AEs or deaths occurred. Baseline mean HAM-D17 score was 18.4. Week 6 least squares (LS) mean CFB in HAM-D17 score was -9.7; 74 % achieved response and 61 % achieved remission. At week 6, at least some improvement was reported by 21 of 22 (95 %) clinicians on CGIC and 22 of 23 (96 %) participants on PGIC. LIMITATIONS: This was a single-arm, open-label study, and enrollment was limited to participants with mild-to-moderate peripartum depression. CONCLUSION: Results from this proof-of-concept study suggest that the Nesos taVNS system is well tolerated and may be an effective non-invasive, non-pharmacological treatment for major depressive disorder with peripartum onset. Further evaluation in larger sham-controlled studies is needed. CLINICALTRIALS: govNCT03972995.

Family history of diabetes moderates metabolic depression endophenotypes in overweight/obese adults.

OBJECTIVE: Insulin resistance (IR) is linked to depressive disorders, and there is growing evidence that targeting IR may be beneficial in treating them. We examine the association between depressive symptoms and a direct measure of IR, and whether family history of type 2 diabetes (FHx-T2DM) or major depressive disorder (FHx-MDD) moderate this relationship. METHODS: Cross-sectional data were collected from 96 primarily overweight/obese adults ages 25-50 without diabetes or clinical depression. Multiple regression and correlation analyses were used to assess the association between depressive symptoms and a direct measure of IR (steady-state plasma glucose) as well as moderating effects of FHx-T2DM or FHx-MDD. RESULTS: In the total sample, elevated depressive symptoms were positively associated with IR (p = 0.005). IR was associated with depressive symptoms in subjects with FHx-T2DM (p = 0.002) or FHx-MDD (p = 0.009) whereas BMI was associated with depressive symptoms in subjects without FHx-T2DM (p = 0.049) or FHx-MDD (p = 0.029). The odds of being in the top tertile of IR increased with elevated depressive symptoms alone (OR, 4.22; 95%CI, 1.15 to 17.33), presence of FHx-T2DM alone (OR, 3.42; 95%CI, 1.26 to 10.00), and presence of both FHx-T2DM and elevated depressive symptoms (OR, 10.08; 95%CI, 1.94 to 96.96). CONCLUSIONS: Our findings indicate that depressive symptoms are positively associated with a direct measure of IR in overweight/obese individuals without diabetes or clinical depression. This association is moderated by FHx-T2DM. Early identification of groups vulnerable to IR related to depressive symptomatology may be useful for determining personalized interventions that have the potential to reduce morbidity in later years.

Maternal attachment insecurity, maltreatment history, and depressive symptoms are associated with broad DNA methylation signatures in infants.

The early environment, including maternal characteristics, provides many cues to young organisms that shape their long-term physical and mental health. Identifying the earliest molecular events that precede observable developmental outcomes could help identify children in need of support prior to the onset of physical and mental health difficulties. In this study, we examined whether mothers' attachment insecurity, maltreatment history, and depressive symptoms were associated with alterations in DNA methylation patterns in their infants, and whether these correlates in the infant epigenome were associated with socioemotional and behavioral functioning in toddlerhood. We recruited 156 women oversampled for histories of depression, who completed psychiatric interviews and depression screening during pregnancy, then provided follow-up behavioral data on their children at 18 months. Buccal cell DNA was obtained from 32 of their infants for a large-scale analysis of methylation patterns across 5 × 106 individual CpG dinucleotides, using clustering-based significance criteria to control for multiple comparisons. We found that tens of thousands of individual infant CpGs were alternatively methylated in association with maternal attachment insecurity, maltreatment in childhood, and antenatal and postpartum depressive symptoms, including genes implicated in developmental patterning, cell-cell communication, hormonal regulation, immune function/inflammatory response, and neurotransmission. Density of DNA methylation at selected genes from the result set was also significantly associated with toddler socioemotional and behavioral problems. This is the first report to identify novel regions of the human infant genome at which DNA methylation patterns are associated longitudinally both with maternal characteristics and with offspring socioemotional and behavioral problems in toddlerhood.

Lower functional hippocampal connectivity in healthy adults is jointly associated with higher levels of leptin and insulin resistance.

BACKGROUND: Metabolic dysregulation is currently considered a major risk factor for hippocampal pathology. The aim of the present study was to characterize the influence of key metabolic drivers on functional connectivity of the hippocampus in healthy adults. METHODS: Insulin resistance was directly quantified by measuring steady-state plasma glucose (SSPG) concentration during the insulin suppression test and fasting levels of insulin, glucose, leptin, and cortisol, and measurements of body mass index and waist circumference were obtained in a sample of healthy cognitively intact adults (n = 104). Resting-state neuroimaging data were also acquired for the quantification of hippocampal functional cohesiveness and integration with the major resting-state networks (RSNs). Data-driven analysis using unsupervised machine learning (k-means clustering) was then employed to identify clusters of individuals based on their metabolic and functional connectivity profiles. RESULTS: K-means clustering identified two clusters of increasing metabolic deviance evidenced by cluster differences in the plasma levels of leptin (40.36 (29.97) vs. 27.59 (25.58) µg/L) and the degree of insulin resistance (SSPG concentration: 161.63 (65.27) vs. 125.72 (66.81) mg/dL). Individuals in the cluster with higher metabolic deviance showed lower functional cohesiveness within each hippocampus and lower integration of posterior and anterior components of the left and right hippocampus with the major RSNs. The two clusters did not differ in general intellectual ability or episodic memory. CONCLUSIONS: We identified two clusters of individuals differentiated by abnormalities in insulin resistance, leptin levels, and hippocampal connectivity, with one of the clusters showing greater deviance. These findings support the link between metabolic dysregulation and hippocampal function even in nonclinical samples.

Hippocampal volume reduction is associated with direct measure of insulin resistance in adults.

Hippocampal integrity is highly susceptible to metabolic dysfunction, yet its mechanisms are not well defined. We studied 126 healthy individuals aged 23-61 years. Insulin resistance (IR) was quantified by measuring steady-state plasma glucose (SSPG) concentration during the insulin suppression test. Body mass index (BMI), adiposity, fasting insulin, glucose, leptin as well as structural neuroimaing with automatic hippocampal subfield segmentation were performed. Data analysis using unsupervised machine learning (k-means clustering) identified two subgroups reflecting a pattern of more pronounced hippocampal volume reduction being concurrently associated with greater adiposity and insulin resistance; the hippocampal volume reductions were uniform across subfields. Individuals in the most deviant subgroup were predominantly women (79 versus 42 %) with higher BMI [27.9 (2.5) versus 30.5 (4.6) kg/m2], IR (SSPG concentration, [156 (61) versus 123 (70) mg/dL] and leptinemia [21.7 (17.0) versus 44.5 (30.4) µg/L]. The use of person-based modeling in healthy individuals suggests that adiposity, insulin resistance and compromised structural hippocampal integrity behave as a composite phenotype; female sex emerged as risk factor for this phenotype.

In utero exposure to antipsychotic medication and psychiatric outcomes in the offspring.

Information on neurodevelopmental effects of antenatal exposure to antipsychotics is limited to 10 studies, all examining children up to 5 years of age or less. The paper aimed to investigate the association between in utero exposure to antipsychotics and psychiatric outcomes in children using Danish nationwide registers. In total, 9011 liveborn singletons born 1998-2015 in Denmark whose mothers took antipsychotic medication before pregnancy were identified. Children whose mothers continued to take antipsychotics during pregnancy were compared with children of mothers who discontinued antipsychotics before pregnancy. As a negative control, paternal antipsychotic use in the same window was investigated. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression for the primary outcome of psychiatric disorders, as well for subcategories of psychiatric disorders. In total, 9.9% of children in the discontinuation group and 11.0% of children in the continuation group received a psychiatric disorder diagnosis during follow-up. The adjusted HR for psychiatric disorders among offspring in the continuation group compared to the discontinuation group was 1.10 (95% CI 0.93-1.30). For antipsychotic use in the fathers, the HR was 1.05 (95% CI 0.89-1.24). The study does not provide evidence of increased risk of psychiatric disorders among children of women who continue antipsychotic treatment during pregnancy. This was observed after accounting for the underlying risk conferred by maternal psychiatric disorders. This suggests women who need to continue antipsychotic medications during pregnancy can do so without adverse psychiatric outcomes for offspring.

Factors associated with parent views about participation in infant MRI research provide guidance for the design of the Healthy Brain and Child Development (HBCD) study.

PURPOSE: The National Institutes of Health announced the Healthy Brain and Child Development (HBCD) study to further understanding of infant brain development. This study examined perceptions and knowledge about research among the demographic groups to be studied in HBCD. METHOD: 1164 participants (n = 548 pregnant people and 616 mothers of infants < 12 months) completed anonymous, on-line surveys. Domains included research literacy, MRI knowledge, and attitudes about research incentives and biospecimen collection. Logistic regression was used to examine factors related to outcome variables. RESULTS: Knowledge of MRI safety was low and research literacy was high across participants. Likelihood of participation given various incentives differed between participants. Those with lower education were less likely to rate any items as increasing likelihood of participation. Substance use during pregnancy improved the model fit only for items about alternate visit structures (home and telephone visits) and confidentiality. CONCLUSION: Overall results support the feasibility of infant imaging studies, such as HBCD with respondents having high research literacy and interest in learning about their baby's development. Educating potential participants about MRI safety and providing flexible incentives for participation will improve the success of infant MRI studies.

Breastfeeding Difficulties Predict Mothers' Bonding with Their Infants from Birth to Age Six Months.

OBJECTIVES: We examined the association between breastfeeding difficulties and trajectories of bonding in the first 6 months postpartum. METHODS: Each month for the first 6 months following birth, 121 mothers of newborn infants (age = 23-45 years, M = 32.31 ± 4.79, 57% White, 23% Asian, 11% Hispanic, 9% Multiracial, 1% Black/African American) were invited to complete self-assessments of bonding. At the first postpartum assessment, mothers who intended to breastfeed also reported whether breastfeeding was more difficult than they had anticipated. We conducted linear mixed modelling to test whether early breastfeeding difficulty was associated with bonding trajectories and examined whether effects remained when accounting for postnatal depression symptoms. RESULTS: We found main effects of breastfeeding difficulty (ß = - .20, 95% CI [ -  .34, - .06]) and postpartum month (ß = .13, 95% CI [.07, .20]) on bonding. On average, women who reported breastfeeding difficulty reported lower bonding than women who did not (Cohen's d = - 0.44, 95% CI [- 0.81, - 0.06]). Additional analyses indicated that, independent of breastfeeding difficulties, women who reported higher postnatal depressive symptoms across the first 6 months postpartum reported lower levels of bonding, on average. Further, within-individual decreases in postnatal depressive symptoms across the first six months were associated with relative improvements in bonding across this period. CONCLUSIONS FOR PRACTICE: Our findings suggest that mothers who experience breastfeeding difficulties are at risk for reduced bonding with their infants in the first 6 months after birth. Moreover, while postnatal depressive symptoms are also associated with reduced bonding, the effect of breastfeeding difficulties on bonding persists over and above the effect of postnatal depressive symptoms.

Management of lithium dosing around delivery: An observational study.

OBJECTIVES: Recommendations on lithium dosing around delivery vary, with several guidelines suggesting that lithium should be discontinued prior to delivery. We aimed to evaluate the validity of these recommendations by investigating 1) maternal lithium blood level changes following delivery, and 2) the association between neonatal lithium blood levels at delivery and neonatal outcomes. METHODS: In this retrospective observational cohort study, we included women with at least one lithium blood level measurement during the final week of pregnancy and the first postpartum week. For aim 2, we included a subcohort of women with neonates for whom neonatal lithium blood levels (obtained from the umbilical cord or a neonatal vein puncture within 24 hours of delivery) were available. RESULTS: There were a total of 233 maternal lithium blood level measurements; 55 (23.6%) in the week before delivery and 178 (76.4%) in the week after. There was no association between time and lithium blood level/dose ratio (Pearson correlation coefficient -0.03, P = .63). Additionally, we included a total of 29 neonates for whom a lithium measurement was performed within 24 hours postpartum. Maternal and neonatal lithium blood levels were strongly correlated. We observed no associations between neonatal lithium blood levels at delivery and neonatal outcomes. CONCLUSION: Based on our findings, we do not recommend lowering the dosage or discontinuation of lithium prior to delivery. Stable dosing can prevent subtherapeutic lithium serum levels, which is especially important in the postpartum period when relapse risks are highest.

Racial and Ethnic Disparities in Hospital-Based Care Associated with Postpartum Depression.

OBJECTIVE: To estimate racial and ethnic differences in rates of hospital-based care associated with postpartum depression. METHODS: This is a retrospective cohort study using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes within data from the Office of Statewide Planning and Development in California. We included primiparous women who underwent delivery hospitalization from 2008 to 2012. The primary outcome was the first postpartum hospital encounter with a ICD-9-CM code for depression over a 9-month period after delivery. We examined the cumulative incidence of hospital-based care for postpartum depression by race/ethnicity. Logistic regression was used to estimate relative risk. RESULTS: The study cohort consisted of 984,167 primiparous women: 314,037 (32%) were non-Hispanic White; 59,754 (6%) were non-Hispanic Black; 150,855 (15%) were non-Hispanic Asian; 448,770 (46%) were Hispanic; and 10,399 (1%) were other races. The cumulative incidence of hospital-based care for postpartum depression was highest for Black women (39; 95% CI = 34-44 per 10,000 deliveries) and lowest for Asian women (7; 95% CI = 5-8 per 10,000 deliveries). Compared with White women, hospital-based care for postpartum depression was more likely to be provided to Black women (OR = 2.3; 95% CI = 1.9-2.7), whereas care was less likely for Asians (OR = 0.4; 95% CI = 0.3-0.5) and Hispanics (OR = 0.8; 95% CI = 0.7-1.0). Similar findings were observed after excluding women with antepartum depression, adjusting for sociodemographic and clinical variables, and stratifying according to care settings. CONCLUSION: Compared with White women, hospital-based care for postpartum depression more frequently impacts Black women. Identifying and improving inequities in access to and utilization of mental health care for postpartum women should be a maternal health priority.

Attachment Security in Pregnancy Mediates the Association Between Maternal Childhood Maltreatment and Emotional and Behavioral Problems in Offspring.

Attachment security may be a mechanism by which exposure to early life adversity affects subsequent generations. We used a prospective cohort design to examine this possibility in a convenience sample of 124 women (age = 23-45 years, M = 32.32 [SD = 4.83] years; 57.3% White, 22.6% Asian) who provided self-reports of attachment style during pregnancy using the Attachment Style Questionnaire, of whom 96 (age = 28-50 years, M = 36.67 [SD = 4.90] years; 60.4% White, 19.8% Asian) were reassessed when their child was preschool-age (M = 4.38 [SD = 1.29] years). Women self-reported on their own childhood maltreatment severity and their child's current emotional and behavioral problems using the Childhood Trauma Questionnaire and the Child Behavior Checklist for ages 1.5-5, respectively. Maternal childhood maltreatment severity was associated with less secure, and more avoidant and anxious attachment. Mediation analyses revealed further that less secure maternal attachment, but not avoidant or anxious attachment, mediated the associations between maternal childhood maltreatment and offspring emotional and behavioral problems. These findings suggest that improving maternal attachment security, which can be identified even prior to the child's birth, is an important target to consider for intervention efforts aimed at minimizing adverse intergenerational effects of early life adversity.

Benzodiazepine use before conception and risk of ectopic pregnancy.

STUDY QUESTION: Are women who fill a benzodiazepine prescription before conception at increased risk of ectopic pregnancy? SUMMARY ANSWER: Risk of ectopic pregnancy is 50% higher among women who fill a benzodiazepine prescription before conception. WHAT IS KNOWN ALREADY: Benzodiazepine use in pregnancy increases the risk of miscarriage, adverse birth outcomes and adverse child development outcomes. STUDY DESIGN, SIZE, DURATION: Using data from US commercial insurance claims, we performed a cohort study of 1 691 366 pregnancies between 1 November 2008 and 30 September 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified ectopic pregnancies using diagnosis and procedure codes and used unadjusted and inverse probability of treatment (IPT)-weighted log-binomial models to calculate relative risks (RR) of ectopic pregnancy for pregnant women who did and did not fill any prescriptions for benzodiazepines in the 90 days before conception. Two sub-groups of women with specific indications for benzodiazepine use were also examined-women who had a least one diagnosis for anxiety disorder and women who had at least one diagnosis of insomnia in the year before conception. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 1 691 366 pregnancies, 1.06% filled at least two benzodiazepine prescriptions totaling at least 10 days supply in the 90 days before conception. Among women with a benzodiazepine prescription, there was an excess of 80 ectopic pregnancies per 10 000 pregnancies, and their IPT-weighted risk of ectopic pregnancies was 1.47 (95% CI 1.32 to 1.63) times greater relative to women without benzodiazepine prescriptions before conception. The IPT-weighted RR between ectopic pregnancy and benzodiazepine use was 1.34 (95% CI 1.18 to 1.53) among women with anxiety disorder diagnoses and 1.28 (95% CI 0.99 to 1.68) among women with an insomnia diagnosis. LIMITATIONS, REASONS FOR CAUTION: We relied on outpatient prescription data to identify benzodiazepine use before conception, which could result in over- or under-estimation of actual benzodiazepine consumption. We relied on medical claim codes to identify pregnancies and conception date, which may result in misclassification of pregnancy outcomes and gestational length. WIDER IMPLICATIONS OF THE FINDINGS: This study found that women who have a benzodiazepine prescription before conception are at an increased risk of ectopic pregnancy. This information can help women, and their healthcare providers make more fully informed decisions about benzodiazepine use in their reproductive years. STUDY FUNDING/COMPETING INTEREST(S): Funding for this project was provided by a Banting Postdoctoral Fellowship and a Stanford Maternal and Child Health Research Institute Postdoctoral Award. Data access for this project was provided by the Stanford Center for Population Health Sciences Data Core. The PHS Data Core is supported by a National Institutes of Health National Center for Advancing Translational Science Clinical and Translational Science Award (UL1 TR001085) and internal Stanford funding. The authors have no competing interest. TRIAL REGISTRATION NUMBER: N/A.

Antidepressant Use around Conception, Prepregnancy Depression, and Risk of Ectopic Pregnancy.

OBJECTIVE: To compare the risk of ectopic pregnancy among women with and women without antidepressant prescriptions around conception and examine whether this risk differs by prepregnancy depression status. METHODS: We conducted a cohort study of all pregnancies between November 1, 2008, and September 30, 2015, identified in the nationwide (American) IBM® MarketScan® Databases. At least one day's supply of antidepressants in the 3 weeks after a woman's last menstrual period defined active antidepressant use around conception. At least one depression diagnosis in the year before the last menstrual period defined prepregnancy depression. Relative risk (RR) of ectopic pregnancy was estimated using unadjusted and inverse probability of treatment (IPT)-weighted log-binomial models. RESULTS: Of the 1,703,245 pregnancies, 106,788 (6.3%) women had a prepregnancy depression diagnosis. Among women with a depression diagnosis, 40,287 (37.7%) had an active antidepressant prescription around conception; the IPT-weighted risk of ectopic pregnancy was similar among women who did and did not fill an antidepressant prescription around conception (IPT-weighted RR = 1.01; 95% CI, 0.93 to 1.10). Overall, the risk of ectopic pregnancy was higher among women who had a prepregnancy depression diagnosis than women who did not have a prepregnancy depression diagnosis (IPT-weighted RR = 1.09; 95% CI, 1.04 to 1.15). CONCLUSIONS: This study's findings suggest that women who have a prepregnancy depression diagnosis are at a slightly increased risk of ectopic pregnancy, and among women who have a prepregnancy depression diagnosis, the use of antidepressants around conception does not increase the risk of ectopic pregnancy.