Amy L. Salisbury

Maternal Smoking during Pregnancy and Newborn Neurobehavior: Effects at 10 to 27 Days

OBJECTIVE To examine effects of maternal smoking during pregnancy on newborn neurobehavior at 10 to 27 days. STUDY DESIGN Participants were 56 healthy infants (28 smoking-exposed, 28 unexposed) matched on maternal social class, age, and alcohol use. Maternal smoking during pregnancy was determined by maternal interview and maternal saliva cotinine. Postnatal smoke exposure was quantified by infant saliva cotinine. Infant neurobehavior was assessed through the NICU Network Neurobehavioral Scale. RESULTS Smoking-exposed infants showed greater need for handling and worse self-regulation (P < .05) and trended toward greater excitability and arousal (P < .10) relative to matched, unexposed infants (all moderate effect sizes). In contrast to prior studies of days 0 to 5, no effects of smoking-exposure on signs of stress/abstinence or muscle tone emerged. In stratified, adjusted analyses, only effects on need for handling remained significant (P < .05, large effect size). CONCLUSIONS Effects of maternal smoking during pregnancy at 10 to 27 days are subtle and consistent with increased need for external intervention and poorer self-regulation. Along with parenting deficits, these effects may represent early precursors for long-term adverse outcomes from maternal smoking during pregnancy. That signs of abstinence shown in prior studies of 0- to 5-day-old newborns did not emerge in older newborns provides further evidence for the possibility of a withdrawal process in exposed infants.

Fetal Effects of Psychoactive Drugs

Psychoactive drug use by pregnant women has the potential to effect fetal development; the effects are often thought to be drug-specific and gestational age dependent. This article describes the effects of three drugs with similar molecular targets that involve monoaminergic transmitter systems: cocaine, methamphetamine, and selective serotonin re-uptake inhibitors (SSRIs) used to treat maternal depression during pregnancy. We propose a possible common epigenetic mechanism for their potential effects on the developing child. We suggest that exposure to these substances acts as a stressor that affects fetal programming, disrupts fetal placental monoamine transporter expression and alters neuroendocrine and neurotransmitter system development. We also discuss neurobehavioral techniques that may be useful in the early detection of the effects of in utero drug exposure.

Single-Family Room Care and Neurobehavioral and Medical Outcomes in Preterm Infants

OBJECTIVE: To determine whether a single-family room (SFR) NICU, including factors associated with the change to a SFR NICU, is associated with improved medical and neurobehavioral outcomes. METHODS: Longitudinal, prospective, quasi-experimental cohort study conducted between 2008 and 2012 comparing medical and neurobehavioral outcomes at discharge in infants born <1500 g. Participants included 151 infants in an open-bay NICU and 252 infants after transition to a SFR NICU. Structural equation modeling was used to determine the role of mediators of relations between type of NICU and medical and neurobehavioral outcomes. RESULTS: Statistically significant results (all Ps ≤.05) showed that infants in the SFR NICU weighed more at discharge, had a greater rate of weight gain, required fewer medical procedures, had a lower gestational age at full enteral feed and less sepsis, showed better attention, less physiologic stress, less hypertonicity, less lethargy, and less pain. NICU differences in weight at discharge, and rate of weight gain were mediated by increased developmental support; differences in number of medical procedures were mediated by increased maternal involvement. NICU differences in attention were mediated by increased developmental support. Differences in stress and pain were mediated by maternal involvement. Nurses reported a more positive work environment and attitudes in the SFR NICU. CONCLUSIONS: The SFR is associated with improved neurobehavioral and medical outcomes. These improvements are related to increased developmental support and maternal involvement.

Maternal depression and anxiety are associated with altered gene expression in the human placenta without modification by antidepressant use: implications for fetal programming.

We sought to determine if maternal depression, anxiety, and/or treatment with selective serotonin reuptake inhibitors (SSRIs) affect placental human serotonin transporter (SLC6A4), norepinephrine transporter (SLC6A2), and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) gene expression. Relative mRNA expression was compared among placental samples (n = 164) from healthy women, women with untreated depression and/or anxiety symptoms during pregnancy, and women who used SSRIs. SLC6A4 expression was significantly increased in placentas from women with untreated mood disorders and from women treated with SSRIs, compared to controls. SLC6A2 and 11β-HSD2 expression was increased in noncontrol groups, though the differences were not significant. SLC6A4, SLC6A2, and 11β-HSD2 expression levels were positively correlated. The finding that maternal depression/anxiety affects gene expression of placental SLC6A4 suggests a possible mechanism for the effect(s) of maternal mood on fetal neurodevelopmental programming. SSRI treatment does not further alter the elevated SLC6A4 expression levels observed with exposure to maternal depression or anxiety.

Predicting Treatment for Neonatal Abstinence Syndrome in Infants Born to Women Maintained on Opioid Agonist Medication

AIM To identify factors that predict the expression of neonatal abstinence syndrome (NAS) in infants exposed to methadone or buprenorphine in utero. DESIGN AND SETTING Multi-site randomized clinical trial in which infants were observed for a minimum of 10 days following birth, and assessed for NAS symptoms by trained raters. PARTICIPANTS A total of 131 infants born to opioid dependent mothers, 129 of whom were available for NAS assessment. MEASUREMENTS Generalized linear modeling was performed using maternal and infant characteristics to predict: peak NAS score prior to treatment, whether an infant required NAS treatment, length of NAS treatment and total dose of morphine required for treatment of NAS symptoms. FINDINGS Of the sample, 53% (68 infants) required treatment for NAS. Lower maternal weight at delivery, later estimated gestational age (EGA), maternal use of selective serotonin re-uptake inhibitors (SSRIs), vaginal delivery and higher infant birthweight predicted higher peak NAS scores. Higher infant birthweight and greater maternal nicotine use at delivery predicted receipt of NAS treatment for infants. Maternal use of SSRIs, higher nicotine use and fewer days of study medication received also predicted total dose of medication required to treat NAS symptoms. No variables predicted length of treatment for NAS. CONCLUSIONS Maternal weight at delivery, estimated gestational age, infant birthweight, delivery type, maternal nicotine use and days of maternal study medication received and the use of psychotropic medications in pregnancy may play a role in the expression of neonatal abstinence syndrome severity in infants exposed to either methadone or buprenorphine.

Neonatal neurobehavior effects following buprenorphine versus methadone exposure

AIM To determine the effects of in utero exposure to methadone or buprenorphine on infant neurobehavior. DESIGN Three sites from the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study, a double-blind, double-dummy, randomized clinical trial participated in this substudy. SETTING Medical Centers that provided comprehensive maternal care to opioid-dependent pregnant women in Baltimore, MD, Providence, RI and Vienna, Austria. PARTICIPANTS Thirty-nine full-term infants. MEASUREMENTS The Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scale (NNNS) was administered to a subgroup of infants on postpartum days 3, 5, 7, 10, 14-15 and 28-30. FINDINGS While neurobehavior improved for both medication conditions over time, infants exposed in utero to buprenorphine exhibited fewer stress-abstinence signs (P < 0.001), were less excitable (P < 0.001) and less over-aroused (P < 0.01), exhibited less hypertonia (P < 0.007), had better self-regulation (P < 0.04) and required less handling (P < 0.001) to maintain a quiet alert state relative to in utero methadone-exposed infants. Infants who were older when they began morphine treatment for withdrawal had higher self-regulation scores (P < 0.01), and demonstrated the least amount of excitability (P < 0.02) and hypertonia (P < 0.02) on average. Quality of movement was correlated negatively with peak NAS score (P < 0.01), number of days treated with morphine for NAS (P < 0.01) and total amount of morphine received (P < 0.03). Excitability scores were related positively to total morphine dose (P < 0.03). CONCLUSION While neurobehavior improves during the first month of postnatal life for in utero agonist medication-exposed neonates, buprenorphine exposure results in superior neurobehavioral scores and less severe withdrawal than does methadone exposure.

Maternal smoking during pregnancy and infant stress response: Test of a prenatal programming hypothesis

BACKGROUND Maternal smoking during pregnancy (MSDP) is associated with early and long-term neurobehavioral deficits; however mechanisms remain unknown. We tested the hypothesis that MSDP programs the hypothalamic pituitary adrenocortical (HPA) axis of the offspring leading to adverse outcomes. In an intensive, prospective study, we investigated associations between MSDP and infant cortisol stress response and explored whether alterations in cortisol response were mediated by epigenetic modulation of the placental glucocorticoid receptor gene (NR3C1). METHODS Participants were 100 healthy mother-infant pairs (53% MSDP-exposed; 42% female) from a low income, racially/ethnically diverse sample (55% minorities). MSDP was assessed by timeline followback interview verified by saliva and meconium cotinine. Infant cortisol responses to a neurobehavioral exam were assessed seven times over the first postnatal month. Methylation of placental NR3C1 promoter exon 1F was assessed using bisulfite pyrosequencing in a subsample (n=45). RESULTS MSDP-exposed infants showed significantly and persistently attenuated basal and reactive cortisol levels over the first postnatal month vs. unexposed infants. Exploratory analyses revealed that MSDP was associated with altered methylation of the placental NR3C1 promoter; degree of methylation of the placental NR3C1 was associated with infant basal and reactive cortisol over the first postnatal month and mediated effects of MSDP on infant basal cortisol. CONCLUSIONS Results provide initial support for our hypothesis that MSDP programs offspring HPA (dys)regulation. Epigenetic regulation of placental GR may serve as a novel underlying mechanism. Results may have implications for delineating pathways to adverse outcomes from MSDP.

Perinatal Antidepressant Use: Understanding Women’s Preferences and Concerns

Perinatal depression is prevalent and linked with a host of adverse consequences for women and newborns. Rates of engagement in depression treatment are, however, strikingly low among pregnant and postpartum women, with the majority of affected women receiving no mental health treatment. Research indicates that perinatal women are extremely reluctant to take antidepressant medications, yet the nature of women’s concerns and treatment decision- making patterns have not been well documented. Developing a clearer understanding of women’s treatment preferences and behaviors may help identify solutions to the under-treatment of perinatal depression. In this mixed methods study, we conducted in-depth interviews with 61 pregnant women, approximately half of whom were experiencing clinical levels of depression. In addition to assessing psychiatric diagnoses, symptoms, and functional impairment, we conducted qualitative interviews addressing women’s preferences for depression treatment, concerns, and decision-making patterns. Consistent with prior reports, women were significantly more likely to voice a preference for non-pharmacologic depression treatments, as opposed to antidepressant medications. Many depressed women reported a great degree of uncertainty regarding how to treat their depression, and those with more severe depression symptoms were more likely to endorse decisional conflict. Analysis of qualitative comments yielded detailed information about the nature of women’s concerns and preferences related to use of antidepressant medications and other aspects of treatment engagement. We discuss findings in the context of improving patient-centered care for perinatal depression. (Journal of Psychiatric Practice 2013;19:443–453)

Fetal assessment before and after dosing with buprenorphine or methadone

AIM To determine pre- and post-dosing effects of prenatal methadone compared to buprenorphine on fetal wellbeing. DESIGN A secondary analysis of data derived from the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study, a double-blind, double-dummy, randomized clinical trial. SETTING Six United States sites and one European site that provided comprehensive opioid-dependence treatment to pregnant women. PARTICIPANTS Eighty-one of the 131 opioid-dependent pregnant women completing the MOTHER clinical trial, assessed between 31 and 33 weeks of gestation. MEASUREMENTS Two fetal assessments were conducted, once before and once after study medication dosing. Measures included mean fetal heart rate (FHR), number of FHR accelerations, FHR reactivity in the fetal non-stress test (NST) and biophysical profile (BPP) score. FINDINGS Significant group differences were found for number of FHR accelerations, non-reactive NST and BPP scores (all Ps < 0.05). There were no significant group differences before time of dosing. Significant decreases (all Ps < 0.05) occurred from pre- to post-dose assessment for mean FHR, FHR accelerations, reactive NST and fetal movement. The decrease in accelerations and reactive NST were significant only for fetuses in the methadone group, and this resulted in a significantly lower likelihood of a reactive NST compared to fetuses in the buprenorphine group. CONCLUSION Buprenorphine compared with methadone appears to result in less suppression of mean fetal heart rate, fetal heart rate reactivity and the biophysical profile score after medication dosing and these findings provide support for the relative safety of buprenorphine when fetal indices are considered as part of the complete risk-benefit ratio.

Variations of NICU sound by location and time of day.

Purpose/Aims. The primary aim of this study was to identify time periods of sound levels >45 decibels (dB) in a large Level III NICU. The second aim was to determine whether there were differences in decibel levels across the five bays of the NICU, the four quadrants within each bay, and two 12-hour shifts. Design. A repeated measures design was used. Bay, quadrant, and shift were randomly selected for sampling. Staff and visitors were blinded to the location of the sound meter, which was placed in one of five identical wooden boxes and was preset to record for 12 hours. Sample. Sound levels were recorded every 60 seconds over 40 12-hour periods, 20 during the day shift and 20 during the night shift. Total hours measured were 480. Data were collected every other day during a three-month period. Covariates of staffing, infant census, infant acuity, and medical equipment were collected. Main Outcome Variable. The main outcome variable was sound levels in decibels, with units of measurement of energy equivalent sound level (Leq), peak instantaneous sound pressure level, and maximum sound pressure level during each interval for a total of 480 hours. Results. All sound levels were >45 dB, with average readings ranging from 49.5 to 89.5 dB. The middle bay had the highest levels, with an Leq of 85.74 dB. Quadrants at the back of a bay were louder than quadrants at the front of a bay. The day shift had higher decibel levels than the night shift. Covariates did not differ across bays or shifts.