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 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.

Predictors of Early Postpartum Maternal Functioning Among Women Veterans.

INTRODUCTION: The perinatal period constitutes an important window of opportunity for optimizing healthy development of offspring but is heavily influenced by maternal mental health. Maternal pregnancy-related anxiety (PrA), depression, and post-traumatic stress disorder (PTSD) have been implicated in adverse outcomes for both mother and child. The current study examined whether psychopathology during pregnancy and postpartum was associated with greater experienced parenting stress and bonding difficulties in women veterans, who may be predisposed to develop psychopathology due to heightened risk of exposure to traumatic events. METHODS: Pregnant veterans (N = 28) completed self-report questionnaires regarding their PrA, depression and PTSD symptoms during pregnancy and postpartum, as well as on their experience of parenting stress and bonding with their infant. RESULTS: PrA was a more robust predictor of postpartum depression (PPD) than depression during pregnancy. PPD, in turn, was significantly associated with bonding and parenting stress, such that more depressed mothers were more likely to experience greater general bonding difficulties, increased rejections and pathological anger towards their infants, greater anxiety towards their infants, and more parenting stress. CONCLUSIONS: PrA might be a high-yield modifiable risk factor in the prevention of PPD for women veterans and their subsequent experiences with high parenting stress and bonding difficulties.

Are alterations in estradiol, cortisol, and inflammatory cytokines associated with depression during pregnancy and postpartum? An exploratory study.

BACKGROUND: Pregnant veterans are a subpopulation known to be at elevated risk of developing mental health symptoms, such as depression and suicidal ideation. Inflammation has been associated with depression, specifically during the perinatal period. Critical changes in estradiol, cortisol, and inflammatory cytokines are necessary for the progression of a healthy pregnancy, which are then rapidly altered in the postpartum period. We explored changes in estradiol, cortisol, and pro-inflammatory cytokines relative to depressive symptoms and suicidal thoughts across pregnancy and postpartum in this pilot and feasibility study. METHODS: We measured estradiol, cortisol, and the inflammatory cytokines IL-1ß, IL-6, IL-8, IFN-γ, and TNF-α in 18 pregnant veterans and analyzed the data using descriptive statistics, dependent t-tests, and correlation analyses. We assessed depression severity with the Edinburgh Postnatal Depression Scale and suicidality with the Columbia-Suicide Severity Rating Scale. Thirteen of the women repeated assessments in the early postpartum period at an average of 6.7 weeks after birth. RESULTS: As anticipated, estradiol (t(12) â€‹= â€‹12.47, p â€‹< â€‹.001) and cortisol (t(12) â€‹= â€‹9.43, p â€‹< â€‹.001) significantly decreased from pregnancy to postpartum. There were no differences in the means of gestational and postpartum IL-1ß, IL-6, TNF-α, or IFN-γ, but IL-8 was significantly increased from pregnancy to postpartum (t(12) â€‹= â€‹-4.60, p â€‹= â€‹.001). Estradiol during pregnancy was positively correlated with IL-6 levels both during pregnancy (r p  â€‹= â€‹.656, p â€‹= â€‹.008) and postpartum (r â€‹= â€‹0.648, p â€‹= â€‹.023). Elevated IL-1ß was associated with suicidal thoughts during pregnancy (r â€‹= â€‹0.529, p â€‹= â€‹.029). Although not statistically significant, depressive symptom severity trended towards a positive association with larger increases in IL-1ß (r â€‹= â€‹0.535, p â€‹= â€‹.09) and TNF-α (r â€‹= â€‹0.501, p â€‹= â€‹.08) from pregnancy to postpartum. CONCLUSION: This preliminary study suggests the feasibility of our approach for exploring a complex interplay between hormonal and pro-inflammatory changes from pregnancy to postpartum, and their relationship with depressive symptoms. Given our small sample and the relatively exploratory nature of our analyses, additional investigation focusing on hormonal and inflammatory changes and their potential associations with perinatal mental health is necessary to confirm and extend our preliminary findings and examine additional potential covariates.

Suicidal Ideation in Pregnant and Postpartum Women Veterans: An Initial Clinical Needs Assessment.

INTRODUCTION: Pregnancy and postpartum, or the perinatal period, are times when women are particularly vulnerable to mental health concerns, including suicidal ideation. Risk factors for suicidal ideation during this period of a woman's life are depression and exposure to trauma, the latter of which may occur during military operations. The number of women veterans in the United States continues to rise, as does their use of maternity benefits. In this pilot study, we examined the feasibility of recruiting pregnant veterans for longitudinal research. We hypothesized that hopelessness and depressive symptoms would be related to suicidal ideation during the perinatal period, and we investigated a possible relationship between post-traumatic stress symptoms (PTSS) and suicidal ideation. MATERIALS AND METHODS: Using the designated Veterans Affairs (VA) maternity care coordinator's census, we contacted pregnant women veterans for assessment during the 3rd trimester of pregnancy and 6 weeks postpartum at the San Diego VA. Between September 2017 and October 2018, 28 women volunteers completed the following measures: the Columbia-Suicide Severity Rating Scale (C-SSRS); the Beck Hopelessness Scale (BHS); the Edinburgh Postnatal Depression Scale (EPDS); and the PTSD Checklist for DSM-5 (PCL-5). We used correlational analyses and descriptive statistics to determine associations among the measures. RESULTS: As gathered from the C-SSRS, over 30% of the veteran women had past lifetime suicide attempts, and over 10% of the veterans had suicidal ideation in the perinatal period. Both depression and PTSS rates neared 30% during pregnancy and postpartum. Hopelessness and depressive symptoms were positively correlated at both time points. While the intensity of lifetime suicidal ideation was correlated with postpartum depressive symptoms, there was no correlation with current suicidal ideation and depressive symptoms. PTSS correlated with both depressive symptoms and hopelessness, but not suicidal ideation, at both time points. There was no correlation between hopelessness and suicidal ideation during the perinatal period in this cohort. CONCLUSIONS: It is important to understand the mental health needs of perinatal veterans given their vulnerability to develop mental health concerns, including suicidal ideation. The unpredicted pattern of correlations determined in this study implies the need for multifaceted measures for safety-related mental health assessment of perinatal veterans, including assessment for PTSS. Strengths of this study include its longitudinal assessment and a sampling from a general population of veterans. Limitations include small sample size, a single gestational time point, and loss of participants who did not return for their postpartum assessment. We demonstrated the feasibility of longitudinal research with pregnant and postpartum veterans, but additional assessment points during the perinatal period could help identify critical times for mental health intervention in this population.

Association of antepartum vitamin D deficiency with postpartum depression: a clinical perspective.

OBJECTIVE: Postpartum depression affects up to 20 % of new mothers within the first 12 months of parturition. 25-Hydroxyvitamin D (25(OH)D) has known importance in bone health, but it may also play an important role in other functions, including reproduction and fertility, immune function and mental health. This clinical commentary reviews literature evaluating 25(OH)D deficiency during pregnancy and the incidence of postpartum depressive symptomatology. DESIGN: Narrative review, summary and recommendations. SETTING/PARTICIPANTS: A literature search revealed five relevant studies of antepartum women, three based in the USA, one in Turkey and one in Iran. RESULTS: Three of the five studies measured serum 25(OH)D concentrations during the first or second trimester and discovered an association with 25(OH)D deficiency and depressive symptoms postpartum. One study determined an almost significant (P=0·058) inverse relationship with first-trimester 25(OH)D concentration and depressive symptoms postpartum, and the last study, which was a secondary analysis, did not find an association. CONCLUSIONS: The Endocrine Society recommends routine vitamin D supplementation during pregnancy and lactation due to increased metabolic demand in the mother, but a recent Cochrane review recommended against screening. Vitamin D should be the target of more studies during pregnancy and the postpartum period since it appears to have an important role for both medical and mental health. Vitamin D supplementation is a relatively safe and cost-effective intervention during pregnancy, and it may prove to be important in the prevention of postpartum depression.

A systematic review of cortisol, thyroid-stimulating hormone, and prolactin in peripartum women with major depression.

Pregnancy and postpartum are periods of high susceptibility to major depression (MD) and other mood disorders. The peripartum period is also a time of considerable changes in the levels of hormones, including cortisol, thyroid-stimulating hormone (TSH), prolactin, gonadotropins, and gonadal steroids. To investigate the relationship between mood and hormonal changes during and after pregnancy, we reviewed published reports of hormonal measures during this time frame, searched via PubMed and Web of Science. Studies were included if women in the antepartum or postpartum periods were clinically diagnosed with MD, and if there were repeated measures of cortisol, TSH, or prolactin. For these three hormones, the numbers of human studies that met these criteria were 15, 7, and 3, respectively. Convergent findings suggest that morning cortisol is reduced in pregnant and postpartum women with MD. Evidence did not support changes in TSH as a marker of MD during the peripartum period, and evidence for changes in prolactin in peripartum MD was equivocal. Aside from reduced morning cortisol in peripartum women with MD, definitive evidence for an association between specific hormonal fluctuations and mood disorders in the peripartum period remains elusive.

Sympathetic innervation, norepinephrine content, and norepinephrine turnover in orthotopic and spontaneous models of breast cancer.

Activation of the sympathetic nervous system (SNS) drives breast cancer progression in preclinical breast cancer models, but it has yet to be established if neoplastic and stromal cells residing in the tumor are directly targeted by locally released norepinephrine (NE). In murine orthotopic and spontaneous mammary tumors, tyrosine hydroxylase (TH)+ sympathetic nerves were limited to the periphery of the tumor. No TH+ staining was detected deeper within these tumors, even in regions with a high density of blood vessels. NE concentration was much lower in tumors compared to the more densely innervated spleen, reflecting the relative paucity of tumor TH+ innervation. Tumor and spleen NE concentration decreased with increased tissue mass. In mice treated with the neurotoxin 6-hydroxydopamine (6-OHDA) to selectively destroy sympathetic nerves, tumor NE concentration was reduced approximately 50%, suggesting that the majority of tumor NE is derived from local sympathetic nerves. To evaluate NE utilization, NE turnover in orthotopic 4T1 mammary tumors was compared to spleen under baseline and stress conditions. In non-stressed mice, NE turnover was equivalent between tumor and spleen. In mice exposed to a stressor, tumor NE turnover was increased compared to spleen NE turnover, and compared to non-stressed tumor NE turnover. Together, these results demonstrate that NE in mammary tumors is derived from local sympathetic nerves that synthesize and metabolize NE. However, differences between spleen and tumor NE turnover with stressor exposure suggest that sympathetic NE release is regulated differently within the tumor microenvironment compared to the spleen. Local mammary tumor sympathetic innervation, despite its limited distribution, is responsive to stressor exposure and therefore can contribute to stress-induced tumor progression.

The antidepressant desipramine and α2-adrenergic receptor activation promote breast tumor progression in association with altered collagen structure.

Emotional stress activates the sympathetic nervous system (SNS) and release of the neurotransmitter norepinephrine to promote breast tumor pathogenesis. We demonstrate here that the metastatic mammary adenocarcinoma cell line 4T1 does not express functional adrenergic receptors (AR), the receptors activated by norepinephrine, yet stimulation of adrenergic receptor in vivo altered 4T1 tumor progression in vivo. Chronic treatment with the antidepressant desipramine (DMI) to inhibit norepinephrine reuptake increased 4T1 tumor growth but not metastasis. Treatment with a highly selective α2-adrenergic receptor agonist, dexmedetomidine (DEX), increased tumor growth and metastasis. Neither isoproterenol (ISO), a ß-AR agonist, nor phenylephrine, an α1-AR agonist, altered tumor growth or metastasis. Neither DMI- nor DEX-induced tumor growth was associated with increased angiogenesis. In DMI-treated mice, tumor VEGF, IL-6, and the prometastatic chemokines RANTES, M-CSF, and MIP-2 were reduced. Tumor collagen microstructure was examined using second harmonic generation (SHG), a nonabsorptive optical scattering process to highlight fibrillar collagen. In DMI- and DEX-treated mice, but not ISO-treated mice, tumor SHG was significantly altered without changing fibrillar collagen content, as detected by immunofluorescence. These results demonstrate that α2-AR activation can promote tumor progression in the absence of direct sympathetic input to breast tumor cells. The results also suggest that SNS activation may regulate tumor progression through alterations in the extracellular matrix, with outcome dependent on the combination of adrenergic receptor activated. These results underscore the complexities underlying SNS regulation of breast tumor pathogenesis, and suggest that the therapeutic use of adrenergic receptor blockers, tricyclic antidepressants, and adrenergic receptor agonists must be approached cautiously in patients with breast cancer.

Early impact of social isolation and breast tumor progression in mice.

Evidence from cancer patients and animal models of cancer indicates that exposure to psychosocial stress can promote tumor growth and metastasis, but the pathways underlying stress-induced cancer pathogenesis are not fully understood. Social isolation has been shown to promote tumor progression. We examined the impact of social isolation on breast cancer pathogenesis in adult female severe combined immunodeficiency (SCID) mice using the human breast cancer cell line, MDA-MB-231, a high ß-adrenergic receptor (AR) expressing line. When group-adapted mice were transferred into single housing (social isolation) one week prior to MB-231 tumor cell injection into a mammary fat pad (orthotopic), no alterations in tumor growth or metastasis were detected compared to group-housed mice. When social isolation was delayed until tumors were palpable, tumor growth was transiently increased in singly-housed mice. To determine if sympathetic nervous system activation was associated with increased tumor growth, spleen and tumor norepinephrine (NE) was measured after social isolation, in conjunction with tumor-promoting macrophage populations. Three days after transfer to single housing, spleen weight was transiently increased in tumor-bearing and non-tumor-bearing mice in conjunction with reduced splenic NE concentration and elevated CD11b+Gr-1+ macrophages. At day 10 after social isolation, no changes in spleen CD11b+ populations or NE were detected in singly-housed mice. In the tumors, social isolation increased CD11b+Gr-1+, CD11b+Gr-1-, and F4/80+ macrophage populations, with no change in tumor NE. The results indicate that a psychological stressor, social isolation, elicits dynamic but transient effects on macrophage populations that may facilitate tumor growth. The transiency of the changes in peripheral NE suggest that homeostatic mechanisms may mitigate the impact of social isolation over time. Studies are underway to define the neuroendocrine mechanisms underlying the tumor-promoting effects of social isolation, and to determine the contributions of increased tumor macrophages to tumor pathogenesis.

ß-Adrenergic receptors (ß-AR) regulate VEGF and IL-6 production by divergent pathways in high ß-AR-expressing breast cancer cell lines.

Activation of ß-adrenergic receptors (ß-AR) drives proangiogenic factor production in several types of cancers. To examine ß-AR regulation of breast cancer pathogenesis, ß-AR density, signaling capacity, and functional responses to ß-AR stimulation were studied in four human breast adenocarcinoma cell lines. ß-AR density ranged from very low in MCF7 and MB-361 to very high in MB-231 and in a brain-seeking variant of MB-231, MB-231BR. Consistent with ß-AR density, ß-AR activation elevated cAMP in MCF7 and MB-361 much less than in MB-231 and MB-231BR. Functionally, ß-AR stimulation did not markedly alter vascular endothelial growth factor (VEGF) production by MCF7 or MB-361. In the two high ß-AR-expressing cell lines MB-231 and MB-231BR, ß-AR-induced cAMP and VEGF production differed considerably, despite similar ß-AR density. The ß(2)-AR-selective agonist terbutaline and the endogenous neurotransmitter norepinephrine decreased VEGF production by MB-231, but increased VEGF production by MB-231BR. Moreover, ß(2)-AR activation increased IL-6 production by both MB-231 and MB-231BR. These functional alterations were driven by elevated cAMP, as direct activation of adenylate cyclase by forskolin elicited similar alterations in VEGF and IL-6 production. The protein kinase A antagonist KT5720 prevented ß-AR-induced alterations in MB-231 and MB-231BR VEGF production, but not IL-6 production. Conclusions ß-AR expression and signaling is heterogeneous in human breast cancer cell lines. In cells with high ß-AR density, ß-AR stimulation regulates VEGF production through the classical ß-AR-cAMP-PKA pathway, but this pathway can elicit directionally opposite outcomes. Furthermore, in the same cells, ß-AR activate a cAMP-dependent, PKA-independent pathway to increase IL-6 production. The complexity of breast cancer cell ß-AR expression and functional responses must be taken into account when considering ß-AR as a therapeutic target for breast cancer treatment.