Elisha M. Wachman

Review of the assessment and management of neonatal abstinence syndrome

Neonatal abstinence syndrome (NAS) secondary to in-utero opioid exposure is an increasing problem. Variability in assessment and treatment of NAS has been attributed to the lack of high-quality evidence to guide management of exposed neonates. This systematic review examines available evidence for NAS assessment tools, nonpharmacologic interventions, and pharmacologic management of opioid-exposed infants. There is limited data on the inter-observer reliability of NAS assessment tools due to lack of a standardized approach. In addition, most scales were developed prior to the prevalent use of prescribed prenatal concomitant medications, which can complicate NAS assessment. Nonpharmacologic interventions, particularly breastfeeding, may decrease NAS severity. Opioid medications such as morphine or methadone are recommended as first-line therapy, with phenobarbital or clonidine as second-line adjunctive therapy. Further research is needed to determine best practices for assessment, nonpharmacologic intervention, and pharmacologic management of infants with NAS in order to improve outcomes.

Breastfeeding rates among mothers of infants with neonatal abstinence syndrome.

BACKGROUND Woman who struggle with drug addiction during pregnancy are perhaps the most vulnerable of new mothers. The opioid substitution medications methadone and buprenorphine are both compatible with breastfeeding. The objective of this study is to determine breastfeeding rates among opioid-dependent women giving birth in a Baby-Friendly Hospital. METHODS We performed a retrospective chart review of all infants born at Boston Medical Center (Boston, MA) between July 2003 and January 2009 with a diagnosis of neonatal abstinence syndrome. Feeding information was obtained, as well as baseline medical information about the mother-infant pairs. Breastfeeding eligibility was determined by a negative urine toxicology screen on admission, no illicit drug use in the third trimester, and a negative human immunodeficiency virus status. RESULTS Two hundred seventy-six mother-infant pairs were identified. Forty percent of the mothers carried one or more psychiatric diagnoses; 24% were taking two or more psychiatric medications. Sixty-eight percent of the mothers were eligible to breastfeed; of those, 24% breastfed to some extent during their infants hospitalization. Sixty-percent of those who initiated stopped breastfeeding after an average of 5.88 days (SD 6.51). CONCLUSIONS Breastfeeding rates among opioid-dependent women were low, with three-quarters of those eligible electing not to breastfeed. Of the minority of women who did choose to breastfeed, more than half stopped within 1 week.

The relationship between maternal opioid agonists and psychiatric medications on length of hospitalization for neonatal abstinence syndrome.

Objective:To examine the relationship between maternal opioid agonists, methadone, or buprenorphine (BPH), and concurrent psychiatric medication use on length of hospitalization (LOS) among infants with neonatal abstinence syndrome (NAS). Methods:We reviewed the charts of infants born at Boston Medical Center between 2003 and 2009 with a diagnosis of NAS whose mothers were prescribed methadone or BPH for opiate addiction. Univariate and multivariate linear regression analyses were used to examine associations between maternal opioid substitution concurrent with psychiatric medication use and infant LOS. We also tested whether exposure to BPH was associated with a shorter hospitalization. Results:A total of 273 mother-infant pairs were identified. The average LOS for all infants was 22.9 days (SD: 10.9). In bivariate analyses, maternal use of any psychiatric medication was associated with a longer infant LOS (P < 0.005). Compared with those prescribed methadone alone (n = 158), those also taking benzodiazepines (n  = 56) had a 5.88-day longer LOS (95% confidence interval [CI]: 2.15–9.60, P = 0.002). Infants of mothers taking methadone plus an selective serotonin re-uptake inhibitor (n = 51) had a longer LOS (&bgr; = 4.47, 95% CI: 1.15–7.79) compared to methadone alone; results remained significant in an initial multivariate model, however the effect was attenuated when additional psychiatric medication use was added to the model. Compared with those exposed to methadone, those exposed to BPH (n = 22) had a significantly shorter LOS (ß = −7.35, CI: −0.18 to −14.52, P = 0.04). Conclusions:Maternal use of prescribed methadone and benzodiazepines, compared to methadone alone, increased LOS for infants with NAS by 6 days. Maternal use of BPH was associated with a shorter LOS.

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.

Caring for Pregnant Women with Opioid Use Disorder in the USA: Expanding and Improving Treatment.

Purpose of the ReviewOpioid use disorder in the USA is rising at an alarming rate, particularly among women of childbearing age. Pregnant women with opioid use disorder face numerous barriers to care, including limited access to treatment, stigma, and fear of legal consequences. This review of opioid use disorder in pregnancy is designed to assist health care providers caring for pregnant and postpartum women with the goal of expanding evidence-based treatment practices for this vulnerable population.Recent FindingsWe review current literature on opioid use disorder among US women, existing legislation surrounding substance use in pregnancy, and available treatment options for pregnant women with opioid use disorder. Opioid agonist treatment (OAT) remains the standard of care for treating opioid use disorder in pregnancy. Medically assisted opioid withdrawal (“detoxification”) is not recommended in pregnancy and is associated with high maternal relapse rates. Extended release naltrexone may confer benefit for carefully selected patients. Histories of trauma and mental health disorders are prevalent in this population; and best practice recommendations incorporate gender-specific, trauma-informed, mental health services. Breastfeeding with OAT is safe and beneficial for the mother-infant dyad.SummaryFurther research investigating options of OAT and the efficacy of opioid antagonists in pregnancy is needed. The US health care system can adapt to provide quality care for these mother-infant dyads by expanding comprehensive treatment services and improving access to care.

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 (β=-6.9 days, p=0.02) and COMT rs740603 A allele (β=-5.3 days, p=0.01) were associated with shorter LOS. The OPRD1 rs204076 A allele in the mothers was associated with a longer LOS by 6.6 days (p=0.008). Results were significant point-wise but did not meet the experiment-wide significance level. 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.

Bringing attention to a need for a standardized treatment and weaning protocol for neonatal abstinence syndrome

Neonatal abstinence syndrome (NAS) due to in-utero opioid exposure has increased 5-fold in the U.S. since 2000, with an incidence of 5.8 per 1,000 live births. NAS now accounts for 3% of all admissions to neonatal intensive care units (NICUs), with associated NICU hospitalization costs of approximately

Revision of Breastfeeding Guidelines in the Setting of Maternal Opioid Use Disorder: One Institution's Experience.

53,000 per infant. Fifty percent to 80% of opioid-exposed infants require extensive pharmacologic treatment for withdrawal symptoms with an average length of hospitalization of three weeks, with a large range from one week to over a month. This variability is due to a variety of maternal-infant factors such as methadone versus buprenorphine exposure, infant feeding method, ability to room-in with the infant, genetic factors, and co-exposures to nicotine, illicit drugs, and psychiatric medications.

Childhood Health and Development in a Cohort of Infants Exposed Prenatally to Methadone or Buprenorphine

Breastfeeding is recommended for women with opioid use disorder who are treated with methadone or buprenorphine. Infants with neonatal abstinence syndrome (NAS) secondary to in-utero opioid exposure have unique challenges related to breastfeeding but also have significant benefits including improved NAS symptoms with a decreased need for pharmacotherapy. Poor understanding of substance use disorder and treatment, lack of evidence-based recommendations, and vague guidelines from national academies create controversy about breastfeeding eligibility for these women. Defining breastfeeding guidelines is often difficult, particularly in large institutions with multiple providers caring for the mother–infant dyad. Based on the available evidence and review of our institutional data, we revised our breastfeeding guidelines for mothers with opioid use disorder. The aims of our new guidelines are (a) to safely promote breastfeeding in all mothers with opioid use disorder who are in recovery, (b) to improve NAS outcomes through use of breastfeeding as a key nonpharmacologic treatment modality, and (c) to improve staff communication and consistency on the subject of breastfeeding in this patient population.

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

Background: Neonatal Abstinence Syndrome (NAS) due to in-utero opioid exposure is a growing problem with largely unknown long-term childhood outcomes. The objective of this study was to compare long-term outcomes of infants exposed to methadone versus buprenorphine in-utero. Method: This retrospective cohort study included all pregnant women on buprenorphine or methadone and their infants born between 2006-2010 at our institution. Inpatient data was merged with outpatient data from 2006-2014 for those infants who continued to receive their paediatric care at our institution. We estimated unadjusted risk ratios (RR) of the following outcomes in buprenorphine versus methadone exposed infants: 1) routine healthcare visits, 2) growth and feeding disorders, 3) developmental delay, 4) visual problems, 5) hearing problems, 6) behavioural/attentional problems. Results: Of 338 infants, 73.1% (N=247) continued to be followed at our hospital. The mean length of follow-up was 25.7 months (95% CI 22.9, 28.9). Infants in the buprenorphine group were less likely to be seen for hepatitis C exposure (19.6 vs. 9.2%, RR=0.60, 95% CI 0.40, 0.91) and more likely to have had a routine weight check (RR=2.14, 95% CI 1.05, 4.34). There were no differences in the incidence of developmental delay, ophthalmologic abnormalities, hearing deficits, or behavioural diagnoses between the groups. Results are limited by small sample size and lack of adjustment for confounders. Conclusion: No significant differences in paediatric outcomes at 2 years of age after in-utero methadone or buprenorphine exposure were found, but the evidence is affected by study limitations. Further studies in a large patient population are warranted.