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Although prenatal opioid exposure and postnatal withdrawal (neonatal abstinence syndrome) are associated with infant neurobehavioral deficits, little is known about the impact of continued maternal opioid treatment in the postnatal period on maternal responsivity and relationship to mother's oxytocin release during dyadic interactions in the Still Face paradigm. Mother and infant dyads (N = 14) were recruited and comprised of mothers on opioid replacement throughout pregnancy and postpartum (opioid-exposed group, n = 7) and a demographically controlled, non-exposed group (n = 7). Salivary oxytocin was collected following 10 min of infant separation before and immediately after a 6-min Still Face paradigm. Oxytocin measures correlated strongly with sensitive and prosocial maternal behaviors in response to infant initiation. Opioid-exposed compared to non-exposed mothers had significantly lower pre-test to post-test rise in salivary oxytocin concentration level as well as fewer sensitive behaviors during the reunion condition of the Still Face paradigm. Maternal opioid dependence during early infancy may impair maternal responsivity and sensitivity through suppression of the oxytocin reflex to infant stimulation.

This pilot study examined changes in cancer-related post-traumatic stress symptoms (PTSS) across time for siblings of children with cancer. Siblings (N = 32; aged 8-18) completed a measure of anxiety, the Child PTSD Symptom Scale (CPSS), and the PTSD section of the Structured Clinical Interview for DSM-IV-TR (SCID) at twelve (SD = .9) and eighteen months (SD = 1.3) post-diagnosis. Moderate-to-severe PTSS was reported by 12 siblings (38%) at T1 and 7 (22%) at T2. Cluster analysis of PTSS data revealed five patterns: Few symptoms, stable across time (31%, n = 10); Mild symptoms, decreasing across time (16%, n = 5); Mild, stable symptoms (28%, n = 9); Moderate/severe symptoms, decreasing across time but remaining moderate (19%, n = 6); and Moderate/severe, stable symptoms (6%, n = 2). SCID data and anxiety scores distinguished siblings in the final two clusters from those with more favorable PTSS levels/trajectories. Additional research with larger samples is needed to validate these trajectories and examine factors that distinguish siblings with consistently elevated cancer-related PTSS from those with mild or significantly improving symptoms.

Introduction Late-life depression has been proposed as a precursor to amnestic Mild Cognitive Impairment (aMCI), the prodrome of Alzheimer’s disease. Both conditions are associated with sleep and cognitive problems. We hypothesized that MCI and current depressive symptoms would co-occur more frequently, but express distinct sleep phenotypes. Methods Independently living older adults (N=80), age 62-90 (M=71.78, SD=5.98), were recruited from a geriatric psychiatry clinic and the community for a home sleep study. A clinical decision board and neurocognitive battery were used to determine MCI status. Participants completed the CES-D and depression history interview where endorsement of current depression was considered positive. Sleep was examined with wrist actigraphy for 7 days. Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Stanford Sleepiness Scale (SSS) provided subjective sleep quality. Results Based on these criteria, 41.2% of the sample were determined to be MCI (n=33); the remainder were deemed normative for age (NC; n=47). Chi-square analyses showed a higher frequency of MCI were positive for current depression than expected (14.2%; p=0.017). Repeated-measures MANOVA, using current depression symptoms and MCI as factors, revealed MCI was associated with longer sleep latency (p=0.035) and wake bout time (p=0.039); whereas, current depression was associated with longer sleep latency, more fragmentation/WASO, and lower sleep efficiency (p’s Conclusion Despite distinct sleep disordered phenotypes, the interaction of MCI and current depression is associated with delayed sleep onset, use sleep medication and report of sleep disturbances. Support This project was sponsored by: NASA, Maine Space Consortium; AG 056176, AG 053164 Vice President for Research, U. Maine; Maine Technology Institute; DoD Phase I SBIR and R44AG059536-01 SBIR Phase II Award.

Background and Objectives There is significant variability in severity of neonatal abstinence syndrome (NAS) due to in utero opioid exposure. Our previous study identified single nucleotide polymorphisms (SNPs) in the prepronociceptin (PNOC) and catechol-O-methyltransferase (COMT) genes that were associated with differences in NAS outcomes. This study looks at the same SNPs in PNOC and COMT in an independent cohort in an attempt to replicate previous findings. Methods For the replication cohort, full-term opioid-exposed newborns and their mothers (n = 113 pairs) were studied. A DNA sample was obtained and genotyped for five SNPs in the PNOC and COMT genes. The association of each SNP with NAS outcomes (length of hospitalization, need for pharmacologic treatment, and total opioid days) was evaluated, with an experiment-wise significance level set at α

Objectives To assess whether preeclampsia was associated with expiratory airflow at school-age in children born either extremely preterm ( Study design Participants comprised 3 cohorts of children born extremely preterm/ELBW in the state of Victoria, Australia, in 1991-1992, 1997, or 2005. Expiratory airflows were measured at age 8 years, and results converted to z scores. Data were compared between those exposed to preeclampsia with those unexposed to preeclampsia; analyses were then adjusted for confounding perinatal variables. Analyses were repeated within subgroups of extremely preterm only and ELBW only. Results Respiratory data were available for 544 of 717 (76%) survivors, of whom 95 (17%) had been exposed to preeclampsia. On univariable analysis, those exposed to preeclampsia had better z scores for flows for the forced expired volume in 1 second (zFEV1) (mean difference 0.29, 95% CI 0.04-0.53; P = .022) and zFEV1/forced vital capacity (mean difference 0.33, 95% CI 0.04-0.61; P = .025); the difference persisted for zFEV1 after adjustment for confounding perinatal variables. Analyses confined to those born extremely preterm revealed little evidence for associations between preeclampsia and airflow. In analyses confined to those born ELBW, preeclampsia was associated with better zFEV1, which persisted after adjustment (mean difference 0.33, 95% CI 0.04-0.63; P = .025). Conclusions Exposure to maternal preeclampsia was not associated with worse expiratory airflow in children born extremely preterm/ELBW; in fact, some airflows were better.

Neonatal abstinence syndrome (NAS) due to in-utero opioid exposure has significant variability of severity. Preliminary studies have suggested that epigenetic variation within the μ-opioid receptor (OPRM1) gene impacts NAS. We aimed to determine if DNA methylation in OPRM1 within opioid-exposed mother-infant dyads is associated with differences in NAS severity in an independent cohort. Full-term opioid-exposed newborns and their mothers (N = 68 pairs) were studied. A DNA sample was obtained and then assessed for level of DNA methylation at 20 CpG sites within the OPRM1 promoter region by next-generation sequencing. Infants were monitored for NAS and treated with replacement opioids according to institutional protocol. The association between DNA methylation level at each CpG site with NAS outcome measures was evaluated using linear and logistic regression models. Higher methylation levels within the infants at the -18 (11.4% vs 4.4%, P = .0001), -14 (46.1% vs 24.0%, P = .002) and +23 (26.3% vs 12.9%, P = .008) CpG sites were associated with higher rates of infant pharmacologic treatment. Higher levels of methylation within the mothers at the -169 (R = 0.43, P = .008), -152 (R = 0.40, P = .002) and +84 (R = 0.44, P = .006) sites were associated point-wise with longer infant length of stay. Maternal associations remained significant point-wise for -169 (β = 0.07, P = .007) and on an experiment-wise level for +84 (β = -0.10, P = .003) using regression models. These results suggest an association of higher levels of OPRM1 methylation at specific CpG sites and increased NAS severity, replicating prior findings. These findings have important implications for personalized treatment regimens for infants at high risk for severe NAS.

Methadone versus morphine for treatment of neonatal abstinence syndrome: A prospective randomized clinical trial

Objective Neonatal abstinence syndrome (NAS) from in utero opioid exposure is highly variable with genetic factors appearing to play an important role. Epigenetic changes in cytosine:guanine (CpG) dinucleotide methylation can occur after drug exposure and may help to explain NAS variability. We correlated DNA methylation levels in the mu-opioid receptor (OPRM1) promoter in opioid-exposed infants with NAS outcomes. Study design DNA samples from cord blood or saliva were analyzed for 86 infants who were being treated for NAS according to institutional protocol. Methylation levels at 16 OPRM1 CpG sites were determined and correlated with NAS outcome measures, including need for treatment, treatment with $2 medications, and length of hospital stay. We adjusted for covariates and multiple genetic testing. Results Sixty-five percent of infants required treatment for NAS, and 24% required $2 medications. Hypermethylation of the OPRM1 promoter was measured at the � 10 CpG in treated vs nontreated infants (adjusted difference d = 3.2% [95% CI, 0.3-6.0%], P = .03; nonsignificant after multiple testing correction). There was hypermethylation at the � 14 (d = 4.9% [95% CI, 1.8%-8.1%], P =. 003),� 10 (d =5 .0% [95% CI, 2.3-7.7%],P = .0005), and +84 (d = 3.5% [95% CI, 0.6-6.4], P = .02) CpG sites in infants requiring $2 medications, which remained significant for � 14 and � 10 after multiple testing correction. Conclusions Increased methylation within the OPRM1 promoter is associated with worse NAS outcomes, consistent with gene silencing. (J Pediatr 2014;165:472-8).

Recent rise in rates of opiate replacement therapy among pregnant women have resulted in increasing number of infants requiring treatment for neonatal abstinence syndrome. Short- and long-term developmental outcomes associated with prenatal opiate exposure are discussed, including symptoms and severity of neonatal abstinence syndrome (NAS), and early cognitive and motor delays. Maternal and infant risk factors are discussed, and include patterns of maternal substance use during pregnancy, genetic risk, polysubstance exposure pharmacologic treatment for NAS and breastfeeding. The importance of characterizing corollary environmental risk factors is also considered.

There is significant variability in the severity of neonatal abstinence syndrome (NAS) due to in-utero opioid exposure. We wanted to determine if single nucleotide polymorphisms (SNPs) in key candidate genes contribute to this variability.Full-term opioid-exposed newborns and their mothers (n=86 pairs) were studied. DNA was genotyped for 80 SNPs from 14 genes utilizing a custom designed microarray. The association of each SNP with NAS outcomes was evaluated.SNPs in two opioid receptor genes in the infants were associated with worse NAS severity: (1) The PNOC rs732636 A allele (OR=3.8, p=0.004) for treatment with 2 medications and a longer hospital stay (LOS) of 5.8 days (p=0.01), and (2) The OPRK1 rs702764 C allele (OR=4.1, p=0.003) for treatment with 2 medications. The OPRM1 rs1799971 G allele (β=-6.9 days, p=0.02) and COMT rs740603 A allele (β=-5.3 days, p=0.01) were associated with shorter LOS. The OPRD1 rs204076 A allele in the mothers was associated with a longer LOS by 6.6 days (p=0.008). Results were significant point-wise but did not meet the experiment-wide significance level.These findings suggest that SNPs in opioid receptor and the PNOC genes are associated with NAS severity. However, further testing in a large sample is warranted. This has important implications for prenatal prediction and personalized treatment regimens for infants at highest risk for severe NAS.

Objective. To examine factors associated with the phenomenon of yonaki, or sleep-related nighttime crying (SRNC), in Japanese childrenMethods. A cross-sectional design incorporating parental self-report was used to investigate relationships between developmental, psychologic, and constitutional/physiological factors in the incidence of SRNC. Participants were the parents of 170 infants, 174 toddlers, and 137 children at a well-infant clinic in Tokyo, Japan.Results. The lifetime incidence rates of SRNC were 18.8% (infants), 64.9% (toddlers), and 59.9% (children). At all ages, children were most likely to cosleep with their parents; however, infants with reported SRNC were found to cosleep more frequently, whereas infants without SRNC were more likely to sleep in separate, child-dedicated beds. Toddlers with frequent SRNC were more likely to have irregular bedtimes and to have nonparental day care than were those without SRNC. Preschoolers who typically slept 9.5 to 10.5 hours per night were less likely to report SRNC than were children with longer or shorter nighttime sleep durations. In all groups, children with frequent SRNC were more likely to suffer from chronic eczema, and toddlers and preschoolers with SRNC exhibited bruxism more frequently.Conclusions. The traditional Japanese arrangement of cosleeping represents an environment in which parents are readily accessible to children during waking episodes. Physical proximity to the parents in infancy, but not at other ages, is associated with SRNC. The higher incidence of bruxism, chronic eczema, and day care use among children with frequent SRNC supports the hypothesis that nighttime anxiety may promote SRNC.

Objective To examine patterns of behavioral states of premature newborns before and after nursing interventions. Design Secondary analysis of videotaped data, using a repeated measures design. Setting 18-bed neonatal intensive-and intermediate-care unit in a 400-bed suburban teaching hospital. Participants Forty medically stable premature newborns with an average postconceptional age of 32.79 weeks at the time of testing. Main outcome measure Behavioral states measured by observations of videotape recordings. Results Five-hour observations of behavioral states revealed that newborns showed more quiet sleep, F (2, 38) = 5.65, p = .023, and fewer waking episodes, F (2, 38) = 14.4, p = .001, in the 30 minutes after nursing interventions than in the 30 minutes before. This repeated measures ANOVA analysis accounted for effects of caffeine or theophylline. Neither the frequency nor the duration of nursing interventions predicted duration or frequency of behavioral states before or after interventions. Some newborns experience waking outside the context of nursing interventions. Conclusions For medically stable newborns, nursing interventions are generally followed by sleep, possibly indicating satiety after feeding or significant energy expenditure. The findings also may suggest that some newborns show anticipation of feeding by waking, although 50% of the newborns did not experience any waking prior to interventions. Further research is needed to examine associations between specific types of nursing interventions and newborn behavioral responses, as well as the relationship of behavioral state patterns and newborn development.

Importance Neonatal abstinence syndrome (NAS) caused by in utero opioid exposure is a growing problem; genetic factors influencing the incidence and severity have not been previously examined. Single-nucleotide polymorphisms (SNPs) in the μ-opioid receptor (OPRM1), multidrug resistance (ABCB1), and catechol-o-methyltransferase (COMT) genes are associated with risk for opioid addiction in adults. Objective To determine whether SNPs in the OPRM1, ABCB1, and COMT genes are associated with length of hospital stay and the need for treatment of NAS. Design, Setting, and Participants Prospective multicenter cohort study conducted at 5 tertiary care centers and community hospitals in Massachusetts and Maine between July 2011 and July 2012. DNA samples were genotyped for SNPs, and then NAS outcomes were correlated with genotype. Eighty-six of 140 eligible mother-infant dyads were enrolled. Infants were eligible if they were 36 weeks' gestational age or older and exposed to methadone or buprenorphine in utero . Main Outcomes and Measures Primary outcome measure was length of hospital stay, with between-group differences expressed as β and calculated with linear regression models. Secondary outcome measures included need for any medical treatment for NAS and treatment with 2 or more medications. Results Infants with the OPRM1 118A>G AG/GG genotype had shortened length of stay (β = −8.5 days; 95% CI, −14.9 to −2.1 days; P = .009) and were less likely to receive any treatment than AA infants (48% vs 72%; adjusted odds ratio, 0.76; 95% CI, 0.63-0.96; P = .006). The COMT 158A>G AG/GG genotype was associated with shortened length of stay (β = −10.8 days; 95% CI, −18.2 to −3.4 days; P = .005) and less treatment with 2 or more medications (18% vs 56%; adjusted odds ratio, 0.68; 95% CI, 0.55-0.86; P = .001) than the AA genotype. Associations with the ABCB1 SNPs were not significant. Conclusions and Relevance Among infants with NAS, variants in the OPRM1 and COMT genes were associated with a shorter length of hospital stay and less need for treatment. These preliminary findings may provide insight into the mechanisms underlying NAS.

A wide range of conditions fall under the category of Mild Traumatic Brain Injury (mTBI) diagnosis. In this article, we focus on a new method during sleep to detect mTBI associated with neuro-cognitive impairment that is not apparent using standard neuro-imaging methods. A wireless pressure sensor system comprising a piezo-resistive flexible substrate paired with a microcontroller and a radio is designed and built to provide information relevant to mTBI detection. The collected information is then processed with a software program to remove noise and interference, and detect both sleep states and cardio-respiratory movements. (5 pages)

The spontaneous motor activity of clinically stable premature infants, 26–36 weeks gestational age, was investigated. Movements were recorded using a pressure-sensitive transducer positioned below the infant's head and torso. Behavior samples were digitized every 0.5 s during 2 and 3-hr continuous recording sessions. Time-series analyses revealed prominent motility cycles of circa 80 min and circa 30 min. These results are consistent with periodicities in motility and REM activation observed in full-term neonates. The longer rhythms of 70–100 min of motility found in this study establish that these periods are present at this stage of development independent of maternal zeitgebers. Developmental changes in motility rhythms and movement burst durations were also observed. Bout durations became somewhat longer in older ( > 30 weeks) infants, but the relative time devoted to movement per session was comparable in older and younger (≤ 30 weeks) infants. © 1993 Wiley & sons. Inc.

To determine if apneic preterm infants currently treated with methylxanthines develop evidence of sleep deprivation from cumulative arousal and motor activational effects. Sleep, wake, arousal and actigraphic movements were monitored in extubated clinically stable premature infants (N=37). Neonates were free of other medications for >72 h and were grouped based on methylxanthine exposure: >5 days with caffeine (n=14), >5 days theophylline (n=13) or no prior exposure (n=10). Duration of methylxanthine treatment predicted increased arousals, wakefulness and actigraphic movements, and decreased active sleep. Recording from 1200 to 0500 hours, methylxanthine-treated groups showed reductions in all arousal parameters: waking state, number of wake epochs, brief arousals and composite arousal index, and shorter fast-burst, sleep-related motility than untreated controls. In apneic preterms, chronic methylxanthine treatment appears to produce sleep deprivation secondary to the stimulatory action of methylxanthines on arousal and motor systems.

IN THIS ISSUE OF JAMA, PATRICK ET AL 1 DESCRIBE THE EFfects on newborn infants of the widespread availability of prescription opiate medications. These medications provide superior pain control for cancer and chronic pain, but have been overprescribed, diverted, and sold illegally, creating a new opiate addiction pathway and a public health burden for maternal and child health. Overdose mortality and dependence rates are highest among disadvantaged, young adults in rural areas (eg, Maine and Kentucky). Young women are nearly as likely as men to abuse opiate medications, leading to an increase in opiate-dependent newborns treated for withdrawal syndrome or neonatal abstinence syndrome (NAS). The standard of care for opiate addiction during pregnancy is methadone maintenance and psychiatric care. Patrick et al demonstrate that the increase in NAS (from an incidence of 1.20 [95% CI, 1.04-1.37] per 1000 hospital births per year in 2000 to 3.39 [95% CI, 3.12-3.67] per 1000 hospital births per year in 2009) has created a health care encumbrance primarily for state Medicaid budgets. In affected states, methadone treatment programs have expanded rapidly and voluntary prescription monitoring programs identify opiate medication use patterns (ie, opiate prescriptions are tracked and individuals who are “shopping” for physicians to prescribe opiates can be identified). However, the burden of addiction on state Medicaid budgets threatens retrenchment of recently established programs despite increased need. This poses a crisis of care for affected fetuses and newborns. However, without accessible treatment of both maternal opiate addiction and new methods of treating NAS, state and federal systems may pay in the future because many of these infants require special services for developmental and behavioral disorders. Patrick et al also observed that over the last decade, there has been no improvement in NAS treatment efficiency as measured by length of stay (LOS). Furthermore, health care expenditures for NAS have increased during the same period. Even within the context of the status quo of medically managed prenatal methadone treatment, opiate-exposed infants risk adverse effects besides the specter of protracted withdrawal. In their analyses of hospital complications of infants with NAS, Patrick et al confirmed other data demonstrating increased rates of prematurity, respiratory disease, and seizures. Opiate withdrawal is often compounded by comorbid polydrug exposure and maternal psychiatric medications, such as antidepressants and benzodiazepines, which have their own withdrawal syndromes. Although the withdrawal from these agents is milder than opiates, such combinatorial withdrawal complicates neonatal care and often extends LOS. Neonatal abstinence syndrome withdrawal severity affects adaptation to postnatal life in critical regulatory areas of sleep, feeding, and autonomic function. Although 60% to 80% of infants exposed in utero to opiates develop NAS and require prolonged hospitalization, averaging 16 days in the study by Patrick et al, there is still considerable uncertainty regarding optimal detoxification protocols and criteria for opiate withdrawal status typically based on symptoms assessed by the Finnegan score calculated every few hours from birth to day 5. Hospitals and clinicians burdened by the increase in NAS incidence can expend substantial efforts to develop treatment protocols to decrease LOS. As outlined by Patrick et al, most clinicians use oral opiate medication (eg, methadone or morphine) and, in difficult cases, a second-line nonopiate drug with -aminobutyric acid (eg, phenobarbital), benzodiazepine (eg, clonazapam), or anti-adrenergic (eg, clonidine) action. Novel pharmacotherapy research is needed to improve maternal opiate maintenance strategies to protect the fetus from in utero withdrawal, and to reduce the incidence and severity of NAS. These efforts have been frustrated by lack of controlled clinical trials. Methadone maintenance therapy during pregnancy is currently idiosyncratic (eg, lack of standardization in maternal care related todosing)andbasedonmaternalwithdrawal symptoms as gestation progresses. Research aimed at predicting which newborns are most at risk for a difficult withdrawal, or will require prompt treatment, has yielded few leads. In the adult pain management literature, individual genetic differences have been found to predict opiate response and dose