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..

Acute Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Pregnancy Is Associated with Placental Angiotensin-Converting Enzyme 2 Shedding.

While the human placenta may be infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the rate of fetal transmission is low, suggesting a barrier at the maternal-fetal interface. Angiotensin-converting enzyme (ACE)2, the main receptor for SARS-CoV-2, is regulated by a metalloprotease cleavage enzyme, a disintegrin and metalloprotease domain 17 (ADAM17). ACE2 is expressed in the human placenta, but its regulation in relation to maternal SARS-CoV-2 infection in pregnancy is not well understood. This study evaluated ACE2 expression, ADAM17 activity, and serum ACE2 abundance in a cohort of matched villous placental and maternal serum samples from control pregnancies (SARS-CoV-2 negative, n = 8) and pregnancies affected by symptomatic maternal SARS-CoV-2 infections in the second trimester [2nd Tri coronavirus disease (COVID), n = 8] and third trimester (3rd Tri COVID, n = 8). In 3rd Tri COVID compared with control and 2nd Tri COVID villous placental tissues, ACE2 mRNA expression was remarkably elevated; however, ACE2 protein expression was significantly decreased with a parallel increase in ADAM17 activity. Soluble ACE2 was also significantly increased in the maternal serum from 3rd Tri COVID infections compared with control and 2nd Tri COVID pregnancies. These data suggest that in acute maternal SARS-CoV-2 infections, decreased placental ACE2 protein may be the result of ACE2 shedding and highlights the importance of ACE2 for studies on SARS-CoV-2 responses at the maternal-fetal interface.

Comparison of Anti-SARS-CoV-2-Specific Antibody Signatures in Maternal and Infant Blood after COVID-19 Infection versus COVID-19 Vaccination during Pregnancy.

OBJECTIVE: The Advisory Committee on Immunization Practices and The American College of Obstetricians and Gynecologists recommend coronavirus disease 2019 (COVID-19) vaccine for pregnant persons to prevent severe illness and death. The objective was to examine levels of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG, IgM, and IgA against spike protein receptor binding domain (RBD) and nucleocapsid protein (NCP) in maternal and infant/cord blood at delivery after COVID 19 vaccination compared with SARS-CoV-2 infection at in mother-infant dyads at specified time points. STUDY DESIGN: Mothers with SARS-CoV-2 infection (n = 31) or COVID-19 vaccination (n = 25) during pregnancy were enrolled between July 2020 and November 2021. Samples were collected at delivery and IgG, IgM, and IgA to RBD of spike and NCPs compared in the infected and vaccinated groups. Timing of infection/vaccination prior to delivery and correlation with antibody levels was performed. RESULTS: The majority of participants received vaccination within 90 days of delivery and over half received the Pfizer BioNTech vaccine. There were no significant correlations between antibody levels and timing of infection or vaccination. Infant IgG levels to the RBD domain of spike protein were higher in the vaccinated group (n = 25) as compared with the infants born to mothers with infection (n = 31). Vaccination against COVID-19 during pregnancy was associated with detectable maternal and infant anti-RBD IgG levels at delivery irrespective of the timing of vaccination. CONCLUSION: Timing of vaccination had no correlation to the antibody levels suggesting that the timing of maternal vaccination in the cohort did not matter. There was no IgM detected in infants from vaccinated mothers. Infants from vaccinated mothers had robust IgG titers to RBD, which have a lasting protective effect in infants. KEY POINTS: · COVID-19 vaccination during pregnancy had detectable antibody.. · No correlation between antibody levels and timing of vaccination.. · Infants from vaccinated mothers had robust IgG titers to RBD..

Impact of Coronavirus Disease-2019 on Hospital Care for Neonatal Opioid Withdrawal Syndrome.

OBJECTIVE: To compare prenatal exposures, hospital care processes, and hospitalization outcomes for opioid-exposed newborns before and during the coronavirus disease 2019 (COVID-19) pandemic. STUDY DESIGN: In this multicenter retrospective analysis, data were collected from 19 Massachusetts hospitals, including 5 academic and 14 community hospitals. The pre-COVID-19 cohort was defined as births occurring during March 1, 2019-February 28, 2020, and the COVID-19 cohort was defined as births occurring during March 1, 2020-December 31, 2020. Opioid-exposed newborns born at ≥35 weeks of gestation were included. Differences in prenatal substance exposures, hospital care processes, and neonatal opioid withdrawal syndrome (NOWS) outcomes, including pharmacologic treatment for NOWS (PharmTx), length of stay (LOS), and as-needed (prn) treatment failure rates, were evaluated. RESULTS: There were 663 opioid-exposed newborns in the pre-COVID-19 group and 476 in the COVID-19 group. No between-group differences were seen in prenatal substance exposures or the need for PharmTx. Compared with the pre-COVID-19 group, in the COVID-19 group there was less rooming-in after maternal discharge (53.8% vs 63.0%; P = .001) and less care in the pediatric unit setting (23.5% vs 25.3%; P = .001), longer LOS (adjusted risk ratio, 1.04; 95% CI, 1.01-1.08), and a higher rate of breast milk receipt at discharge (aOR, 2.03; 95% CI, 1.22-3.39). Within the subset of academic centers, more infants failed prn treatment in the COVID-19 group (53.8% vs 26.5%, P = .02; aOR, 3.77; 95% CI, 0.98-14.5). CONCLUSIONS: Among the hospitals in our collaborative, hospital processes for NOWS, including care setting, rooming-in, and LOS were negatively impacted in the COVID-19 group, particularly in academic medical centers.

SARS-CoV-2 in infant urine and fecal samples after in utero COVID-19 exposure.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a pandemic that has and will continue to affect many pregnant women. Knowledge regarding the risk of vertical transmission is limited. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) real-time reverse transcriptase-polymerase chain reaction (RT-PCR) of nasopharyngeal swabs typically have been used to confirm the diagnosis among infants, but whether the virus can be detected in other biological specimens, and therefore potentially transmitted in other ways, is unknown. Positive SARS-CoV-2 RT-PCR has been reported from feces and urine from adult patients. We hypothesize that the presence of SARS-CoV-2 in infant urine and fecal samples after prenatal COVID-19 exposure is low. METHODS: We examined the presence of SARS-CoV-2 RNA using RT-PCR in urine and fecal samples among 42 infants born to SARS-CoV-2-infected mothers during different stages of pregnancy. RESULTS: A urine sample was collected from 39 of 42 infants and fecal samples from all 42 infants shortly after birth. Although the majority of the women had the symptomatic disease (85.6%), we were unable to detect the presence of SARS-CoV-2 virus from any infant urine or fecal samples. CONCLUSIONS: SARS-CoV-2 was not detected in infant urine or feces after maternal infection during pregnancy, providing further evidence for low rates of perinatal transmission. IMPACT: SARS-CoV-2 was not detected in the urine or feces of infants of mothers with COVID-19 during various time points in pregnancy. This study provides further evidence for low rates of perinatal transmission of SARS-CoV-2. Results help to provide guidance on perinatal care practices for infants exposed to COVID-19 in utero.

Mother-Infant Dyads with COVID-19 at an Urban, Safety-Net Hospital: Clinical Manifestations and Birth Outcomes.

OBJECTIVE: This study aimed to describe maternal characteristics and clinical outcomes of infants born to mothers with positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tests during pregnancy at an urban, safety-net hospital in Boston. STUDY DESIGN: We abstracted electronic chart data from 75 pregnant women with positive SARS-CoV-2 tests at any stage of gestation until 72 hours after birth who delivered consecutively between March 31 and August 6, 2020 at our center. We collected clinical data on maternal and infant characteristics, including testing, signs, and symptoms of coronavirus disease 2019 (COVID-19), delivery outcomes, newborn care practices (skin-to-skin care, location of care, and breastfeeding) and 30-day postdischarge infant emergency room visits and readmissions. We described categorical characteristics as percentages for this case series. RESULTS: Among 75 pregnant women, 47 (63%) were Hispanic, 10 (13%) had hypertension, 23 (30%) had prepregnancy obesity, and 57 (76%) had symptomatic SARS-CoV-2 infection. Regarding birth outcomes, 32 (41%) had cesarean delivery and 14 (19%) had preterm birth. Among 75 infants, 5 (7%) had positive SARS-CoV-2 polymerase chain reaction tests in the first week of life, all of whom were born to Hispanic mothers with symptomatic SARS-CoV-2 infection and had clinical courses consistent with gestational age. Six (8%) infants visited the emergency department within 30 days of discharge; one was admitted with a non-COVID-19 diagnosis. CONCLUSION: At our urban, safety-net hospital among pregnant women with positive SARS-CoV-2 tests, 41% had a cesarean delivery and 19% had a preterm birth. Seven percent of infants had one or more positive SARS-CoV-2 tests and all infants had clinical courses expected for gestational age. KEY POINTS: · Among 75 pregnant women with SARS-CoV-2 positive testing at our center, five infants (7%) had one or more SARS-CoV-2 positive tests in the first week of life.. · Infants with positive SARS-CoV-2 tests had clinical courses expected for gestational age..

Impact of cuddler service-learning program in medical student education of opioid use disorder in pregnancy and neonatal opioid withdrawal syndrome.

Background: Given the increasing incidence of neonatal opioid withdrawal syndrome (NOWS), medical student training on substance use disorders (SUDs) and opioid use disorder (OUD) in pregnancy must be augmented. Through the Cuddling Assists in Lowering Maternal and Infant Stress (CALM) service-learning program, medical students attend SUD-related didactics and provide monthly cuddling services to infants with NOWS. Objective: This study examines the impact of CALM on medical students' attitudes toward individuals with SUDs and self-reported comfort with clinical skills related to caring for this population. Methods: Self-reported pre- and post-survey data was collected at the beginning and end of an academic year from the intervention group, CALM cuddlers, and the control group, non-cuddlers for 2 years. Mean total survey scores and individual survey questions using a 3-point Likert scale were compared before and after 1 year of participation for cuddlers and for non-cuddlers using paired t-tests and two sample t-tests. Results: The mean total score increased for cuddlers after participation in the intervention (MD 0.13, SD 0.26, p = 0.03). Mean scores for the comfort-related subset of questions also increased significantly for cuddlers after participation in the intervention (MD 0.22, SD 0.41, p = 0.01). Cuddlers felt more comfortable discussing substance use with appropriate language (72.0% vs 51.5%, p = 0.03), talking with patients about substance use (72.0% vs 36.0%, p = 0.01), and asking about substance use or recovery (80.0% vs 48.0%, p = 0.01). Conclusion: OUD- and NOWS-related service-learning positively impacts student attitudes and self-reported comfort with skills related to caring for individuals with SUDs, such as communicating about substance use.

Neurodevelopmental Outcomes of Neonates Randomized to Morphine or Methadone for Treatment of Neonatal Abstinence Syndrome.

OBJECTIVE: To evaluate the effects of pharmacologic treatment of neonatal abstinence syndrome on neurodevelopmental outcome from a randomized, controlled trial. STUDY DESIGN: Eight sites enrolled 116 full-term newborn infants with neonatal abstinence syndrome born to mothers maintained on methadone or buprenorphine into a randomized trial of morphine vs methadone. Ninety-nine infants (85%) were evaluated at hospital discharge using the NICU Network Neurobehavioral Scale. At 18 months, 83 of 99 infants (83.8%) were evaluated with the Bayley Scales of Infant and Toddler Development-Third Edition and 77 of 99 (77.7%) with the Child Behavior Checklist (CBCL). RESULTS: Primary analyses showed no significant differences between treatment groups on the NICU Network Neurobehavioral Scale, Bayley Scales of Infant and Toddler Development-Third Edition, or CBCL. However in post hoc analyses, we found differences by atypical NICU Network Neurobehavioral Scale profile on the CBCL. Infants receiving adjunctive phenobarbital had lower Bayley Scales of Infant and Toddler Development-Third Edition scores and more behavior problems on the CBCL. In adjusted analyses, internalizing and total behavior problems were associated with use of phenobarbital (P = .03; P = .04), maternal psychological distress (measured by the Brief Symptom Inventory) (both P < .01), and infant medical problems (both P = .02). Externalizing problems were associated with maternal psychological distress (P < .01) and continued maternal substance use (P < .01). CONCLUSIONS: Infants treated with either morphine or methadone had similar short-term and longer term neurobehavioral outcomes. Neurodevelopmental outcome may be related to the need for phenobarbital, overall health of the infant, and postnatal caregiving environment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01958476.

Racial and Ethnic Disparities in Maternal and Infant Outcomes Among Opioid-Exposed Mother-Infant Dyads in Massachusetts (2017-2019).

Objectives. To examine the extent to which differences in medication for opioid use disorder (MOUD) in pregnancy and infant neonatal opioid withdrawal syndrome (NOWS) outcomes are associated with maternal race/ethnicity.Methods. We performed a secondary analysis of a statewide quality improvement database of opioid-exposed deliveries from January 2017 to April 2019 from 24 hospitals in Massachusetts. We used multivariable mixed-effects logistic regression to model the association between maternal race/ethnicity (non-Hispanic White, non-Hispanic Black, or Hispanic) and prenatal receipt of MOUD, NOWS severity, early intervention referral, and biological parental custody at discharge.Results. Among 1710 deliveries to women with opioid use disorder, 89.3% (n = 1527) were non-Hispanic White. In adjusted models, non-Hispanic Black women (AOR = 0.34; 95% confidence interval [CI] = 0.18, 0.66) and Hispanic women (AOR = 0.43; 95% CI = 0.27, 0.68) were less likely to receive MOUD during pregnancy compared with non-Hispanic White women. We found no statistically significant associations between maternal race/ethnicity and infant outcomes.Conclusions. We identified significant racial/ethnic differences in MOUD prenatal receipt that persisted in adjusted models. Research should focus on the perspectives and treatment experiences of non-Hispanic Black and Hispanic women to ensure equitable care for all mother-infant dyads.

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.

Perinatal Transmission of Hepatitis C Virus: Defining the Cascade of Care.

OBJECTIVES: The US National Viral Hepatitis Action Plan calls for major efforts to expand hepatitis C virus (HCV) diagnosis and treatment; prenatal care settings are potential venues for expanding HCV testing. We aimed to characterize the HCV diagnostic cascade for women and infants and investigate factors associated with linkage and follow-up. STUDY DESIGN: We used electronic health records for a 10-year cohort of 879 women with opioid use disorder from an obstetric clinic serving women with substance use disorders. RESULTS: Altogether, 744 women (85%) were screened for HCV; 510 (68%) were seropositive, of whom 369 (72%) had nucleic acid testing performed and of these 261 (71%) were viremic. Of 404 infants born to HCV-seropositive women, 273 (68%) were tested at least once for HCV, 180 (45%) completed the American Academy of Pediatrics-recommended perinatal HCV screening, and 5 (2.8%) were diagnosed with HCV infection and linked to care. More recent delivery date (2014-2015) was associated with maternal linkage to care (aOR, 2.5; 95% CI, 1.4-4.7). Maternal coinfection with HIV (aOR, 9.0; 95% CI, 1.1-72.8) and methadone maintenance therapy, compared with buprenorphine (aOR, 1.5; 95% CI, 0.9-2.5), were associated with higher rates of infant HCV testing. CONCLUSIONS: HCV prevalence among pregnant women with opioid use is high and infant HCV screening is imperfect. Programmatic changes to improve both mother and infant follow-up may help to bridge identified gaps in the cascade to cure.

Neonatal Abstinence Syndrome: Advances in Diagnosis and Treatment.

IMPORTANCE: Neonatal abstinence syndrome, which occurs as a result of in utero opioid exposure, affects between 6.0 and 20 newborns per 1000 live US births. There is substantial variability in how neonatal abstinence syndrome is diagnosed and managed. OBJECTIVE: To summarize key studies examining the diagnosis and management (both pharmacologic and nonpharmacologic) of neonatal abstinence syndrome published during the past 10 years. EVIDENCE REVIEW: PubMed, Web of Science, and CINAHL were searched for articles published between July 1, 2007, and December 31, 2017. Abstracts were screened and included in the review if they pertained to neonatal abstinence syndrome diagnosis or management and were judged by the authors to be clinical trials, cohort studies, or case series. FINDINGS: A total of 53 articles were included in the review, including 9 randomized clinical trials, 35 cohort studies, 1 cross-sectional study, and 8 case series-representing a total of 11 905 unique opioid-exposed mother-infant dyads. Thirteen studies were identified that evaluated established or novel neonatal abstinence syndrome assessment methods, such as brief neonatal abstinence syndrome assessment scales or novel objective physiologic measures to predict withdrawal. None of the new techniques that measure infant physiologic parameters are routinely used in clinical practice. The most substantial number of studies of neonatal abstinence syndrome management pertain to nonpharmacologic care-specifically, interventions that promote breastfeeding or encourage parents to room-in with their newborns. Although these nonpharmacologic interventions appear to decrease the need for pharmacologic treatment and result in shorter hospitalizations, the interventions are heterogeneous and there are no high-quality clinical trials to support them. Regarding pharmacologic interventions, only 5 randomized clinical trials with prespecified sample size calculations (4 infant, 1 maternal treatment) have been published. Each of these trials was small (from 26 to 131 participants) and tested different therapies, limiting the extent to which results can be aggregated. There is insufficient evidence to support an association between any diagnostic or treatment approach and differential neurodevelopmental outcomes among infants with neonatal abstinence syndrome. CONCLUSIONS AND RELEVANCE: Evidence pertaining to the optimal diagnosis and treatment strategies for neonatal abstinence syndrome is based on small or low-quality studies that focus on intermediate outcomes, such as need for pharmacologic treatment or length of hospital stay. Clinical trials are needed to evaluate health and neurodevelopmental outcomes associated with objective diagnostic approaches as well as pharmacologic and nonpharmacologic treatment modalities.

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).

Trainees' knowledge, attitudes, and practices towards caring for the substance-exposed mother-infant dyad.

BACKGROUND: As rates of substance use disorder during pregnancy rise, pediatric trainees are increasingly caring for infants with neonatal abstinence syndrome (NAS). This study evaluated the knowledge, attitudes, and practices of trainees caring for substance-exposed newborns and their families, comparing differences by level and type of training, and personal experience with addiction or trauma. METHODS: A cross-sectional survey of medical students and pediatric, medicine/pediatric, and family medicine residents in 2015-2106. Measures included knowledge about NAS, attitudes towards mothers who use drugs, and practices around discussing addiction and trauma with families. Descriptive and bivariate analyses were conducted. RESULTS: The overall response rate was 70%, with 229 trainees included in the final sample (99 students, 130 residents). Fifty percent of trainees endorsed personal experience with addiction, 50% with trauma, and 35% with both addiction and trauma. Increasing years of pediatric training was associated with greater comfort in managing symptoms of NAS but decreased comfort discussing addiction and trauma. Family medicine and medicine/pediatric residents were more comfortable discussing addiction and trauma than categorical pediatric residents (P < .01). Twenty-two percent of trainees felt confident that mothers would disclose illicit drug use, 39% felt that they would actively care for their infants with NAS, and 43% felt that mothers would not make unreasonable demands. Personal experience with addiction or trauma did not significantly impact trainees' attitudes towards women with substance use disorder. CONCLUSIONS: Trainees may benefit from educational interventions focused on developing a 2-generational model of trauma-informed care to improve attitudes and ultimately the care of substance-exposed infants and their families.

Comparison of Neonatal Abstinence Syndrome Manifestations in Preterm Versus Term Opioid-Exposed Infants.

BACKGROUND: Twenty percent to 40% of infants exposed to in utero opioid were delivered preterm. There is currently no neonatal abstinence syndrome (NAS) scoring tool known to accurately evaluate preterm opioid-exposed infants. This can lead to difficulties in titrating pharmacotherapy in this population. PURPOSE: To describe NAS symptoms in preterm opioid-exposed infants in comparison with matched full-term controls. METHODS: This was a retrospective cohort study from a single tertiary care center of methadone-exposed infants born between 2006 and 2010. Using modified Finnegan scale scores recorded every 3 to 4 hours beginning at 6 hours of life until 24 to 48 hours after medication discontinuation, NAS symptoms was compared between 45 preterm infants and 49 full-term matched controls. Concurrent neonatal medical diagnoses were also compared. RESULTS: The median gestational age in the preterm group was 35 weeks (interquartile range [IQR] = 33-36) versus 39 weeks (IQR = 38-40) in the term group. Preterm infants scored less frequently for many items including sleep disturbance (24.4% vs 46.2%), tremors (77.9% vs 89.7%), muscle tone (87.9% vs 97.4%), sweating (2.1% vs 9.4%), nasal stuffiness (11.9% vs 20.5%), and loose stools (7.0% vs 14.3%) than full-term controls. Preterm infants scored more frequently for hyperactive moro reflex (26.4% vs 5.5%), tachypnea (19.3% vs 16.1%), and poor feeding (24.6% vs 11.8%). IMPLICATIONS FOR PRACTICE: Provider awareness of differences in manifestations of preterm and term infants with NAS, as well as concurrent prematurity diagnoses that can influence NAS scoring, is needed. These findings mandate the development of a modified NAS scoring tool for the preterm NAS population. IMPLICATIONS FOR RESEARCH: A preterm NAS scoring tool needs to be developed and validated to more accurately evaluate and treat preterm opioid-exposed infants.

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.

Advances in the Care of Infants With Prenatal Opioid Exposure and Neonatal Opioid Withdrawal Syndrome.

A significant number of advances have been made in the last 5 years with respect to the identification, diagnosis, assessment, and management of infants with prenatal opioid exposure and neonatal opioid withdrawal syndrome (NOWS) from birth to early childhood. The primary objective of this review is to summarize major advances that will inform the clinical management of opioid-exposed newborns and provide an overview of NOWS care to promote the implementation of best practices. First, advances with respect to standardizing the clinical diagnosis of NOWS will be reviewed. Second, the most commonly used assessment strategies are discussed, with a focus on presenting new quality improvement and clinical trial data surrounding the use of the new function-based assessment Eat, Sleep, and Console approach. Third, both nonpharmacologic and pharmacologic treatment modalities are reviewed, highlighting clinical trials that have compared the use of higher calorie and low lactose formula, vibrating crib mattresses, morphine compared with methadone, buprenorphine compared with morphine or methadone, the use of ondansetron as a medication to prevent the need for NOWS opioid pharmacologic treatment, and the introduction of symptom-triggered dosing compared with scheduled dosing. Fourth, maternal, infant, environmental, and genetic factors that have been found to be associated with NOWS severity are highlighted. Finally, emerging recommendations on postdelivery hospitalization follow-up and developmental surveillance are presented, along with highlighting ongoing and needed areas of research to promote infant and family well-being for families impacted by opioid use.

Case Series of Individuals Treated With Naltrexone During Pregnancy for Opioid and/or Alcohol Use Disorder.

OBJECTIVE: There is a lack of knowledge about the relative safety and efficacy of naltrexone for the treatment of pregnant individuals with opioid and/or alcohol use disorder, including the range of outcomes, in both the pregnant individual and the infant, over the course of peripartum period. Our objective was to describe these outcomes in a cohort of pregnant individuals on naltrexone. METHODS: In this prospective case series, 7 pregnant individuals with opioid use disorder (OUD) or alcohol use disorder (AUD) treated with naltrexone were followed from pregnancy through 12 months after delivery. Clinical treatment protocols and outcomes related to safety and efficacy during pregnancy, delivery, and the postpartum period are described. RESULTS: There were 4 pregnant individuals with OUD and 3 with AUD, of which 3 were managed with oral and 4 with extended-release naltrexone. The mean gestational age at study enrollment was 21.7 (SD, 12) weeks. Of the 7 participants, there was no return to nonprescribed opioid use and 2 who experienced a return to alcohol use over the course of the study. All individuals delivered vaginally at a mean of 37 weeks gestation without any peripartum pain difficulties. Five of the individuals (71.4%) remained on naltrexone 12 months after delivery. There were no reported fetal anomalies and one preterm delivery. None of the infants developed neonatal opioid withdrawal syndrome. CONCLUSIONS: For pregnant individuals with OUD or AUD treated with naltrexone, there were low rates of return to nonprescribed use and reassuring pregnant person and infant outcomes to 12 months postpartum.

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.

Short term outcomes of neonatal opioid withdrawal syndrome: a comparison of two approaches.

OBJECTIVE: To evaluate outcomes in opioid exposed neonates (OENs) assessed by the Eat, Sleep, Console (ESC) tool compared to the Finnegan Neonatal Abstinence Scoring System (FNASS). METHODS: Retrospective analysis of a statewide database of OENs from 2017 to 2020 with birthing hospitals classified based on the assessment tool used. Four main outcomes were examined using multivariable and Poisson logistic regression models. RESULTS: Of 2375 OENs, 42.1% received pharmacotherapy (PT) with a consistent decrease in PT, length of treatment (LOT), and length of stay (LOS) over the study period. There was no change in use of mother's own milk (MoM). While outcomes were significantly associated with several specific variables, there were no differences in outcomes between assessment methods. CONCLUSION: While there was a significant decrease over time in PT, LOT, and LOS, improvements were independent of the assessment tool used and likely related to the increased use of non-pharmacologic care.