Michael Papsdorf

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.

Pain reactivity in 2-month-old infants after prenatal and postnatal serotonin reuptake inhibitor medication exposure.

Objective. In this prospective study, we examined biobehavioral responses to acute procedural pain at 2 months of age in infants with prenatal and postnatal selective serotonin reuptake inhibitor (SSRI) medication exposure. Based on previous findings showing reduced pain responses in newborns after prenatal exposure, we hypothesized that altered pain reactivity would also be found at 2 months of age. Methods. Facial action (Neonatal Facial Coding System) and cardiac autonomic reactivity derived from the respiratory activity and heart rate variability (HRV) responses to a painful event (heel-lance) were compared between 3 groups of infants: (1) infants with prenatal SSRI exposure alone (n = 11; fluoxetine, n = 2; paroxetine, n = 9); (2) infants with prenatal and postnatal SSRI (via breast milk) exposure (total n = 30; fluoxetine, n = 6; paroxetine, n = 20; sertraline, n = 4); and (3) control infants (n = 22; nonexposed) during baseline, lance, and recovery periods. Measures of maternal mood and drug levels were also obtained, and Bayley Scales of Infant Development-II were administered at ages 2 and 8 months. Results. Facial action increased in all groups immediately after the lance but was significantly lower in the pSE group during the lance period. HR among infants in the pSE and ppSE groups was significantly lower during recovery. Using measures of HRV and the transfer relationship between heart rate and respiration, exposed infants had a greater return of parasympathetic cardiac modulation in the recovery period, whereas a sustained sympathetic response continued in control infants. Although postnatal exposure via breast milk was extremely low when infant drug levels could be detected in ppSE infants, changes in HR and HRV from lance to recovery were greater compared among infants with levels too low to be quantified. Neither maternal mood nor the presence of clonazepam influenced pain responses. Conclusions. Blunted facial-action responses were observed among infants with prenatal SSRI exposure alone, whereas both prenatal and postnatal exposure was associated with reduced parasympathetic withdrawal and increased parasympathetic cardiac modulation during recovery after an acute noxious event. These findings are consistent with patterns of pain reactivity observed in the newborn period in the same cohort. Given that postnatal exposure via breast milk was extremely low and altered biobehavioral pain reactivity was not associated with levels of maternal reports of depression, these data suggest possible sustained neurobehavioral outcomes beyond the newborn period. This is the first study of pain reactivity in infants with prenatal and postnatal SSRI exposure, and our findings were limited by the lack of a depressed nonmedicated control group, small sample size, and understanding of infant behaviors associated with pain reactivity that could have also have been influenced by prenatal SSRI exposure. The developmental and clinical implications of our findings remain unclear, and the mechanisms that may have altered 5-hydroxytryptamine-mediated pain modulation in infants after SSRI exposure remain to be studied. Treating maternal depression with antidepressants during and after pregnancy and promoting breastfeeding in this setting should remain a key goal for all clinicians. Additional study is needed to understand the long-term effects of prenatal and early postnatal SSRI exposure.

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.

A Prospective Controlled Study of Neurodevelopment in HIV-Uninfected Children Exposed to Combination Antiretroviral Drugs in Pregnancy

OBJECTIVE. Our intent was to investigate the neurodevelopment of HIV-uninfected children exposed to combination highly active antiretroviral therapy in pregnancy compared with children not exposed to highly active antiretroviral therapy but with similar socioeconomic backgrounds. PATIENTS AND METHODS. A prospective controlled cross-sectional study of the neurodevelopment of children exposed to highly active antiretroviral therapy versus those not exposed was performed by using the Bayley Scales of Infant Development and Vineland Adaptive Behavior Scales at 18 to 36 months of age. The highly active antiretroviral therapy–exposed children were born to HIV-infected women but were uninfected themselves. The control children were born to HIV-uninfected women with similar anticipated socioeconomic background (hepatitis C infected and high proportion of substance use). Sociodemographic, clinical, highly active antiretroviral therapy (antenatal, intrapartum, neonatal), and substance-use histories were collected. Results were compared by using analyses of covariance and χ2 analysis. RESULTS. Thirty-nine highly active antiretroviral therapy–exposed and 24 control children were assessed. All mean scores were lower for those in the highly active antiretroviral therapy–exposed group than those in the control group (Bayley Mental Development Index: 85.4 vs 94.3; Bayley Psychomotor Development Index: 93.4 vs 96.6; Vineland mean communication score: 90.1 vs 94.4; Vineland mean daily-living score: 91.2 vs 93.6; Vineland mean socialization score: 97.1 vs 98.4). However, when maternal substance use during pregnancy was controlled for, there were no significant differences between the groups in any domains assessed. Children in both groups exposed to maternal substance use scored significantly lower than children not exposed in all domains except communication skills. It is important to note that there were no differences between the highly active antiretroviral therapy–exposed children with no substance exposure and the control children with no substance exposure in any of the scores. CONCLUSIONS. HIV- and highly active antiretroviral therapy–exposed HIV-uninfected children had lower development and adaptive behavior scores when compared with children who had not been exposed. However, these differences were not significant after correcting for maternal substance use, which had a greater impact on neurodevelopment than highly active antiretroviral therapy exposure. These results suggest that perinatal highly active antiretroviral therapy exposure is not associated with altered development and behavior at 18 to 36 months of age.

Neonatal S100B protein levels after prenatal exposure to selective serotonin reuptake inhibitors.

OBJECTIVE: This study investigated neonatal S100B levels as a biomarker of prenatal selective serotonin reuptake inhibitor (SSRI) exposure. METHODS: Maternal (delivery; N = 53) and neonatal (cord; N = 52) serum S100B levels were compared between prenatally SSRI-exposed (maternal, N = 36; neonatal, N = 37; duration: 230 ± 71 days) and nonexposed (maternal, N = 17; neonatal, N = 15) groups. Measures of maternal depression and anxiety symptoms were assessed during the third trimester (33–36 weeks), and neonatal outcomes, including Apgar scores, birth weight, gestational age at birth, and symptoms of poor neonatal adaptation, were recorded. RESULTS: S100B levels were significantly lower in prenatally SSRI-exposed neonates than in nonexposed neonates, controlling for gestational age and third-trimester maternal mood (P = .036). In contrast, SSRI-exposed mothers had significantly higher maternal serum S100B levels, compared with nonexposed mothers (P = .014), even controlling for maternal mood in the third trimester. S100B levels were not associated with maternal or neonatal drug levels, duration of prenatal exposure, demographic variables, or risk for poor neonatal adaptation. CONCLUSIONS: Prenatal SSRI exposure was associated with decreased neonatal serum S100B levels, controlling for prenatal maternal mood. Neonatal S100B levels did not reflect neonatal behavioral outcomes and were not related to pharmacologic indices. These findings are consistent with prenatal alcohol and cocaine exposures, which also alter central serotonin levels.

Perfectionistic Self-Presentation in Children and Adolescents: Development and Validation of the Perfectionistic Self-Presentation Scale—Junior Form

Research on adults indicates that perfectionistic self-presentation, the interpersonal expression of ones perfection, is associated with a variety of psychopathological outcomes independent of trait perfectionism and Big Five traits. The current article reports on the development and evidence for the validity of the subtest score interpretations of an 18-item self-report measure of perfectionistic self-presentation for children and adolescents. Analyses conducted on data from two clinical samples and one nonclinical sample of children and adolescents found that the Perfectionistic Self-Presentation Scale--Junior Form (PSPS-Jr) reflected a multidimensional model of perfectionistic self-presentation with three subscales: Perfectionistic Self Promotion, Nondisplay of Imperfection, and Nondisclosure of Imperfection. The subscale scores were found to demonstrate internal consistency, and there was good evidence supporting the validity of the interpretation of subscale scores based on this new measure. The subscales were associated with maladaptive outcomes, but were not influenced unduly by biases that included social desirability and differential item functioning by gender. Overall, the PSPS-Jr appears to be a useful measure of the expression of perfection among youths and an important tool in attempting to understand the nature and the consequences of perfectionistic self-presentation in children and adolescents.

Quality of Life and Patient-Reported Outcomes in Breast Cancer Survivors: A Multicenter Comparison of Four Abdominally Based Autologous Reconstruction Methods

Background: Approximately 20 percent of women select autologous tissue for postmastectomy breast reconstruction, and most commonly choose the abdomen as the donor site. An increasing proportion of women are seeking muscle-sparing procedures, but the benefit remains controversial. It is therefore important to determine whether better outcomes are associated with these techniques, thereby justifying longer operative times and increased costs. Methods: Patients from five North American centers were eligible if they underwent reconstruction by means of the deep inferior epigastric artery perforator (DIEP) flap, muscle-sparing free transverse abdominis myocutaneous (TRAM) flap, free TRAM flap, or the pedicled TRAM flap. Patients were sent the BREAST-Q. Demographics and complications were collected. Results: The authors analyzed 1790 charts representing 670 DIEP, 293 muscle-sparing free TRAM, 683 pedicled TRAM, and 144 free TRAM patients with an average follow-up of 5.5 years. Flap loss did not differ by flap type. Partial flap loss was higher in pedicled TRAM compared with DIEP (p = 0.002). Fat necrosis was higher in pedicled TRAM compared with DIEP and muscle-sparing free TRAM (p < 0.001). Hernia/bulge was highest in pedicled TRAM (p < 0.001). Physical well-being (abdomen) scores were higher in DIEP compared with pedicled TRAM controlling for confounders. Conclusions: Complications and patient-reported outcomes differ when comparing abdominally based breast reconstruction techniques. The results of this study show that the DIEP flap was associated with the highest abdominal well-being and the lowest abdominal morbidity compared with the pedicled TRAM flap, but did not differ from muscle-sparing free TRAM and free TRAM flaps. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Child motor vehicle occupant and pedestrian casualties before and after enactment of child restraint seats legislation in Japan.

Problem. Prevention of injuries to child passengers is a significant public health priority, as motor vehicle-related injuries remain a leading cause of death for children in Japan. The purpose of compulsory child restraint seats legislation in April 2000 was to reduce the number of child passengers killed or injured in motor vehicle crashes. Methods. The objectives of this preliminary evaluation are to measure the effectiveness, benefits and usage of safety seats for child passengers aged 1–5 years by analysing the child casualty data for the period of 1997–2002. Population and vehicle miles travelled based injury and fatality rates were used to compare before and after legislation trends in child casualties. Results. Despite overall increases in the use of child restraint seats (as observed by different national surveys), overall casualty rates in motor vehicle occupants in the 1–5 year age group did not change (fatalities and serious injuries) or even increased (minor injuries). Conclusions. Casualties among restrained children have not decreased since the law came to effect in the year 2000, perhaps because of incorrect usage of the seats. Given that exposure to crash environments is increasing, traffic safety advocates and public health community need to be aware of the importance of child restraints as a means of reducing the likelihood of injury. It is necessary to implement effective community-based child safety seat campaigns to disseminate the information on appropriate restraint use and to increase efforts to enforce the existing legislation.

Impact of caring for a child with cancer on single parents compared with parents from two-parent families†

It is currently unknown how the intensive and often prolonged treatment of childhood cancer impacts on the lives of single parents. Our aims were to determine whether single parents differ from parents from two‐parent families in terms of caregiver demand (the time and effort involved in caregiving), and health‐related quality of life (HRQL).

Autologous Breast Reconstruction in Women Older Than 65 Years Versus Women Younger Than 65 Years: A Multi-center Analysis

BackgroundAutologous breast reconstruction has been shown to have fewer complications and superior outcomes. In the elderly patient population, a paucity of literature on the subject may render the surgeon reluctant to recommend or perform such a procedure. The objective of this study was to compare complications and satisfaction after abdominally based breast reconstruction in patients older than versus younger than 65 years. MethodsA retrospective study was performed with data from 5 North American centers from 2002 to 2012. Patients who underwent autologous reconstruction were identified retrospectively, and chart review was performed. The BREAST-Q questionnaire was sent to these patients via mail. Patient variables, operative outcomes and BREASTQ results were analyzed. The Pearson &khgr;2 and analysis of variance tests were used. Given the number of analyses, a more conservative &agr; of 0.01 was used for each comparison. ResultsA total of 1809 patients were included with 1751 patients younger than 65 years and 58 patients aged 65 years or older. Analysis of postoperative complications showed no significant differences between the age groups, though there was a trend toward higher seroma development (17.2% vs 8.1%; P = 0.013) and infection (19.0% vs 10.0%; P = 0.028) in the older group with statistical significance set at P less than 0.01 to account for multiple comparisons. A total of 1809 BREAST-Q surveys were sent with a response rate of 52.5%. Patient satisfaction results were equally high between the 2 age groups. ConclusionsThis is the largest study to compare patients undergoing autologous breast reconstruction older than and younger than 65 years within the same cohort. Women older than 65 years represent a minority and constituted only 3% of patients in this multicenter 10-year review. We have shown that with careful patient selection, abdominally based autologous reconstruction should be considered in the elderly patient population because it is well tolerated and achieves high patient satisfaction.