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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.

Aims: Epigenetic variation of DNA methylation of the mu-opioid receptor gene (OPRM1) has been identified in the blood and saliva of individuals with opioid use disorder (OUD) and infants with neonatal opioid withdrawal syndrome (NOWS). It is unknown whether epigenetic variation in OPRM1 exists within placental tissue in women with OUD and whether it is associated with NOWS outcomes. In this pilot study, we aimed to 1) examine the association between placental OPRM1 DNA methylation levels and NOWS outcomes, and 2) compare OPRM1 methylation levels in opioid-exposed versus non-exposed control placentas. Methods: Placental tissue was collected from eligible opioid (n = 64) and control (n = 29) women after delivery. Placental DNA was isolated and methylation levels at six cytosine-phosphate-guanine (CpG) sites within the OPRM1 promoter were quantified. Methylation levels were evaluated for associations with infant NOWS outcome measures: need for pharmacologic treatment, length of hospital stay (LOS), morphine treatment days, and treatment with two medications. Regression models were created and adjusted for clinical co-variates. Methylation levels between opioid and controls placentas were also compared. Results: The primary opioid exposures were methadone and buprenorphine. Forty-nine (76.6%) of the opioid-exposed infants required pharmacologic treatment, 10 (15.6%) two medications, and average LOS for all opioid-exposed infants was 16.5 (standard deviation 9.7) days. There were no significant associations between OPRM1 DNA methylation levels in the six CpG sites and any NOWS outcome measures. No significant differences were found in methylation levels between the opioid and control samples. Conclusions: No significant associations were found between OPRM1 placental DNA methylation levels and NOWS severity in this pilot cohort. In addition, no significant differences were seen in OPRM1 methylation in opioid versus control placentas. Future association studies examining methylation levels on a genome-wide level are warranted.

Neonatal abstinence syndrome (NAS) after in-utero opioid exposure remains a poorly understood condition with multiple factors contributing to severity. Exposure to maternal stress may be one contributing factor. Hair cortisol measurement represents a novel technique for assessing prenatal stress. In this pilot study, the association between maternal hair cortisol levels and NAS severity was examined in 70 postpartum women with opioid use disorder within 72 hr of delivery. Infants were monitored for NAS and treated according to institutional protocol. Forty-four (63%) of the infants were pharmacologically treated for NAS, with a mean length of hospital stay (LOS) for all infants of 14.2 (SD 9.0) days. The mean cortisol level in the mothers was 131.8 pg/mg (SD 124.7). In bivariate analysis, higher maternal hair cortisol levels were associated with shorter infant LOS (R = -.26, p = .03) and fewer infant opioid treatment days (R = -.28, p = .02). Results were no longer statistically significant in regression models after adjusting for maternal opioid and smoking. In conclusion, we demonstrated the feasibility of hair cortisol assaying within the first few days after delivery in mothers with opioid use disorder as a novel marker for NAS. The findings suggest that maternal stress may impact the severity of infant opioid withdrawal.

Aims: Epigenetic variation of DNA methylation of the mu-opioid receptor gene (OPRM1) has been identified in the blood and saliva of individuals with opioid use disorder (OUD) and infants with neonatal opioid withdrawal syndrome (NOWS). It is unknown whether epigenetic variation in OPRM1 exists within placental tissue in women with OUD and whether it is associated with NOWS outcomes. In this pilot study, the authors aimed to 1) examine the association between placental OPRM1 DNA methylation levels and NOWS outcomes, and 2) compare OPRM1 methylation levels in opioid-exposed versus non-exposed control placentas. Methods: Placental tissue was collected from eligible opioid (n = 64) and control (n = 29) women after delivery. Placental DNA was isolated and methylation levels at six cytosine-phosphate-guanine (CpG) sites within the OPRM1 promoter were quantified. Methylation levels were evaluated for associations with infant NOWS outcome measures: need for pharmacologic treatment, length of hospital stay (LOS), morphine treatment days, and treatment with two medications. Regression models were created and adjusted for clinical co-variates. Methylation levels between opioid and controls placentas were also compared. Results: The primary opioid exposures were methadone and buprenorphine. Forty-nine (76.6%) of the opioid-exposed infants required pharmacologic treatment, 10 (15.6%) two medications, and average LOS for all opioid-exposed infants was 16.5 (standard deviation 9.7) days. There were no significant associations between OPRM1 DNA methylation levels in the six CpG sites and any NOWS outcome measures. No significant differences were found in methylation levels between the opioid and control samples. Conclusions: No significant associations were found between OPRM1 placental DNA methylation levels and NOWS severity in this pilot cohort. In addition, no significant differences were seen in OPRM1 methylation in opioid versus control placentas. Future association studies examining methylation levels on a genome-wide level are warranted.

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.

8040 Background: Early therapeutic intervention with lenalidomide has shown to be effective in delaying progression in patients with high-risk smoldering multiple myeloma (HR-SMM) (Lonial J Clin Oncol 2020). Quadruplet regimen of daratumumab, bortezomib, lenalidomide and dexamethasone (D-RVD) has demonstrated significant activity in multiple myeloma, achieving high rates of minimal residual disease (MRD) negativity (Voorhees Blood 2020). Thus, we proposed to examine the activity and safety of D-RVD in patients with HR-SMM. Methods: This is a phase II single center, single-arm, open label study evaluating the combination of D-RVD in HR-SMM. Eligibility included high risk per Mayo 2018 “20-2-20” model and other previously established criteria including Mayo 2008 criteria, presence of immunoparesis, evolving type of SMM, and high risk FISH. Primary objective is rate of sustained MRD negativity at 2 years. Secondary objectives include PFS, response rates and safety. Treatment duration with modified D-RVD is for total of 2 years (24 cycles). Daratumumab is administered subcutaneously (SQ) per standard dose and schedule, bortezomib given weekly on days 1, 8, 15 for cycles 1-6 and then biweekly until completion of cycle 24. Lenalidomide is administered on days 1-21 and dexamethasone is administered weekly. All eligible patients will undergo stem cell collection after 6 cycles of therapy. Results: At the time of data cut off, 20 patients have been enrolled with a median follow up of 6 months. The median age is 58 years old (range 40-73). Sixteen out of 20 (80%) patients met high risk criteria per Mayo 2018 model with median plasmacytosis of 20%, median M protein value of 2.6 g/dl and median FLC ratio of 28.2. Seven patients had high-risk FISH: 5 with 1q duplication, 2 with t(4;14). Most common toxicities of any grade included neutropenia (65%), WBC decreased (55%) insomnia (50%), constipation (45%) and hypophosphatemia (45%). Most common grade 3 toxicities included neutropenia (15%), ALT increased (5%), thrombocytopenia (5%), hyperglycemia (5%), hypertension (5%), diarrhea (5%), syncope (5%). No patients discontinued therapy due to toxicity. The overall response rate is 90% with 40% PR, 25% VGPR and 25% CR. All patients have achieved at least a MR and 50% achieved VGPR or greater with responses deepening over time. No patients have progressed on treatment. MRD was evaluable in 16 patients and 8 patients have undergone MRD testing, with MRD negativity rate of 50% (4/8) and 25% (2/8) at thresholds of 10-5 and 10-6, respectively. Stem cells were successfully collected in all patients with mean stem cell yield of 5.78 x 106 CD34+/kg cells. Conclusions: D-RVD is well tolerated in patients with HR-SMM demonstrating significant early activity. Responses continue to deepen over time with patients achieving MRD negative disease. Clinical trial information: NCT04775550.

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.

Background Among opioid-exposed infants, psychiatric medication co-exposure is common. Our objective was to compare Neonatal Abstinence Syndrome (NAS) outcomes based on individual psychiatric medication co-exposures. Methods A retrospective study of 744 opioid-exposed mother-infant dyads from a single institution was performed. Mothers on pharmacotherapy with methadone or buprenorphine at delivery were included. Data were collected on maternal demographics, psychiatric medication use, and NAS outcomes, including any medication treatment, adjunctive medication treatment, length of hospital stay (LOS), and opioid treatment days. The extent to which individual psychiatric medication and polypharmacy exposure were associated with NAS outcomes was assessed using multivariable regression. Results Fifty-four percent of the mothers were on ≥1 psychiatric medication, with 32% on ≥2 or psychiatric medications (polypharmacy group). In adjusted models, polypharmacy exposure was associated with longer LOS (β = 4.31 days, 95% CI 2.55–6.06) and opioid treatment days (β = 3.98 days, 95% CI 2.24–5.72) and more treatment with adjunctive medication for NAS (aOR = 2.49, 95% CI 1.57–3.95). Benzodiazepines were associated with longer LOS (β = 4.94, 95% CI 2.86–7.03) and opioid treatment days (β = 4.86, 95% CI 2.61–6.75), and more adjunctive medication treatment (aOR = 2.57, 95% CI 1.49–4.42). Gabapentin was associated with longer LOS (β = 2.79, 95% CI 0.54–5.03), more NAS medication treatment (aOR = 2.96, 95% CI 1.18–7.42) including more adjunctive medications (aOR = 1.92, 95% CI 1.05–3.53). Conclusion For infants of mothers with OUD who are also on concurrent psychiatric medications, polypharmacy was associated with worse NAS severity. When medically indicated, limiting use of multiple psychiatric medications, particularly benzodiazepines and gabapentin, during pregnancy should be considered to improve NAS outcomes.

Objectives: Among opioid-exposed newborns, breastfeeding is associated with less severe withdrawal signs, yet breastfeeding rates remain low. We determined the extent to which hospital, maternal, and infant characteristics are associated with breastfeeding initiation and continuation among opioid-exposed dyads. Materials and Methods: We examined breastfeeding initiation and continuation until infants' discharge among opioid-exposed dyads from 2006 to 2016. Among dyads meeting hospital breastfeeding guidelines, we assessed hospital (changes in breastfeeding guidelines and improvement initiatives [using delivery year as a proxy]), maternal (demographics, comorbid conditions, methadone versus buprenorphine treatment, and delivery mode), and infant (gestational age and birth weight) characteristics. We used multivariable logistic regression to examine independent associations of characteristics with breastfeeding initiation and continuation. Results: Among 924 opioid-exposed dyads, 61% (564) met breastfeeding criteria. Overall, 50% (283/564) of dyads initiated and 33% (187/564) continued breastfeeding until discharge. Breastfeeding initiation and continuation rates increased from 38% and 8% in 2006, to 56% and 34% in 2016, respectively. In adjusted models, infants born after reducing restrictions in hospital breastfeeding guidelines and prenatal breastfeeding education (adjusted odds ratio, aOR 2.6 [95% confidence interval, CI 1.5–4.5]) had increased odds of receiving any maternal breast milk versus infants born with earlier hospital policies. Cesarean versus vaginal delivery (aOR 0.3 [95% CI 0.2–0.6]) and length of infant hospitalization (aOR 0.94 [95% CI 0.92–0.97]) were negatively associated with breastfeeding continuation. Conclusions: Despite increasing breastfeeding rates among opioid-exposed dyads, rates remain suboptimal. Hospital-level factors were the greatest predictor of breastfeeding initiation. The findings suggest that changes in hospital guidelines and initiatives can impact breastfeeding initiation among this vulnerable population.

OBJECTIVES: We compared hospitalization outcomes in infants with neonatal opioid withdrawal syndrome (NOWS) treated with a novel symptom-triggered methadone approach (STMA) versus a fixed-schedule methadone taper (FSMT). METHODS: This was a single-center quality-improvement study of infants pharmacologically treated for NOWS. Outcomes were compared over time by using statistical process control charts and between the baseline FSMT (July 2016–November 2017) and intervention STMA (December 2017–May 2018) groups, including median hospital length of stay (LOS), methadone treatment days, total milligrams of methadone, and need for adjunctive agents. RESULTS: There were 48 infants in the FSMT group and 28 in the STMA group. Infants treated with STMA had a median LOS of 10.5 days (interquartile range [IQR] 10.5) versus 17.0 days (IQR 3.9; P = .003) in the FSMT group, with a 9.2-day difference in methadone treatment days (2.5 [IQR 9.0] vs 11.7 [IQR 4.0]; P = .0001), meeting criteria for statistical process control special cause variation. The average number of symptom-triggered doses was 2.1 (SD 1.0). Six infants in the STMA group were converted to FSMT after failing a trial of STMA. Infants successfully treated with the STMA (N = 22) had a median LOS of 10.0 days (IQR 4.0) compared with 17.0 (IQR 3.9) in the baseline FSMT group (P < .0001). CONCLUSIONS: STMA was associated with a significant reduction in median LOS and amount of methadone treatment. A symptom-triggered approach to NOWS may reduce LOS and medication exposure.

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

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.

To improve Neonatal Abstinence Syndrome (NAS) inpatient outcomes through a comprehensive quality improvement (QI) program. Inclusion criteria were opioid-exposed infants ≥36 weeks. QI methodology including stakeholder interviews and plan-do-study-act (PDSA) cycles were utilized. We compared pre- and post-intervention NAS outcomes after a QI initiative that included: A non-pharmacologic care bundle, function-based assessments consisting of symptom prioritization and then the “Eat, Sleep, Console” (ESC) Tool; and a switch to methadone for pharmacologic treatment. Pharmacologic treatment decreased from 87.1 to 40.0%; adjunctive agent use from 33.6 to 2.4%; hospitalization length from a mean 17.4 to 11.3 days, and opioid treatment days from 16.2 to 12.7 (p

Language exposure is important for neurodevelopment, but is sparse in the neonatal intensive care unit (NICU). We introduced Reach Out and Read (ROR) in the NICU as a quality improvement initiative to increase language exposure. Measures included availability of books, accessibility of parents, and enrollment of infants, percent infants read to by their parents, and data from parental surveys. 98 infants were included (40 before, 58 after). We obtained books in the mother’s language for 95% of infants, 82% eligible infants were enrolled, and 70% read to their infants (mean of 0.45 ± 0.35 times/day). Surveyed parents enjoyed reading, noted positive effect(s), and intended to read post-discharge. We launched a well-received pilot ROR program in the NICU and reached our goal of ≥50% infants being read to by their parents. Further study is needed to assess the impact of reading in the NICU on parents and infants.

There is variation in cardiorespiratory monitoring practices for neonatal abstinence syndrome. We examined the incidence of cardiorespiratory adverse events in infants with neonatal abstinence syndrome who were treated or nontreated pharmacologically. Eight (10%) in the nontreated and 23 (19%) in the treated group experienced adverse events. This warrants further investigation in a larger cohort.

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.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.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.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).