Effect of Neonatal Abstinence Syndrome Treatment Status and Maternal Depressive Symptomatology on Maternal Reports of Infant Behaviors.

OBJECTIVE: The objective of this study is to investigate the effects of maternal perinatal depression symptoms and infant treatment status for neonatal abstinence syndrome (NAS) on maternal perceptions of infant regulatory behavior at 6 weeks of age. METHODS: Mothers and their infants (N = 106; 53 dyads) were recruited from a rural, White cohort in Northeast Maine. Mothers in medication-assisted treatment (methadone) and their infants (n = 35 dyads) were divided based on the infant's NAS pharmacological treatment (n = 20, NAS+ group; n = 15, NAS- group) and compared with a demographically similar, nonexposed comparison group (n = 18 dyads; COMP group). At 6 weeks postpartum, mothers reported their depression symptoms Beck Depression Inventory-2nd Edition) and infant regulatory behaviors [Mother and Baby Scales (MABS)]. Infant neurobehavior was assessed during the same visit using the Neonatal Network Neurobehavioral Scale (NNNS). RESULTS: Mothers in the NAS+ group showed significantly higher depression scores than the COMP group (p < .05) while the NAS- group did not. Across the sample, mothers with higher depression scores reported higher infant "unsettled-irregularity" MABS scores, regardless of group status. Agreement between maternal reports of infant regulatory behaviors and observer-assessed NNNS summary scares was poor in both the NAS+ and COMP groups. CONCLUSIONS: Postpartum women in opioid recovery with infants requiring pharmacological intervention for NAS are more at risk for depression which may adversely influence their perceptions of their infants' regulatory profiles. Unique, targeted attachment interventions may be needed for this population.

Sleep movements and respiratory coupling as a biobehavioral metric for early Alzheimer's disease in independently dwelling adults.

INTRODUCTION: Sleep disorder is often the first symptom of age-related cognitive decline associated with Alzheimer's disease (AD) observed in primary care. The relationship between sleep and early AD was examined using a patented sleep mattress designed to record respiration and high frequency movement arousals. A machine learning algorithm was developed to classify sleep features associated with early AD. METHOD: Community-dwelling older adults (N = 95; 62-90 years) were recruited in a 3-h catchment area. Study participants were tested on the mattress device in the home bed for 2 days, wore a wrist actigraph for 7 days, and provided sleep diary and sleep disorder self-reports during the 1-week study period. Neurocognitive testing was completed in the home within 30-days of the sleep study. Participant performance on executive and memory tasks, health history and demographics were reviewed by a geriatric clinical team yielding Normal Cognition (n = 45) and amnestic MCI-Consensus (n = 33) groups. A diagnosed MCI group (n = 17) was recruited from a hospital memory clinic following diagnostic series of neuroimaging biomarker assessment and cognitive criteria for AD. RESULTS: In cohort analyses, sleep fragmentation and wake after sleep onset duration predicted poorer executive function, particularly memory performance. Group analyses showed increased sleep fragmentation and total sleep time in the diagnosed MCI group compared to the Normal Cognition group. Machine learning algorithm showed that the time latency between movement arousals and coupled respiratory upregulation could be used as a classifier of diagnosed MCI vs. Normal Cognition cases. ROC diagnostics identified MCI with 87% sensitivity; 89% specificity; and 88% positive predictive value. DISCUSSION: AD sleep phenotype was detected with a novel sleep biometric, time latency, associated with the tight gap between sleep movements and respiratory coupling, which is proposed as a corollary of sleep quality/loss that affects the autonomic regulation of respiration during sleep. Diagnosed MCI was associated with sleep fragmentation and arousal intrusion.

Sleep Signal Analysis for Early Detection of Alzheimer's Disease and Related Dementia (ADRD).

OBJECTIVE: Alzheimer's Disease and Related Dementia (ADRD) is growing at alarming rates, putting research and development of diagnostic methods at the forefront of the biomedical research community. Sleep disorder has been proposed as an early sign of Mild Cognitive Impairment (MCI) in Alzheimer's disease. Although several clinical studies have been conducted to assess sleep and association with early MCI, reliable and efficient algorithms to detect MCI in home-based sleep studies are needed in order to address both healthcare costs and patient discomfort in hospital/lab-based sleep studies. METHODS: In this paper, an innovative MCI detection method is proposed using an overnight recording of movements associated with sleep combined with advanced signal processing and artificial intelligence. A new diagnostic parameter is introduced which is extracted from the correlation between high frequency, sleep-related movements and respiratory changes during sleep. The newly defined parameter, Time-Lag (TL), is proposed as a distinguishing criterion that indicates movement stimulation of brainstem respiratory regulation that may modulate hypoxemia risk during sleep and serve as an effective parameter for early detection of MCI in ADRD. By implementing Neural Networks (NN) and Kernel algorithms with choosing TL as the principle component in MCI detection, high sensitivity (86.75% for NN and 65% for Kernel method), specificity (89.25% and 100%), and accuracy (88% and 82.5%) have been achieved.

Neonatal sleep development and early learning in infants with prenatal opioid exposure.

The aim of this chapter is to examine the role of sleep and cognition in the context of the cumulative risk model examining samples of at-risk infants and maternal-infant dyads. The cumulative risk model posits that non-optimal developmental outcomes are the result of multiple factors in a child's life including, but not limited to, prenatal teratogenic exposures, premature birth, family socioeconomic status, parenting style and cognitions as well as the focus of this volume, sleep. We highlight poor neonatal sleep as both an outcome of perinatal risk as well as a risk factor to developing attentional and cognitive capabilities during early childhood. Outcomes associated with and contributing to poor sleep and cognition during infancy are examined in relation to other known risks in our clinical population. Implications of this research and recommendations for interventions for this population are provided.

Change Across Time in Cancer-Related Traumatic Stress Symptoms of Siblings of Children with Cancer: A Preliminary Investigation.

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.

Maternal responsivity and oxytocin in opioid-dependent mothers.

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.

Neonatal abstinence syndrome: Neurobehavior at 6 weeks of age in infants with or without pharmacological treatment for withdrawal.

Use and abuse of prescription opioids and concomitant increase in Neonatal Abstinence Syndrome (NAS), a condition that may lead to protracted pharmacological treatment in more than 60% of infants, has tripled since 2000. This study assessed neurobehavioral development using the NICU Network Neurobehavioral Scale in 6-week old infants with prenatal methadone exposure who did (NAS+; n = 23) or did not (NAS-; n = 16) require pharmacological treatment for NAS severity determined by Finnegan Scale. An unexposed, demographically similar group of infants matched for age served as comparison (COMP; n = 21). NAS+, but not NAS- group, had significantly lower scores on the regulation (p < .01) and quality of movement (p < .01) summary scales than the COMP group. The NAS+ and NAS- groups had higher scores on the stress-abstinence scale than the COMP group (p < .05). NAS diagnosis (NAS +) was associated with poorer regulation and quality of movement at 6 weeks of age compared to infants without prenatal methadone exposure from the same demographic.

Association of maternal and infant variants in PNOC and COMT genes with neonatal abstinence syndrome severity.

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 < .003 and point-wise level of α < .05. SNP associations in a combined cohort of n = 199 pairs (replication cohort plus 86 pairs previously reported), were also examined. RESULTS: In the replication cohort, mothers with the COMT rs4680 G allele had infants with a reduced risk for treatment with two medications for NAS (adjusted OR = .5, p = .04), meeting point-wise significance. In the combined cohort, infants with the PNOC rs4732636 A allele had a reduced need for medication treatment (adjusted OR 2.0, p = .04); mothers with the PNOC rs351776 A allele had infants who were treated more often with two medications (adjusted OR 2.3, p = .004) with longer hospitalization by 3.3 days (p = .01). Mothers with the COMT rs740603 A allele had infants who were less often treated with any medication (adjusted OR .5, p = .02). Though all SNP associations all met point wise and clinical significance, they did not meet the experiment-wise significance threshold. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: We found differences in NAS outcomes depending on PNOC and COMT SNP genotype. This has important implications for identifying infants at risk for severe NAS who could benefit from tailored treatment regimens. Further testing in a larger sample is warranted. This has important implications for prenatal prediction and personalized treatment regimens for infants with NAS. (Am J Addict 2017;26:42-49).

Variations in opioid receptor genes in neonatal abstinence syndrome.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 (ß=-6.9 days, p=0.02) and COMT rs740603 A allele (ß=-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. CONCLUSIONS: 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.

Epigenetic variation in the mu-opioid receptor gene in infants with neonatal abstinence syndrome.

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 δ = 3.2% [95% CI, 0.3-6.0%], P = .03; nonsignificant after multiple testing correction). There was hypermethylation at the -14 (δ = 4.9% [95% CI, 1.8%-8.1%], P = .003), -10 (δ = 5.0% [95% CI, 2.3-7.7%], P = .0005), and +84 (δ = 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.

Development of auditory event-related potentials in infants prenatally exposed to methadone.

Developmental features of the P2 auditory ERP in a change detection paradigm were examined in infants prenatally exposed to methadone. Opiate dependent pregnant women maintained on methadone replacement therapy were recruited during pregnancy (N = 60). Current and historical alcohol and substance use, SES, and psychiatric status were assessed with a maternal interview during the third trimester. Medical records were used to collect information regarding maternal medications, monthly urinalysis, and breathalyzer to confirm comorbid drug and alcohol exposures. Between birth and 4 months infant ERP change detection performance was evaluated on one occasion with the oddball paradigm (.2 probability oddball) using pure-tone stimuli (standard = 1 kHz and oddball = 2 kHz frequency) at midline electrode sites, Fz, Cz, Pz. Infant groups were examined in the following developmental windows: 4-15, 16-32, or 33-120 days PNA. Older groups showed increased P2 amplitude at Fz and effective change detection performance at P2 not seen in the newborn group. Developmental maturation of amplitude and stimulus discrimination for P2 has been reported in developing infants at all of the ages tested and data reported here in the older infants are consistent with typical development. However, it has been previously reported that the P2 amplitude difference is detectable in neonates; therefore, absence of a difference in P2 amplitude between stimuli in the 4-15 days group may represent impaired ERP performance by neonatal abstinence syndrome or prenatal methadone exposure.

Association of OPRM1 and COMT single-nucleotide polymorphisms with hospital length of stay and treatment of neonatal abstinence syndrome.

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 ß 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 (ß = -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 (ß = -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.

Neonatal abstinence syndrome: treatment and pediatric outcomes.

Recent rise in rates of opiate replacement therapy among pregnant women have resulted in increasing number of infants requiring treatment for neonatal abstinence syndrome (NAS). Short-term and long-term developmental outcomes associated with prenatal opiate exposure are discussed, including symptoms and severity of 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 pharmacological treatment for NAS and breastfeeding. The importance of characterizing corollary environmental risk factors is also considered.

Opioid dependency in pregnancy and length of stay for neonatal abstinence syndrome.

OBJECTIVE: To examine opioid replacement therapy in pregnancy and effect on neonatal outcomes, including length of hospital stay for neonatal abstinence syndrome. DESIGN: Retrospective descriptive study. SETTING: Labor and delivery unit and neonatal intensive care unit (NICU), Eastern Maine Medical Center, Bangor, Maine. PARTICIPANTS: One hundred fifty-two opioid-dependent pregnant women on methadone maintenance therapy (MMT) (n = 136) or buprenorphine maintenance therapy (BMT) (n = 16) during pregnancy and their neonates. The neonates were born between January 1, 2005 and December 31, 2007. METHODS: A review of the electronic medical record (EMR) was conducted of all opioid-dependent women who were maintained on MMT or BMT at the time of admission for labor and delivery and their neonates. RESULTS: Maternal methadone dose and concomitant in-utero exposure to benzodiazepines prolonged the length of hospital stay for neonates. Length of stay was shorter in breastfed neonates than formula-fed neonates or neonates who received formula and breast milk. Neonates with prenatal exposure to MMT spent more days in the hospital (21 vs. 14 days) for treatment of neonatal abstinence syndrome (NAS) than infants with prenatal exposure to BMT. CONCLUSION: These findings are consistent with previous research on the simultaneous use of methadone and benzodiazepines during pregnancy and provide further direction for the treatment of opioid dependency during pregnancy. Harm reduction strategies for opioid-dependent pregnant women in substance abuse treatment with MMT may one day include guidance on daily treatment doses and recommendations to avoid the concomitant use of benzodiazepines to lessen NAS. Breastfeeding should be recommended to shorten length of stay. Understanding perinatal and neonatal outcomes of pregnant women on methadone or buprenorphine will help to identify optimal treatment for opioid dependency in pregnancy.

Temperament and Sleep-Wake Behaviors from Infancy to Toddlerhood.

Sleep-wake behaviors and temperament were examined longitudinally for trait stability and relationship to behavioral state regulation from infancy to early childhood. Subjects were 120 low-risk, full-term infants from a middle class sample. At 6 weeks, parents completed 3 consecutive days of the Baby's Day Diary which measures sleep, wake, fuss, feed and cry states and the Infant Characteristics Questionnaire. At 16 months, parents assessed sleep behaviors with the Sleep Habits Inventory and temperament with the Toddler Symptom Checklist. At 24 months, parents repeated 3 days of the Baby's Day Diary. Structural Equation Modeling was used to examine cross-age hypotheses for sleep-wake and temperament associations. From early infancy to toddlerhood, sleep-wake behaviors and irritable temperament were notably stable but independent in this cohort.

Sleep fragmentation and evidence for sleep debt in alcohol-exposed infants.

BACKGROUND: Infants exposed prenatally to alcohol are at increased risk for poor neurodevelopmental outcome including Sudden Infant Death Syndrome. AIM: To examine the relationship between prenatal alcohol exposure, sleep, arousal and sleep-related spontaneous motor movements in early infancy. STUDY DESIGN: Low-income women (N=13) were interviewed regarding pre- and pregnancy rates of alcohol, cigarette smoking and other substance use in the perinatal period. Infants were examined in a laboratory nap study using EEG, videography and actigraphy at 6-8 weeks of age. Estimates of maternal pre- and pregnancy alcohol use were used to divide infants into high vs. low maternal alcohol use groups. SUBJECTS: Mother-infant dyads recruited from a family practice clinic. OUTCOME MEASURES: Sleep-related spontaneous movements, behavioral state, and maternal assessments of infant alertness and irritability. RESULTS: Pre-pregnancy rates of alcohol consumption including binge drinking correlated with maternal report of poor infant alertness, and increased irritability. High maternal exposure groups showed increased sleep fragmentation, e.g., frequency and duration of wakefulness following sleep onset and decreased active sleep. Bout analysis of the temporal structure of sleep-related spontaneous movements showed significantly reduced bout duration associated with high maternal alcohol use. CONCLUSION: These results present evidence that prenatal alcohol exposure disrupts postnatal sleep organization and suppresses spontaneous movements during sleep, and increased sleep fragmentation promotes sleep deprivation. Results are consistent with the SIDS model of chronic sleep debt and suggest that attenuated sleep-related movements should be examined as an important modulator of cardiorespiratory functions during sleep in high-risk groups.

Yawning frequency and distribution in preterm and near term infants assessed throughout 24-h recordings.

Yawning has been observed in foetuses and preterm infants. The aim of this study was to assess the frequency and the 24 h distribution of yawning in preterm infants. Twelve low-risk infants between 31 and 40 weeks of post-conceptional age (PCA) were continuously video-recorded for 24 h in their incubator. Spontaneous yawning was defined as opening of the mouth to its full extension in a dramatic stretch movement. The results showed that the rate of yawning across the 24-h period was 1.10/h. The highest incidence of yawns was in the waking motility pattern when compared to active sleep or quiet sleep motility patterns. Between 31 and 40 weeks, yawn incidence significantly decreased mainly during the day. The marked decrease in yawn frequency with age may be related to the development of circadian and homeostatic control of sleep and wake.

Sleep-related nighttime crying (yonaki) in Japan: a community-based study.

OBJECTIVE: To examine factors associated with the phenomenon of yonaki, or sleep-related nighttime crying (SRNC), in Japanese children METHODS: 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.