The impact of preexisting maternal anxiety on pain and opioid use following cesarean delivery: a retrospective cohort study.

BACKGROUND: Anxiety disorders are the most common mental health condition. They are associated with negative pain experiences and can hinder rehabilitation in the hospital setting. Anxiety has been shown to be predictive of increased postoperative pain in patients undergoing nonobstetrical surgery. OBJECTIVE: To evaluate the impact of preexisting maternal anxiety disorders on average self-reported pain scores and opioid use in the first 24 hours following cesarean delivery STUDY DESIGN: This was a single-center retrospective cohort study of cesarean deliveries between January 1, 2016 and December 31, 2017. The primary outcome was average pain, calculated by averaging all documented self-reported pain scores (0-10 scale) during the first 24 hours postdelivery. The secondary outcome included the oral morphine milligram equivalents used in the first 24 hours postdelivery. Analysis of the impact of anxiety disorders on these outcomes was performed using multivariable linear regression to control for confounding variables. RESULTS: A total of 2228 cesarean deliveries were analyzed, of which 578 (25.9%) had an anxiety disorder documented. Women with a diagnosis of anxiety had higher average pain scores (3.9 vs 3.5; P<.001) and morphine milligram equivalents use (110.4 mg vs 102.2 mg; P<.001) than women without anxiety. CONCLUSION: Patients with preexisting anxiety diagnoses reported higher average pain scores and opioid pain medication use in the first 24 hours following cesarean delivery.

Postpartum Depression: Identification and Treatment in the Clinic Setting.

Perinatal care, including the management of mental health issues, often falls under the auspices of primary care providers. Postpartum depression (PPD) is a common problem that affects up to 15% of women. Most women at risk can be identified before delivery based on psychiatric history, symptoms during pregnancy, and recent psychosocial stressors. Fortunately, there have been a variety of treatment studies using antidepressants, nonpharmacologic interactions, and most recently, allopregnanolone (Brexanolone) infusion that have shown benefits. The most commonly used screening scale, Edinburgh Postnatal Depression Scale, a 10-item self-rated scale, has been translated into a variety of languages.

Magnetocardiographic identification of prolonged fetal corrected QT interval in women receiving treatment for opioid use disorder.

AIM: Pregnant women undergoing treatment for opioid use disorder (OUD) may be exposed to multiple QT prolonging agents. We used magnetocardiography to measure fetal QT intervals in mothers with OUD on buprenorphine therapy. METHODS: Fetal and maternal magnetocardiography was performed in pregnant women receiving buprenorphine-assisted treatment (Disorder group); these were matched by gestational age to pregnant women who were opiate naïve (Reference group). Corrected QT intervals were determined using Bazett's formula and compared between groups. RESULTS: A total of eight women in the Disorder group matched to eight in the Reference group. Seven of the mothers (88%) in the Disorder group were smokers; there were no smokers in the Reference group. The average fetal corrected QT was significantly longer (P = 0.022) in the Disorder group than that in the Reference group (505 milliseconds [ms] ± 68.6 [standard deviation] vs 383 ms ± 70.3 [standard deviation]). CONCLUSION: Novel data from this small sample demonstrate prolongation of fetal corrected QT in women with OUD participating in buprenorphine assisted therapy. Additional investigation from a larger sample is needed to clarify if fetal buprenorphine and/or tobacco exposure is associated with changes in fetal QT which would warrant further prenatal and postnatal testing.

Major depressive disorder during pregnancy: Psychiatric medications have minimal effects on the fetus and infant yet development is compromised.

Psychotropic medication use and psychiatric symptoms during pregnancy each are associated with adverse neurodevelopmental outcomes in offspring. Commonly, studies considering medication effects do not adequately assess symptoms, nor evaluate children when the effects are believed to occur, the fetal period. This study examined maternal serotonin reuptake inhibitor and polypharmacy use in relation to serial assessments of five indices of fetal neurobehavior and Bayley Scales of Infant Development at 12 months in N = 161 socioeconomically advantaged, non-Hispanic White women with a shared risk phenotype, diagnosed major depressive disorder. On average fetuses showed the expected development over gestation. In contrast, infant average Bayley psychomotor and mental development scores were low (M = 84.10 and M = 89.92, range of normal limits 85-114) with rates of delay more than 2-3 times what would be expected based on this measure's normative data. Controlling for prenatal and postnatal depressive symptoms, prenatal medication effects on neurobehavioral development were largely undetected in the fetus and infant. Mental health care directed primarily at symptoms may not address the additional psychosocial needs of women parenting infants. Speculatively, prenatal serotonin reuptake inhibitor exposure may act as a plasticity rather than risk factor, potentially enhancing receptivity to a nonoptimal postnatal environment in some mother-infant dyads.

Prenatal stress, regardless of concurrent escitalopram treatment, alters behavior and amygdala gene expression of adolescent female rats.

Depression during pregnancy has been linked to in utero stress and is associated with long-lasting symptoms in offspring, including anxiety, helplessness, attentional deficits, and social withdrawal. Depression is diagnosed in 10-20% of expectant mothers, but the impact of antidepressant treatment on offspring development is not well documented, particularly for females. Here, we used a prenatal stress model of maternal depression to test the hypothesis that in utero antidepressant treatment could mitigate the effects of prenatal stress. We also investigated the effects of prenatal stress and antidepressant treatment on gene expression related to GABAergic and serotonergic neurotransmission in the amygdala, which may underlie behavioral effects of prenatal stress. Nulliparous female rats were implanted with osmotic minipumps delivering clinically-relevant concentrations of escitalopram and mated. Pregnant dams were exposed to 12 days of mixed-modality stressors, and offspring were behaviorally assessed in adolescence (postnatal day 28) and adulthood (beyond day 90) to determine the extent of behavioral change. We found that in utero stress exposure, regardless of escitalopram treatment, increased anxiety-like behavior in adolescent females and profoundly influenced amygdala expression of the chloride transporters KCC2 and NKCC1, which regulate GABAergic function. In contrast, prenatal escitalopram exposure alone elevated amygdala expression of 5-HT1A receptors. In adulthood, anxiety-like behavior returned to baseline and gene expression effects in the amygdala abated, whereas deficits emerged in novel object recognition for rats exposed to stress during gestation. These findings suggest prenatal stress causes age-dependent deficits in anxiety-like behavior and amygdala function in female offspring, regardless of antidepressant exposure.

The use of antidepressant medication in pregnancy.

The use of antidepressant medications during pregnancy has stimulated much professional and public debate. As a consequence, considerable data on the reproductive safety of antidepressants has been generated that exceeds the available information for most, if not all, other classes of medications that may be used in the perinatal period. Despite progress to date, definitive conclusions are limited by the methodological issues inherent to clinical research involving illness versus treatment effects in pregnancy. A notable shortcoming is the limited discussion of statistically significant (a mathematical determination) versus clinically significant (incorporation of incidence and effect sizes into practical relevance). Research emphasises completing an individualised 'risk-benefit' assessment, which is a laudable goal but falls short in providing succinct practical guidelines that includes the key educational points for patients. In this chapter, we focus on areas in which the preponderance of data are consistent, and there is concordance with the preclinical literature to generate a practical approach for antidepressant use in pregnancy.

Prenatal exposure to escitalopram and/or stress in rats: a prenatal stress model of maternal depression and its treatment.

RATIONALE: A rigorously investigated model of stress and antidepressant administration during pregnancy is needed to evaluate possible effects on the mother. OBJECTIVE: The objective of this study was to develop a model of clinically relevant prenatal exposure to an antidepressant and stress during pregnancy to evaluate the effects on maternal care behavior. RESULTS: Female rats implanted with 28-day osmotic minipumps delivering the SSRI escitalopram throughout pregnancy had serum escitalopram concentrations in a clinically observed range (17-65 ng/ml). A separate cohort of pregnant females exposed to a chronic unpredictable mild stress paradigm on gestational days 10-20 showed elevated baseline (305 ng/ml), and acute stress-induced (463 ng/ml), plasma corticosterone concentrations compared to unstressed controls (109 ng/ml). A final cohort of pregnant dams were exposed to saline (control), escitalopram, stress, or stress and escitalopram to determine the effects on maternal care. Maternal behavior was continuously monitored over the first 10 days after parturition. A reduction of 35 % in maternal contact and 11 % in nursing behavior was observed due to stress during the light cycle. Licking and grooming behavior was unaffected by stress or drug exposure in either the light or dark cycle. CONCLUSIONS: These data indicate that: (1) clinically relevant antidepressant treatment during human pregnancy can be modeled in rats using escitalopram; (2) chronic mild stress can be delivered in a manner that does not compromise fetal viability; and (3) neither of these prenatal treatments substantially altered maternal care post parturition.

DNA methylation in neonates born to women receiving psychiatric care.

Prenatal exposure both to maternal psychiatric illness and psychiatric medication has been linked with adverse child outcomes that affect physiological, emotional and psychiatric development. Studies suggest that epigenetic mechanisms, such as DNA methylation, may facilitate these effects. In this report, we explore the association between maternal psychiatric illness and treatment during pregnancy and neonatal DNA methylation patterns in a prospectively-characterized clinical cohort of 201 dyads. Associations between the percent of umbilical cord blood DNA methylated at 27,578 CpG sites and maternal psychiatric diagnosis, symptoms and antidepressant use were evaluated by fitting a separate linear mixed effects model for each CpG site. There were no significant changes in neonatal DNA methylation attributable to maternal psychiatric diagnosis or depressive symptoms during pregnancy. Exposure to an antidepressant medication was associated with differential methylation of CpG sites in TNFRSF21 and CHRNA2 (false discovery rate < 0.05), but the average difference in methylation for both CpG sites was less than 3% between each group. The results were not specific to type of antidepressant or duration of the exposure. This study suggests that there are no large effects of maternal psychiatric illness, depressive symptoms or prenatal exposure to antidepressants on neonatal DNA methylation. Delineation of the influence of maternal psychiatric illness and pharmacological exposures on the developing fetuses has critical implications for clinical care during pregnancy.

Maternal depression and anxiety differentially impact fetal exposures during pregnancy.

OBJECTIVE: To examine the association between severity of maternal depression and anxiety during pregnancy and the maternal use of medicinal agents and habit-forming substances. METHOD: Participants in a prospective study of prenatal DSM-IV depressive and anxiety disorders at the Emory Women's Mental Health Program who completed weekly documentation of prenatal drug exposure and ≥ 3 administrations of the Hamilton Depression Rating Scale (HDRS) or Hamilton Anxiety Rating Scale (HARS) were included. The primary outcome measures were the HDRS and HARS. Correlation coefficients were computed for cumulative drug exposure with HDRS area under the curve (AUC) and HARS AUC. Data collection was completed between January 2007 and June 2010. RESULTS: Among 195 participants, both HDRS AUC and HARS AUC were negatively correlated with prenatal vitamin exposure (r = -0.22 [P = .002] and r = -0.26 [P = .0003], respectively) and positively correlated with tobacco (r = 0.21 [P = .003] and r = 0.20 [P = .006], respectively) and hypnotic (r = 0.28 [P < .0001] and r = 0.19 [P = .008], respectively) exposure. Only HDRS AUC correlated with exposure to antiemetics (r = 0.14 [P = .05]), opioid analgesics (r = 0.14 [P = .05]), and all prescription drugs (r = 0.16 [P = .02]). Only HARS AUC correlated with benzodiazepine exposure (r = 0.17 [P = .02]). CONCLUSIONS: Both prenatal depression and anxiety are associated with decreased prenatal vitamin compliance and increased use of hypnotics and tobacco, but only depression is associated with exposure to a broader array of medications targeting physical symptoms that often accompany depression. These findings confirm and extend previous studies, underscoring the importance of addressing prenatal depression and anxiety.

The Pregnancy Depression Scale (PDS): a screening tool for depression in pregnancy.

Depression in pregnancy can be underdiagnosed as a consequence of the symptoms being misattributed to "normal pregnancy." There are currently no validated clinician-rated scales that assess for depression specifically during pregnancy. We sought to develop a brief, convenient screening tool to identify depression in pregnant women in the community setting. Prospective mood data using the 28-item Hamilton Depression Rating Scale (HDRS) were collected monthly in 196 pregnant women with a history of a major depressive disorder. These data were analyzed to delineate those HDRS items associated (elevated) with normal pregnancy vs. those indicative of a pregnant woman meeting diagnostic criteria for a major depressive episode. Endorsement of symptoms on seven items of the HDRS were highly predictive of having a major depressive episode during pregnancy. We present a well-validated, brief scale to screen pregnant women for clinical depression. Whether this study will generalize to women who do not have a history of major depression remains to be studied.

The emerging importance of transporter proteins in the psychopharmacological treatment of the pregnant patient.

P-glycoprotein, breast cancer resistance protein, and multidrug resistance proteins have physiological functions in placental tissue. Several antidepressants, antipsychotics, and anti-epileptic drugs have been found to be substrates of P-glycoprotein and other transporters. The extent that drugs pass through the placental barrier is likely influenced by drug transporters. The rational choice of psychoactive drugs to treat mental illness in women of child-bearing age should incorporate knowledge of both drug disposition as well as expected pharmacologic effects. This review summarizes the current data on drug transporters in the placental passage of medications, with a focus on medications used in clinical psychopharmacology.

Venlafaxine in the treatment of depressive and vasomotor symptoms in women with perimenopausal depression.

Perimenopause is often marked by vasomotor symptoms and dysphoria. Antidepressant studies have demonstrated decreased frequency and severity of hot flashes in breast cancer survivors and menopausal women. We hypothesized that venlafaxine would relieve both depressive and vasomotor symptoms in depressed perimenopausal women. Sixteen women fulfilling clinical criteria for climacteric phase and Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for a depressive episode were enrolled in an open-label 8-week trial of extended-release venlafaxine. Depressive and climacteric symptoms were monitored using the Hamilton Rating Scales for Depression (Ham-D) and Anxiety (Ham-A), Clinical Global Impression (CGI) scale, and Greene Climacteric Scale (GCS). Serum follicular stimulating hormone (FSH) and estradiol concentrations were monitored. Significant decreases in Ham-D and Ham-A scores and the GCS psychiatric subscale were seen after 2 weeks of treatment. In an intention-to-treat analysis, 81% of the subjects demonstrated a therapeutic antidepressant response (>50% decline in Ham-D score) and 75% achieved clinical remission (Ham-D score < or =7) after 8 weeks of venlafaxine therapy (75-225 mg/day). Total GCS scores declined 60%, and GCS vasomotor subscores decreased among those with vasomotor symptoms at baseline. These data suggest that venlafaxine treatment improves overall well-being, reduces depressive symptoms, and may diminish baseline vasomotor symptoms in depressed perimenopausal women. Further studies are warranted to investigate the utility of venlafaxine in perimenopausal depression.