Shaila Misri

Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses

Background: In animal models, variations in early maternal care are associated with differences in hypothalamic-pituitary-adrenal (HPA) stress response in the offspring, mediated via changes in the epigenetic regulation of glucocorticoid receptor (GR) gene (Nr3c1) expression. Objective: To study this in humans, relationships between prenatal exposure to maternal mood and the methylation status of a CpG-rich region in the promoter and exon 1F of the human GR gene (NR3C1) in newborns and HPA stress reactivity at age 3 months were examined. Methods: The methylation status of a CpG-rich region of the NR3C1 gene, including exon 1F, in genomic DNA from cord blood mononuclear cells was quantified by bisulfite pyrosequencing in infants of depressed mothers treated with a serotonin reuptake inhibitor antidepressant (SRI) (n=33), infants of depressed non treated mothers (n=13) and infants of non depressed/non treated mothers (n=36). To study the functional implications of the newborn methylation status of NR3C1 in newborns, HPA function was assessed at 3 months using salivary cortisol obtained before and following a non noxious stressor and at a late afternoon basal time. Results: Prenatal exposure to increased third trimester maternal depressed/anxious mood was associated with increased methylation of NR3C1 at a predicted NGFI-A binding site. Increased NR3C1 methylation at this site was also associated with increased salivary cortisol stress responses at 3 months, controlling for prenatal SRI exposure, postnatal age, and pre and postnatal maternal mood. Conclusions: Methylation status of the human NR3C1 gene in newborns is sensitive to prenatal maternal mood and may offer a potential epigenetic process that links antenatal maternal mood and altered HPA stress reactivity during infancy.

The Impact of Partner Support in the Treatment of Postpartum Depression

Objective: To determine the impact of partner support in the treatment of mothers suffering from postpartum depression (PPD). Method Patients underwent a comprehensive psychiatric assessment and were enrolled in the study only if they met the DSM-IV criteria for major depressive disorder with postpartum onset. Patients with PPD (n = 29) were assigned randomly to 2 treatment groups: group 1 (control group) consisted of patients only (n = 13), while group 2 (support group) consisted of patients (n = 16) and their partners. The patients in both groups were seen for 7 psychoeducational visits each. In group 2, partners participated in 4 of the 7 visits. Patients in both groups were administered a set of questionnaires that included the Edinburgh Postnatal Depression Scale (EPDS), the Kellner Symptom Questionnaire, the Dyadic Adjustment Scale (DAS), and the Parental Bonding Instrument (PBI). In addition, during visits 1 and 7, all patients underwent assessment using the Mini International Neuropsychiatric Instrument (MINI), section A (major depressive episode). The partners in both groups completed the DAS and the General Health Questionnaire (GHQ). Results Relative to the control-group patients, the support-group patients displayed a significant decrease in depressive symptoms and other psychiatric conditions. Relative to the support group, the general health of the partners in the control group deteriorated. Conclusion Partner support has a measurable effect on women experiencing PPD.

Major congenital malformations following prenatal exposure to serotonin reuptake inhibitors and benzodiazepines using population‐based health data

BACKGROUND To determine a population-based incidence of congenital anomalies following prenatal exposure to serotonin reuptake inhibitor (SRI) antidepressants used alone and in combination with a benzodiazepines (BZ). METHODS Population health data, maternal health, and prenatal prescription records were linked to neonatal records, representing all live births (British Columbia, Canada, N=119,547) during a 39-month period (1998-2001). The incidence and risk differences (RD) for major congenital anomalies (CA) and congenital heart disease (CHD), including ventricular and atrial septal defects (VSD, ASD), from infants of mothers treated with an SRI alone, a benzodiazepine (BZ) alone, or SRI+BZ in combinationcompared to outcomesno exposure. RESULTS Risk for a CA or CHD did increase following combined SRI+BZ exposure compared with no exposure. However, using a weighted regression model, controlling for maternal illness characteristics, combination therapy risk remained significantly associated only with CHD. The risk for an ASD was higher following SRI monotherapy compared with no exposure, after adjustment for maternal covariates. Dose/day was not associated with increased risk. CONCLUSIONS Infants exposed to prenatal SRIs in combination with BZs had a higher a incidence of CHD compared to no exposure, even after controlling for maternal illness characteristics. SRI monotherapy was not associated with an increased risk for major CA, but was associated with an increased incidence of ASD. Risk was not associated with first trimester medication dose/day.

Effects of timing and duration of gestational exposure to serotonin reuptake inhibitor antidepressants: population-based study

BACKGROUND Late-gestational serotonin reuptake inhibitor (SRI) exposure has been linked to adverse neonatal outcomes; however, the impact of timing and duration of exposure is unknown. AIMS To determine whether late-gestational exposure to an SRI is associated with increased risk of adverse neonatal outcome relative to early exposure. METHOD Population-based maternal and neonatal health records were linked to prenatal maternal prescription records for an SRI medication (n=3500). RESULTS After controlling for maternal illness and duration of exposure, using propensity score matching, neonatal outcomes did not differ between late and early exposure (P>0.05). After controlling for maternal illness, longer prenatal exposure increased the risks of lower birth weight, respiratory distress and reduced gestational age (P<0.05). CONCLUSIONS Using population health data, length of gestational SRI exposure, rather than timing, increased the risk for neonatal respiratory distress, lower birth weight and reduced gestational age, even when controlling for maternal illness and medication dose. These findings highlight the importance of distinguishing the specific impact of medication exposure from exposure to maternal illness itself.

Prolonged prenatal psychotropic medication exposure alters neonatal acute pain response

Selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines are frequently used to treat maternal depression during pregnancy, however the effect of increased serotonin (5HT) and γ-amino-butyric acid (GABA) agonists in the fetal human brain remains unknown. 5HT and GABA are active during fetal neurologic growth and play early roles in pain modulation, therefore, if prolonged prenatal exposure alters neurodevelopment this may become evident in altered neonatal pain responses. To examine biologic and behavioral effects of prenatal exposure, neonatal responses to acute pain (phenylketonuria heel lance) in infants with prolonged prenatal exposure were examined. Facial action (Neonatal Facial Coding System) and cardiac autonomic reactivity derived from the relationship between respiratory activity and short term variations of heart rate (HRV) were compared between 22 infants with SSRI exposure (SE) [fluoxetine (n = 7), paroxetine (n = 11), sertraline (n = 4)]; 16 infants exposed to SSRIs and clonazepam (SE+) [paroxetine (n = 14), fluoxetine (n = 2)]; and 23 nonexposed infants during baseline, lance, and recovery periods of a heel lance. Length of maternal SSRI use did not vary significantly between exposure groups—[mean (range)] SE:SE+ 183 (31–281):141 (54–282) d (p > 0.05). Infants exposed to SE and SE+ displayed significantly less facial activity to heel lance than control infants. Mean HR increased with lance, but was significantly lower in SE infants during recovery. Using measures of HRV and the transfer relationship between heart rate and respiration, SSRI infants had a greater return of parasympathetic cardiac modulation in the recovery period, whereas a sustained sympathetic response continued in the control group. Prolonged prenatal SSRI exposure appears to be associated with reduced behavioral pain responses and increased parasympathetic cardiac modulation in recovery following an acute neonatal noxious event. Possible 5HT-mediated pain inhibition, pharmacologic factors and the developmental course remain to be studied.

Prenatal effects of selective serotonin reuptake inhibitor antidepressants, serotonin transporter promoter genotype (SLC6A4), and maternal mood on child behavior at 3 years of age.

OBJECTIVES To investigate whether prenatal selective serotonin reuptake inhibitor (SSRI) antidepressant exposure affects behavior in 3-year-olds of antenatally anxious or depressed mothers and whether risk was moderated by the serotonin transporter promoter (SLC6A4) genotype. DESIGN Prospective longitudinal cohort design. SETTING Vancouver. PARTICIPANTS Mothers and their 3-year-old children (n = 33 SSRI exposed and n = 42 nonexposed). Main Exposures Prenatal exposure to SSRI antidepressants and prenatal and postnatal maternal mood disturbances. MAIN OUTCOME MEASURES Parent report of child behavior (Child Behavior Checklist, ages 1.5-5 years) and the child SLC6A4 genotype. The covariates used were maternal mood during the third trimester, 3 months postpartum, and at the 3-year follow-up study and the childs 5-minute Apgar score. RESULTS Prenatal exposure to both maternal depressed mood and SSRI antidepressants were associated with increased internalizing behaviors during early childhood, whereas current maternal mood increased risk for externalizing behaviors. Increased child anxiety and depression symptoms were predicted by higher third-trimester maternal anxiety only in children with 2 short S alleles. In contrast, increased aggression and externalizing behaviors were predicted by third-trimester maternal anxiety only in children with 2 copies of the L allele. CONCLUSIONS Exposure to prenatal SSRIs and maternal mood had distinct effects on child behavior at 3 years of age, reflected in an increased level of internalizing behaviors. The impact of antenatal maternal anxiety on child mood was moderated by the child SLC6A4 genotype. Despite SSRI treatment for prenatal maternal mood disturbances, childhood behavior at 3 years of age remained at risk.

Breast-Feeding and Postpartum Depression: Is There a Relationship?

Objective: To study the relationship between breast-feeding cessation and the onset of postpartum depression. Method: The association between breast-feeding and depression was retrospectively examined in an obstetrical outpatient sample of 51 postpartum women who were suffering from major depression and who had stopped breast-feeding. Self-report questionnaire data were obtained from the subjects; the severity of the illness and the clinical course of each subject were evaluated. Results: The majority (39 out of 51; 83%) of the women reported that their depression began before the cessation of breast-feeding, while only 8 patients (17%) stated that their depression was subsequent to breast-feeding cessation. Conclusions: In an outpatient sample of depressed postpartum women, the onset of depression preceded the cessation of breast-feeding. The severity of the illness did not appear to influence breast-feeding persistence significantly.

A controlled study of light therapy in women with late luteal phase dysphoric disorder

Previous studies suggest that light therapy, as used to treat seasonal affective disorder, may be beneficial for pre-menstrual depressive disorders. We conducted a six-menstrual cycle randomized, double-blind, counter-balanced, crossover study of dim vs. bright light therapy in women with late luteal phase dysphoric disorder (LLPDD). Fourteen women who met DSM-III-R criteria for LLPDD completed two menstrual cycles of prospective baseline monitoring of pre-menstrual symptoms, followed by two cycles of each treatment. During the 2-week luteal phase of each treatment cycle, patients were randomized to receive 30 min of evening light therapy using: (1) 10000 lx cool-white fluorescent light (active condition); or (2) 500 lx red fluorescent light (placebo condition), administered by a light box at their homes. After two menstrual cycles of treatment, patients were immediately crossed over to the other condition for another two cycles. Outcome measures were assessed at the mid-follicular and luteal phases of each cycle. Results showed that the active bright white light condition significantly reduced depression and pre-menstrual tension scores during the symptomatic luteal phase, compared to baseline, while the placebo dim red light condition did not. These results suggest that bright light therapy is an effective treatment for LLPDD.

Treatment of Perinatal Mood and Anxiety Disorders: A Review

Objectives: To review the nonpharmacologic and pharmacologic treatment modalities for perinatal mood and anxiety disorders and to discuss the importance of weighing the risks and the benefits of exposing the fetus or baby to maternal mental illness as opposed to exposure to antidepressant medications. Methods: We conducted a literature search of the PubMed and MEDLINE databases. Key words included the following: perinatal, pregnancy, postpartum, depression, anxiety, pharmacologic, nonpharmacologic, psychotherapy, and treatment. Results: Recent literature reflects that both pharmacologic and nonpharmacologic treatments for perinatal women are associated with positive and negative outcomes. No treatment decision was found to be risk-free. The detrimental effects of untreated mental illness on the mother, as well as on the baby, highlight the need for treatment intervention. The long-term effects of exposure to either medications or maternal mental illness are unknown, as yet. Conclusion: Women with perinatal depression and anxiety disorders require timely and efficient management with a goal of providing symptom relief for the suffering mother while simultaneously ensuring the babys safety. Although knowledge in the area of appropriate intervention is constantly evolving, rigorous and scientifically sound research in the future is critical.

Antenatal depression and anxiety affect postpartum parenting stress: a longitudinal, prospective study.

Objective: Postpartum depression has been associated with parenting stress, impacting attachment and child development. However, the relation between antenatal depression or anxiety and postpartum parenting stress has not been investigated. We studied the effect of antenatal depression and anxiety and treatment with selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors (antidepressants [ADs]) on postpartum parenting stress. Method: Ninety-four pregnant women (part of a larger study examining prenatal AD exposure on infants) were prospectively monitored for depression and anxiety during the third trimester and 3- and 6-months postpartum using the Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale. Parenting stress was assessed using the Parenting Stress Index—Short Form at 3- and 6-months postpartum. Results: Both antenatal third trimester depression and anxiety were significant predictors of 3- and 6-month postpartum parenting stress, after controlling for maternal age, number of children, and exposure to prenatal ADs (all Ps < 0.001). Third trimester depression accounted for 13% to 22% of the variance in postpartum stress at 3 and 6 months. Prenatal AD use was not a significant predictor in any of the models (all Ps > 0.2). Twenty of 41 mothers on ADs achieved remission (HDRS = 7) in pregnancy and had average parenting stress scores of about 1 standard deviation lower than those who did not at 3- and 6-months postpartum (t = 3.32, df = 32, P = 0.002 and t = 2.52, df = 32, P = 0.02, respectively). Conclusions: Our findings indicate that antenatal depression and anxiety directly impact postpartum parenting stress, regardless of antenatal AD treatment. Ongoing maternal mental illness in pregnancy is an important predictor of postpartum parenting stress. Early recognition and treatment to remission is key.