Hair Cortisol Concentrations in Opioid-Exposed versus Nonexposed Mother-Infant Dyads.

OBJECTIVE: To pilot measurement of hair cortisol concentration (HCC) in pregnant women with opioid use disorder and their infants over time and study the potential utility of hair cortisol as a biomarker of chronic stress in this population. STUDY DESIGN: In this pilot prospective cohort study of mother-infant dyads with and without prenatal opioid exposure, we obtained mother-infant HCCs at delivery and again within 1 to 3 months' postpartum. HCCs were compared between the opioid and control groups and between the two time points. RESULTS: There were no significant differences between opioid and control group maternal or infant HCCs at either time point. However, within the opioid-exposed group, there was a significant increase in infant HCCs across the two time points. CONCLUSION: This pilot study describes our experience with the measurement of HCCs in opioid-exposed mother-infant dyads. KEY POINTS: · Maternal stress impacts fetal and child health.. · Many stressors in pregnant women with opioid use disorder.. · Hair cortisol may be a useful stress biomarker..

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.

Maternal hair cortisol levels as a novel predictor of neonatal abstinence syndrome severity: A pilot feasibility study.

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.

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).

Neurobehavioral outcomes of infants exposed to buprenorphine-naloxone compared with naltrexone during pregnancy.

BACKGROUND: Naltrexone is a medication used to treat both opioid and alcohol use disorder with limited experience in pregnant individuals, particularly in comparison to more commonly utilized treatments such as buprenorphine-naloxone. The long-term outcomes of infants exposed to naltrexone has not been previously examined. AIMS: To compare the neurobehavioral outcomes of naltrexone versus buprenorphine-naloxone exposed infants. STUDY DESIGN: Multi-centered prospective cohort study. SUBJECTS: Pregnant people on prescribed buprenorphine-naloxone or naltrexone were enrolled during pregnancy and the dyad followed until 12 months after delivery. OUTCOME MEASURES: Infants were evaluated at 4-6 weeks corrected gestational age (CGA) using the NICU Neonatal Neurobehavioral Scale (NNNS) and at the 12-month CGA visit using the Ages and Stages Questionnaire, Third Edition (ASQ-3). RESULTS: There were 7 dyads in the naltrexone group and 34 in the buprenorphine-naloxone group. On the NNNS, infants exposed to naltrexone had higher median scores for arousal and excitability, and lower median scores for attention and regulation at 4-6 weeks CGA compared to the buprenorphine-naloxone group. None of the infants in the naltrexone group were monitored for NOWS and had shorter length of hospital stay compared with the buprenorphine-naloxone group. Although no statistically significant differences were observed, more infants in the buprenorphine-naloxone group were identified as at risk for development delays in the communication, problem solving, and personal social domains of the ASQ-3 at 12 months CGA. Results should be interpreted with caution given this study's small sample size and lack of a prospective comparison cohort. CONCLUSIONS: In this small cohort, there are differences noted in infant neurobehavior by NNNS at 4-6 weeks of age when comparing the buprenorphine-naloxone and naltrexone groups. At 12 months, ASQ-3 scores were similar but with percentage differences in potential development delay risk observed between the two groups. Larger cohort studies are needed to determine the long-term child outcomes after naltrexone exposure in pregnancy.

Medication for Opioid Use Disorder During Pregnancy - Maternal and Infant Network to Understand Outcomes Associated with Use of Medication for Opioid Use Disorder During Pregnancy (MAT-LINK), 2014-2021.

Problem: Medication for opioid use disorder (MOUD) is recommended for persons with opioid use disorder (OUD) during pregnancy. However, knowledge gaps exist about best practices for management of OUD during pregnancy and these data are needed to guide clinical care. Period Covered: 2014-2021. Description of the System: Established in 2019, the Maternal and Infant Network to Understand Outcomes Associated with Medication for Opioid Use Disorder During Pregnancy (MAT-LINK) is a surveillance network of seven clinical sites in the United States. Boston Medical Center, Kaiser Permanente Northwest, The Ohio State University, and the University of Utah were the initial clinical sites in 2019. In 2021, three clinical sites were added to the network (the University of New Mexico, the University of Rochester, and the University of South Florida). Persons receiving care at the seven clinical sites are diverse in terms of geography, urbanicity, race and ethnicity, insurance coverage, and type of MOUD received. The goal of MAT-LINK is to capture demographic and clinical information about persons with OUD during pregnancy to better understand the effect of MOUD on outcomes and, ultimately, provide information for clinical care and public health interventions for this population. MAT-LINK maintains strict confidentiality through robust information technology architecture. MAT-LINK surveillance methods, population characteristics, and evaluation findings are described in this inaugural surveillance report. This report is the first to describe the system, presenting detailed information on funding, structure, data elements, and methods as well as findings from a surveillance evaluation. The findings presented in this report are limited to selected demographic characteristics of pregnant persons overall and by MOUD treatment status. Clinical and outcome data are not included because data collection and cleaning have not been completed; initial analyses of clinical and outcome data will begin in 2023. Results: The MAT-LINK surveillance network gathered data on 5,541 reported pregnancies with a known pregnancy outcome during 2014-2021 among persons with OUD from seven clinical sites. The mean maternal age was 29.7 (SD = ±5.1) years. By race and ethnicity, 86.3% of pregnant persons were identified as White, 25.4% as Hispanic or Latino, and 5.8% as Black or African American. Among pregnant persons, 81.6% had public insurance, and 84.4% lived in urban areas. Compared with persons not receiving MOUD during pregnancy, those receiving MOUD during pregnancy were more likely to be older and White and to have public insurance. The evaluation of the surveillance system found that the initial four clinical sites were not representative of demographics of the South or Southwest regions of the United States and had low representation from certain racial and ethnic groups compared with the overall U.S. population; however, the addition of three clinical sites in 2021 made the surveillance network more representative. Automated extraction and processing improved the speed of data collection and analysis. The ability to add new clinical sites and variables demonstrated the flexibility of MAT-LINK. Interpretation: MAT-LINK is the first surveillance system to collect comprehensive, longitudinal data on pregnant person-infant dyads with perinatal outcomes associated with MOUD during pregnancy from multiple clinical sites. Analyses of clinical site data demonstrated different sociodemographic characteristics between the MOUD and non-MOUD treatment groups. Public Health Actions: MAT-LINK is a timely and flexible surveillance system with data on approximately 5,500 pregnancies. Ongoing data collection and analyses of these data will provide information to support clinical and public health guidance to improve health outcomes among pregnant persons with OUD and their children.

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.

Pilot Study Comparing Adverse Cardiorespiratory Events among Pharmacologically and Nonpharmacologically Treated Infants Undergoing Monitoring for Neonatal Abstinence Syndrome.

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.

Placental OPRM1 DNA methylation and associations with neonatal opioid withdrawal syndrome, a pilot study.

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.

Naltrexone Treatment for Pregnant Women With Opioid Use Disorder Compared With Matched Buprenorphine Control Subjects.

PURPOSE: The use of the opioid antagonist naltrexone (NTX) for pregnant women with opioid use disorder (OUD) remains understudied. The purpose of this pilot study was to examine pregnancy and neonatal outcomes in a cohort of NTX-treated women. METHODS: This single-center, retrospective cohort study included 6 mother-infant dyads taking NTX compared with 13 taking buprenorphine (BUP) between 2017 and 2019. Maternal demographic characteristics, any unprescribed or illicit opioid use per urine toxicology or provider report during the pregnancy or 6 months' postdelivery, delivery outcomes, gestational age, birth weight, Apgar scores, neonatal intensive care unit admission, and neonatal abstinence syndrome (NAS) outcomes (NAS diagnosis, pharmacologic treatment, and total hospital length of stay) were compared. FINDINGS: Maternal and infant demographic characteristics were similar between the 2 groups, with the exception of cigarette smoking in the BUP group being more common (92% vs 33%; P = 0.02). None of the women on NTX versus 23% of the women on BUP had documented opioid misuse (P = 0.52). No infants in the NTX group had a NAS diagnosis versus 92% in the BUP group (P < 0.001). Forty-six percent of the BUP-exposed infants were treated for NAS versus 0% in the NTX group (P < 0.001). NTX-exposed infants had a shorter length of stay (mean [SD], 3.2 [1.6] vs 10.9 [8.2] days; P = 0.008). IMPLICATIONS: Maintaining women on NTX during pregnancy was associated with favorable outcomes. These results support the need for larger multicenter studies sufficiently powered to detect possible differences between the medications on long-term maternal and child safety and efficacy outcomes.

Standard Fixed-Schedule Methadone Taper Versus Symptom-Triggered Methadone Approach for Treatment of Neonatal Opioid Withdrawal Syndrome.

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.

Examination of Hospital, Maternal, and Infant Characteristics Associated with Breastfeeding Initiation and Continuation Among Opioid-Exposed Mother-Infant Dyads.

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.

Implementation of a pilot program of Reach Out and Read® in the neonatal intensive care unit: a quality improvement initiative.

OBJECTIVE: Language exposure is important for neurodevelopment, but is sparse in the neonatal intensive care unit (NICU). STUDY DESIGN: 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. RESULT: 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. CONCLUSION: 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.

Impact of psychiatric medication co-exposure on Neonatal Abstinence Syndrome severity.

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 (ß = 4.31 days, 95% CI 2.55-6.06) and opioid treatment days (ß = 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 (ß = 4.94, 95% CI 2.86-7.03) and opioid treatment days (ß = 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 (ß = 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.

Quality improvement initiative to improve inpatient outcomes for Neonatal Abstinence Syndrome.

OBJECTIVES: To improve Neonatal Abstinence Syndrome (NAS) inpatient outcomes through a comprehensive quality improvement (QI) program. DESIGN: 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. RESULTS: 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 < 0.001 for all). Total hospital charges decreased from $31,825 to $20,668 per infant. Parental presence increased from 55.6 to 75.8% (p < 0.0001). No adverse events were noted. CONCLUSIONS: A comprehensive QI program focused on non-pharmacologic care, function-based assessments, and methadone resulted in significant sustained improvements in NAS outcomes. These findings have important implications for establishing potentially better practices for opioid-exposed newborns.