Effects of Prenatal Exposure to Second-Generation Antipsychotics on Development and Behavior Among Preschool-Aged Children: Preliminary Results From the National Pregnancy Registry for Psychiatric Medications.

Objective: Data are lacking on the neurodevelopmental outcomes of children prenatally exposed to second-generation antipsychotics (SGAs). The objective of this study is to examine neurodevelopmental outcomes of children exposed in utero to SGAs compared to those unexposed in a cohort of mothers with psychiatric morbidity.Methods: We conducted a cross-sectional assessment of preschool-aged children whose mothers were enrolled in the National Pregnancy Registry for Psychiatric Medications. Two validated, parent-report developmental and behavioral screening assessments, the Ages and Stages Questionnaire, Third Edition (ASQ-3) and the Preschool Child Behavior Checklist for Ages 1½-5 (CBCL/1½-5), respectively, were delivered electronically to eligible participants. Outcomes of children exposed in utero to SGAs were compared to those unexposed to SGAs in a cohort of mothers with a history of psychiatric illness. Exposure to other psychotropic medications during pregnancy was not an exclusion criterion for either group.Results: From January 2, 2018, to February 2, 2021, 520 children were eligible, and 352 responses were collected (67.7%), including 178 children in the SGA-exposed group (mean age = 2.6 years) and 174 children in the unexposed comparison group (mean age = 2.1 years). No significant differences between groups were detected (OR = 1.24, 95% CI, 0.74-2.09) with respect to developmental outcomes assessed by the ASQ-3. Similarly, for behavioral outcomes, adjusted analysis showed no significant differences in odds of an abnormal "clinical" score on the CBCL/1½-5 composite scales.Conclusions: The current study is the first to examine neurobehavioral outcomes of preschool-aged children exposed prenatally to SGAs. No significant differences in overall development or behavior were detected in the exposed versus unexposed group. These preliminary findings are an important step in delineating neurodevelopmental effects of prenatal SGA exposure.

Stressors and coping mechanisms among pregnant women with psychiatric disorders during the COVID-19 pandemic.

BACKGROUND: Women with psychiatric disorders are vulnerable to relapse in pregnancy, and the COVID-19 pandemic has presented an additional stressor. METHODS: Data came from a supplemental study offered to women enrolled in the Massachusetts General Hospital Center for Women's Mental Health National Pregnancy Registry for Psychiatric Medications. Registry participants were also invited to complete an email questionnaire relating to their experiences of pregnancy during the pandemic. Prepartum experiences of 230 respondents were analyzed. RESULTS: The most common diagnoses in this group were depression (30%), anxiety disorders (29%), and bipolar affective disorder (17%). Common stressors included changes in employment, greater childcare and/or schooling responsibilities, more conflict in the household, and increased isolation. Participants reported negative impacts and/or coping mechanisms associated with the pandemic, such as sleep problems, reduced physical activity, changes in eating, and greater amounts of screen time. Positive impacts and/or coping mechanisms were also reported, including more quality time with family, more time in nature, and being more appreciative of aspects of life previously taken for granted. CONCLUSIONS: Our findings suggest that the COVID-19 pandemic has had an overall negative psychosocial impact on many pregnant women with preexisting psychiatric disorders. We also observed positive coping mechanisms, which could be drawn on as sources of resilience.

Risk of Major Malformations in Infants After First-Trimester Exposure to Stimulants: Results From the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications.

PURPOSE/BACKGROUND: The prevalence of attention-deficit/hyperactivity disorder in adult females is 3% to 4%. Attention-deficit/hyperactivity disorder is highly comorbid with other psychiatric disorders such as mood, anxiety, and substance use disorders. For reproductive-aged women, the treatment of attention-deficit/hyperactivity disorder with stimulant medications may be considered during pregnancy or breastfeeding, although historically, data are lacking to inform these decisions. The aim of this investigation was to determine the risk of major malformations in infants after first-trimester prescription stimulant exposure in a small but rigorously characterized sample. METHODS/PROCEDURES: The Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications systematically ascertains information from pregnant females including demographic information, medical and psychiatric history, use of prescription medications, and other information relevant to fetal outcomes. Participants provide verbal informed consent and are interviewed twice during gestation and again at approximately 3 months postpartum. The primary outcome of interest is the presence of a major malformation identified within 6 months after birth. Redacted cases of major malformations are reviewed by a dysmorphologist blinded to medication exposure. FINDINGS/RESULTS: A total of N = 1988 women were eligible for this analysis, including the following exposures: n = 173 to mixed amphetamine salts; n = 40 to lisdexamfetamine; n = 45 to methylphenidate; n = 3 to dexmethylphenidate; and n = 1755 controls. The odds ratio of a major malformation among infants after first-trimester exposure to any stimulant was 0.39 (95% confidence interval, 0.09-1.61) compared with controls. There were no major malformations observed in infants exposed to lisdexamfetamine, methylphenidate, or dexmethylphenidate. IMPLICATIONS/CONCLUSIONS: Although preliminary, this analysis from an ongoing pregnancy registry provides reassurance that these stimulants do not appear to have major teratogenic effects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01246765 .

Risk of Major Malformations Following First-Trimester Exposure to Olanzapine: Preliminary Data From the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications.

PURPOSE/BACKGROUND: Since its US Food and Drug Administration approval in 1996, olanzapine has been one of the most commonly prescribed atypical antipsychotics, making a better understanding of its reproductive safety profile critical. The goal of the current analysis was to determine the risk of major malformations among infants exposed to olanzapine during pregnancy compared with a group of nonexposed infants. METHODS/PROCEDURES: The National Pregnancy Registry for Psychiatric Medications is a prospective pharmacovigilance program in which pregnant women are enrolled and interviewed during pregnancy and the postpartum period. Labor and delivery and pediatric medical records were screened for evidence of major malformations followed by adjudication by a dysmorphologist blinded to medication exposure. Infants with first-trimester exposure to olanzapine were compared with controls without second-generation antipsychotic exposure. FINDINGS/RESULTS: As of April 18, 2022, 2619 women have enrolled in the study. At the time of data extraction, 49 olanzapine-exposed infants and 1156 infants in the comparison group were eligible for these analyses. There were no major malformations associated with olanzapine exposure in the first trimester. The absolute risk for major malformations in the exposure group was 0.00% (95% confidence interval, 0.00-7.25) for olanzapine compared with 1.64% (95% confidence interval, 0.99-2.55) in the control group. IMPLICATIONS/CONCLUSIONS: In this prospective cohort, no major malformations were associated with olanzapine exposure during the first trimester. Although these data are preliminary and cannot rule out more modest effects, they are nonetheless important, adding to the growing reproductive safety data for olanzapine.

Risk of Poor Neonatal Adaptation Syndrome Among Infants Exposed to Second-Generation Atypical Antipsychotics Compared to Antidepressants: Results From the National Pregnancy Registry for Psychiatric Medications.

Objective: While poor neonatal adaptation syndrome (PNAS) has been particularly well described among infants exposed to antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), this is not the case for second-generation antipsychotics (SGAs). In 2011, the US Food and Drug Administration (FDA) issued a drug safety warning regarding fetal antipsychotic exposure and risk for PNAS and extrapyramidal symptoms (EPS). The primary objective of this study was to examine the risk for PNAS among infants exposed to SGAs compared to SSRI/SNRI-exposed infants, leveraging the prospective, longitudinal design of the National Pregnancy Registry for Psychiatric Medications (NPRPM).Methods: The NPRPM is a prospective pharmacovigilance program in which pregnant women, aged 18-45 years, are enrolled and followed prospectively. Medical records were systematically reviewed and data abstracted using a checklist of PNAS and EPS symptoms specifically outlined in the FDA drug safety warning. The two study groups included infants exposed to an SGA during pregnancy and infants exposed to an SSRI/SNRI during pregnancy. The primary outcome was the presence of at least one or more PNAS symptoms during the first month of life. Other neonatal outcomes following exposure to the medication of interest, including preterm birth, neonatal intensive care unit (NICU) admission, rates of EPS, and whether infants were discharged home with their mothers, are also reported.Results: Of the 2,145 women enrolled in this study as of December 16, 2020, a total of 373 women and their infants (n = 384) were eligible for inclusion (n = 193 SGA-exposed infants and 191 SSRI/SNRI-exposed infants). Among SGA-exposed infants, 32.6% (63/193) experienced at least 1 PNAS sign compared to 34.6% of infants (66/191) in the SSRI/SNRI-exposed group. The majority of infants in each group showed no symptoms of PNAS. No differences were observed between the two groups with respect to rates of preterm birth, NICU admission, prevalence of EPS, and timing of infants being discharged home with their mothers.Conclusions: PNAS symptomatology was comparable among infants exposed prenatally to an SGA or to an SSRI/SNRI. These preliminary findings provide an estimated risk of PNAS among infants exposed to SGAs of roughly 30%. Interestingly, these findings are also consistent with estimates in the literature of PNAS in SSRI/SNRI-exposed infants, suggesting a possible common pathway underlying this phenomenon.Trial Registration: ClinicalTrials.gov identifier: NCT01246765.

Reproductive Safety of Lurasidone and Quetiapine: Update from the National Pregnancy Registry for Psychiatric Medications.

Background: Second-generation antipsychotics (SGAs), also called atypical antipsychotics, are common therapies for women with a spectrum of psychiatric disorders. No systematically ascertained human reproductive safety data are available for lurasidone, and prospective data for quetiapine are limited, making decisions regarding use of these medications during pregnancy complicated. Materials and Methods: The National Pregnancy Registry for Psychiatric Medications is a prospective cohort study designed to collect reproductive safety data relative to SGAs. Pregnant women aged 18-45 years, with psychiatric illness and prenatal psychotropic medication exposure completed three phone interviews during pregnancy and the postpartum period. Cases of presumed malformations are abstracted from medical records for adjudication by a teratologist blinded to medication exposure. Results: Of 2,293 women enrolled at the time of analysis, 134 in the lurasidone group, 264 in the quetiapine group, and 886 controls completed the postpartum interview and were therefore eligible for inclusion. Dropped or lost-to-follow-up participants (13%) and those currently pregnant were excluded. Participants were predominantly White, college-educated, and married (lurasidone = 88.1%, 76.9%, 77.6%; quetiapine = 89.8%, 71.2%, 75.0%; controls = 92.7%, 86.7%, 89.1%). Absolute risks of major malformations were 2.19% (lurasidone), 1.85% (quetiapine), and 1.77% (controls). Odds ratios comparing lurasidone and quetiapine with controls were 1.24 (95% confidence interval [CI] = 0.36-4.32) and 1.04 (95% CI = 0.38-2.85), respectively. Conclusions: No specific patterns of malformations were observed in infants exposed to the medications of interest. Lurasidone and quetiapine did not appear to be major teratogens, but further information is needed to refine risk estimates. Food and Drug Administration guidance underscores the importance of pregnancy registries. Clinical trial number: NCT01246765.

Risk for postpartum depressive symptoms among pregnant women in a tertiary care setting with and without a positive COVID-19 test.

OBJECTIVE: This study systematically examines risk for postpartum depressive symptoms based on COVID-19 positivity status during pregnancy. METHODS: This is a retrospective matched cohort study of pregnant patients admitted to labor and delivery units from March through December 2020. Patients were administered three depression screening questions followed by the Edinburgh Postnatal Depression Scale (EPDS). RESULTS: 129 patients with positive COVID-19 tests (most with mild symptoms) were matched with 516 COVID-19 negative controls. We found no significant differences in rates of positive responses to screening questions (14/129, 10.9% vs. 72/516, 14.0%; p = .35) or EPDS scores >9 (6/97, 6.2% vs. 42/410, 10.2%; p = .22). Prior history of psychiatric illness was the only significant predictor of an EPDS score > 9 (adjOR 2.57, p = .002) or a positive brief screen for postpartum depressive symptoms (adjOR 2.93, p < .001). CONCLUSIONS: No significant differences in the rates for postpartum depressive symptoms were observed among pregnant women with and without a positive COVID-19 test during pregnancy, suggesting that testing positive for COVID-19 during pregnancy was not associated with an increased risk for the development of depressive symptoms during the acute postpartum period. Overall rates of postpartum depression symptoms were low, perhaps owing to the higher socioeconomic status of the sample.

Risk of major malformations in infants after first-trimester exposure to benzodiazepines: Results from the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications.

BACKGROUND: Perinatal anxiety affects 20% of women, and untreated maternal mental illness can cause deleterious effects for women and their children. Benzodiazepines are commonly used to treat anxiety disorders. The reported risk of congenital malformations after in utero benzodiazepine exposure has been inconsistent. METHODS: The Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications prospectively enrolls pregnant women with psychiatric illness who take one or more psychiatric medications. Participants are interviewed twice during pregnancy and at 12 weeks postpartum. Women taking any benzodiazepine during the first trimester of pregnancy were compared with a group of women taking psychiatric medication(s) other than benzodiazepines during pregnancy. RESULTS: A total of 1053 women were eligible for this analysis; N = 151 women who had taken a benzodiazepine during the first trimester, and the comparison group was N = 902 women. There were 5 (3.21%) major malformations in the exposure group and 32 (3.46%) in the comparison group (odds ratio 0.92; 95% confidence interval 0.35-2.41). CONCLUSION: This ongoing pregnancy registry offers reassurance that benzodiazepines do not appear to have major teratogenic effects. The precision of relative risk estimate will improve as the number of participants increases. This and other pregnancy registries will better inform the reproductive safety of benzodiazepines.

Pregnancy outcomes after first-trimester exposure to buspirone: prospective longitudinal outcomes from the MGH National Pregnancy Registry for Psychiatric Medications.

Buspirone is commonly used to treat anxiety disorders among reproductive-aged women. To date, the reproductive safety of buspirone in humans has been particularly sparse. We sought to provide preliminary data from the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications (NPRPM) on the risk of major malformations after first-trimester buspirone exposure. The NPRPM enrolls pregnant women with psychiatric disorders to prospectively assess for major congenital malformations after in utero exposure to psychotropics. Women are interviewed twice during pregnancy and once at 12 weeks postpartum. Data regarding women who took buspirone during the first trimester were extracted from the NPRPM database. Data were assessed as a rigorously ascertained case series to determine the incidence of major malformations among those exposed to buspirone. The primary outcome was obtained by maternal postpartum interview and medical record review. As of January 6, 2022, N = 97 women enrolled in the registry took buspirone during their first trimester. Of these women, 68 were evaluable and eligible for this analysis. Four women had twins, resulting in 72 infants. Among this sample, there were no malformations present. These preliminary data represent the only prospectively ascertained sample of pregnancy outcomes after first-trimester buspirone exposure. Albeit a small sample, no major malformations were observed in this cohort. The rigorous prospective ascertainment of outcomes is a strength of this study. Future analyses are planned that will include larger numbers of women with exposures to buspirone and comparison with control groups matched for demographic and diagnostic variables.

Discontinuing antidepressants: Pearls and pitfalls.

Stopping antidepressants can be challenging due to the high rate of discontinuation symptoms. Patients with antidepressant discontinuation syndrome (ADS) commonly experience insomnia, flu-like symptoms, mood disturbances, dizziness, and paresthesias, but a broad array of adverse effects is possible. Symptoms can last for days to months, and different symptoms have different durations. Patient education, identification of patients most at risk for developing symptoms, and a slow antidepressant taper or cross-taper are important steps in mitigating the risk of ADS and managing patient concerns about ADS. Tapers should be carried out over weeks to months. Discontinuation symptoms should be managed with restarting the prior dose of antidepressant and then tapering even more slowly, with additional symptomatic management as needed.

Breastfeeding practices among women taking second-generation antipsychotics: findings from the National Pregnancy Registry for Atypical Antipsychotics.

The purpose of this study is to examine initiation rates of breastfeeding and other breastfeeding outcomes among women taking second generation antipsychotics (SGAs). Participants were enrolled in the National Pregnancy Registry for Atypical Antipsychotics; an ongoing prospective cohort study enrolling women age 18-45 years who are exposed and unexposed to SGAs during pregnancy. A 3-month postpartum interview collects information regarding breastfeeding behaviors. Specifically, women are asked the following questions about ever breastfeeding, still breastfeeding at 3 months postpartum, and whether women are breastfeeding exclusively, bottle-feeding exclusively, or breast and bottle feeding. Descriptive statistics were used to summarize demographic variables and breastfeeding practices. Rates of breastfeeding initiation and continuation were higher among participants who did not use SGAs. Among women not on SGAs, 88.2% of women reported "ever breastfeeding" compared to 59.3% of women on an SGA. At 3 months postpartum, 47% of women on a non-SGA were exclusively breastfeeding compared to 23% of women on an SGA. While the majority of women on an SGA initiated breastfeeding, breastfeeding rates were considerably lower than for women who were not on a SGA. More research is needed on the safety of lactation and use of combinations of psychotropics for women in pregnancy and postpartum.

Perinatal experiences of pregnant women with psychiatric disorders during the COVID-19 pandemic.

OBJECTIVE: We sought to examine the impact of the COVID-19 pandemic on the pregnancy, delivery and postpartum experiences of women with histories of psychiatric disorders. METHOD: Women already enrolled in a United States registry which prospectively studies the relationship between the use of psychiatric medications during pregnancy and major congenital malformations were invited to participate in this study. Subjects were asked about their experiences across the pandemic through interviews during pregnancy and the postpartum period and through an emailed questionnaire. Data were collected between May 2020 and February 2021. RESULTS: Interview and email questionnaire data were collected from 488 individuals. Most participants reported disruption, or planned changes, to their perinatal care due to the pandemic. Women expressed concerns about reduced postpartum support, and the reduction of positive social interactions and opportunities for family/friends to bond with the baby. CONCLUSION: Our findings suggest that the pandemic has had a negative impact on the experiences of many pregnant women with pre-existing psychiatric disorders, particularly in relation to changes in care and perceived social support. Given that the risk of relapse of psychiatric disorders is already high in the postpartum period, it is important to identify what factors cause most distress for this at-risk population.

Correction. Reproductive Safety of Second-Generation Antipsychotics: Updated Data From the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics.

This corrects the article DOI: 10.4088/JCP.20m13745.

Reproductive Safety of Second-Generation Antipsychotics: Updated Data From the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics.

Objective: Second-generation antipsychotics (SGAs) are prescribed for a wide range of indications in women of reproductive age. The National Pregnancy Registry for Atypical Antipsychotics (NPRAA) was established to determine the risk of major malformations among infants exposed to these medications during the first trimester relative to a comparison group of unexposed infants of mothers with histories of psychiatric morbidity.Methods: Women, aged 18-45 years, with histories of psychiatric illness were prospectively followed through pregnancy and during the postpartum period. Pediatric and maternal medical records were obtained and screened for evidence of major malformations. Potential cases were adjudicated by a dysmorphologist who was blinded to drug exposure.. Recruitment to the Registry, which is based at the Ammon-Pinizzotto Center for Women's Mental Health at Massachusetts General Hospital (MGH), includes nationwide provider referral, self-referral, and advertisement through the MGH Center for Women's Mental Health website.Results: As of April 9, 2020, 1,906 women had enrolled, including 889 in the exposure group and 1,017 controls. A total of 1,311 women completed the study and were eligible for inclusion in the analysis. Medical records were obtained for 81.3% of participants. Among 640 live births in the exposure group, 16 (2.50%) had confirmed major malformations reported, and among 704 live births in the control group, 14 (1.99%) had confirmed major malformations reported. The estimated odds ratio for major malformations comparing exposed and unexposed infants was 1.48 (95% CI, 0.625-3.517).Conclusions: Data from the Registry assessing SGAs as a class indicate that they are unlikely to have a major teratogenic effect. These findings provide pertinent information for women and their health care providers regarding decisions about atypical antipsychotic use during pregnancy.Trial Registration: ClinicalTrails.gov identifier: NCT01246765.

Reproductive safety of aripiprazole: data from the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics.

Aripiprazole has become one of the most commonly prescribed psychotropics, making a more comprehensive understanding of its reproductive safety profile a priority. The goal of the current analysis was to determine the risk of major malformations in infants exposed during the first trimester of pregnancy to aripiprazole compared to infants whose mothers had psychiatric diagnoses but did not use an atypical antipsychotic during pregnancy. The National Pregnancy Registry for Atypical Antipsychotics is a prospective pharmacovigilance program in which pregnant women are enrolled and interviewed during pregnancy and the postpartum period. Medical records are assessed to confirm presence or absence of major malformations. Pregnant women ages 18-45 with psychiatric diagnoses are enrolled. As of April 2020, N = 848 women who had delivered infants were eligible for analyses. A total of 158 women with first trimester exposure to aripiprazole were compared to 690 controls. For 163 infants born to women in the exposed group, seven major malformations were confirmed (4.29%), compared to fourteen of the 690 unexposed infants (1.99%). The unadjusted odds ratio for major malformations between aripiprazole-exposed and unexposed infants was 2.21 (95% confidence interval [CI] = (0.88, 5.57) The adjusted odds ratio for major malformations was 1.35 (95% confidence interval [CI] = (0.43, 4.20). After adjustment for confounding variables, the risk of major malformations after first trimester exposure to aripiprazole was not significant compared to controls. While these results are reassuring, they are limited by relatively small numbers of participants. Future analyses with larger numbers are expected to provide more of a complete and precise reproductive safety profile regarding aripiprazole use during pregnancy. Trial registration: clinicaltrials.gov NCT01246765.