Methadone and neonatal abstinence syndrome (NAS): what we think we know, but do not.

Since the first use of methadone to treat OUD in pregnancy in the 1970s, there has been a long, controversial, and confusing history of studies, regulatory actions, and practice changes that have clouded an accurate perception of methadone's use in pregnancy. This review will trace this history with a focus on the effect of methadone exposure during pregnancy on neonatal abstinence syndrome (NAS). A new laboratory measure, the serum methadone/metabolite ratio (MMR), has provided a tool for documenting the profoundly dynamic nature of perinatal metabolism. Continuous induction of metabolic enzymes during pregnancy requires dose adjustments and dose frequency changes. The concept of "fetal methadone dosing" emphasizes that relative stability of methadone levels in the fetus is an important consideration for methadone dosing in pregnancy. Finally, the effects of the societal "war on drugs" on pediatric management of neonatal withdrawal risks will be discussed, as well as the importance of comprehensive services for mother and child including the "rooming-in" approach of neonatal care which has considerably replaced the older NICU care model of maternal/infant separation.

Neonatal Outcomes after Combined Opioid and Nicotine Exposure in Utero: A Scoping Review.

BACKGROUND: The majority of women who are pregnant with opioid use disorder (OUD) also smoke tobacco but are rarely offered tobacco cessation counseling. While the effects of exposure to opioids and nicotine in utero are well-understood separately, understanding the impact of the combined exposure to these substances on neonatal outcomes is lacking. METHODS: A scoping review was conducted using PubMed and Scopus databases for studies addressing the combined exposure to opioids and nicotine during pregnancy published between 1 January 1980 and 9 July 2019. A total of 29 papers met the eligibility criteria for inclusion, with nine being identified as clinical trials (three from the MOTHER study) and two as secondary data analysis of clinical trial data. RESULTS: Neonatal outcomes for infants who had a combined exposure to opioids and nicotine in utero indicated a reduction in birth weight and birth length. Findings in infants exposed to both nicotine and opioids were mixed with regard to the duration of neonatal abstinence syndrome (NAS), the likelihood of treatment for NAS, doses of medicine used to treat NAS, and NAS scores when compared with infants who had opioid exposure without nicotine. CONCLUSIONS: The combined exposure to nicotine and opioids during pregnancy may lead to a reduction in neonatal birth weight and birth length and more severe NAS signs, compared with opioid use alone, but more research is necessary to identify the minimum dosage and length of nicotine exposure to accurately predict these outcomes.

Association of a Simplified Finnegan Neonatal Abstinence Scoring Tool With the Need for Pharmacologic Treatment for Neonatal Abstinence Syndrome.

Importance: Observer-rated scales, such as the Finnegan Neonatal Abstinence Scoring Tool (FNAST), are used to quantify the severity of neonatal abstinence syndrome (NAS) and guide pharmacologic therapy. The FNAST, a comprehensive 21-item assessment tool, was developed for research and subsequently integrated into clinical practice; a simpler tool, designed to account for clinically meaningful outcomes, is urgently needed to standardize assessment. Objectives: To identify FNAST items independently associated with the decision to use pharmacologic therapy and to simplify the FNAST while minimizing loss of information for the treatment decision. Design, Setting, and Participants: This multisite cohort study included 424 neonates with opioid exposure who had a gestational age of at least 36 weeks with follow-up from birth to hospital discharge in the derivation cohort and 109 neonates with opioid exposure from the Maternal Opioid Treatment: Human Experimental Research Study in the validation cohort. Neonates in the derivation cohort were included in a medical record review at the Universities of Louisville and Kentucky or in a randomized clinical trial and observational study conducted at Tufts University (2014-2018); the Maternal Opioid Treatment: Human Experimental Research was conducted from 2005 to 2008. Data analysis was conducted from May 2017 to August 2019. Exposures: Prenatal opioid exposure. Main Outcomes and Measures: All FNAST items were dichotomized as present or not present, and logistic regression was used to identify binary items independently associated with pharmacologic treatment. The final model was validated with an independent cohort of neonates with opioid exposure. Results: Among 424 neonates (gestational age, ≥36 weeks; 217 [51%] female infants), convulsions were not observed, and high-pitched cry and hyperactive Moro reflex had extremely different frequencies across cohorts. Therefore, these 3 FNAST items were removed from further analysis. The 2 tremor items were combined, and 8 of the remaining 17 items were independently associated with pharmacologic treatment, with an area under the curve of 0.86 (95% CI, 0.82-0.89) compared with 0.90 (95% CI, 0.87-0.94) for the 21-item FNAST. External validation of the 8 items resulted in an area under the curve of 0.86 (95% CI, 0.79-0.93). Thresholds of 4 and 5 on the simplified scale yielded the closest agreement with FNAST thresholds of 8 and 12 (weighted κ = 0.55; 95% CI, 0.48-0.61). Conclusions and Relevance: The findings of this study suggest that 8 signs of NAS may be sufficient to assess whether a neonate meets criteria for pharmacologic therapy. A focus on these signs could simplify the FNAST tool and may enhance its clinical utility.

The Epidemic of Neonatal Abstinence Syndrome, Historical References of Its' Origins, Assessment, and Management.

Neonatal abstinence syndrome (NAS) refers to a constellation of signs that are present in some newborn infants resulting from the abrupt cessation of passive transfer of maternal opioids used during pregnancy. The classic NAS refers to infants born to mothers who used opioids during pregnancy, but the term has broadened to include infants whose mothers have used or abused other psychoactive substances during pregnancy that contribute to the expression of the syndrome. Pregnant women who use opioids do so illicitly, and/or as medically prescribed for pain relief, and/or as medication assisted treatment for opioid dependence. The first case of NAS in infants and the subsequent treatment (or lack thereof) was reported in 1875 and was called Congenital Morphinism. By 2012, the incidence of NAS increased to more than 30 per 1,000 hospital live births, along with an increase in the number of infants being treated pharmacologically for NAS, resulting in an increase in the length of stay and healthcare expenses. We present historical references on NAS, the various factors and events that led to its increasing prevalence and today's current epidemic. We also review the current tools to assess infants with NAS and treatment options in its management.

Simplification of the Finnegan Neonatal Abstinence Scoring System: retrospective study of two institutions in the USA.

OBJECTIVE: To develop a simplified Finnegan Neonatal Abstinence Scoring System (sFNAS) that will highly correlate with scores ≥8 and ≥12 in infants being assessed with the FNAS. DESIGN, SETTING AND PARTICIPANTS: This is a retrospective analysis involving 367 patients admitted to two level IV neonatal intensive care units with a total of 40 294 observations. Inclusion criteria included neonates with gestational age ≥37 0/7 weeks, who are being assessed for neonatal abstinence syndrome (NAS) using the FNAS. Infants with a gestational age <37 weeks were excluded. METHODS: A linear regression model based on the original FNAS data from one institution was developed to determine optimal values for each item in the sFNAS. A backward elimination approach was used, removing the items that contributed least to the Pearson's correlation. The sFNAS was then cross-validated with data from a second institution. RESULTS: Pearson's correlation between the proposed sFNAS and the FNAS was 0.914. The optimal treatment cut-off values for the sFNAS were 6 and 10 to predict FNAS scores ≥8 and ≥12, respectively. The sensitivity and specificity of these cut-off values to detect FNAS scores ≥8 and ≥12 were 0.888 and 0.883 for a cut-off of 6, and 0.637 and 0.992 for a cut-off of 10, respectively. The sFNAS cross-validation resulted in a Pearson's correlation of 0.908, sensitivity and specificity of 0.860 and 0.873 for a cut-off of 6, and 0.525 and 0.986 for a cut-off of 10, respectively. CONCLUSION: The sFNAS has a high statistical correlation with the FNAS, and it is cross-validated for the assessment of infants with NAS. It has excellent specificity and negative predictive value for identifying infants with FNAS scores ≥8 and ≥12.

Neonatal abstinence syndrome: where are we, and where do we go from here?

PURPOSE OF REVIEW: Over the last 15 years the prevalence of neonatal abstinence syndrome (NAS) increased almost five-fold. A considerable diversity seems to prevail in the management of NAS. This review provides an overview of factors affecting the expression and course of NAS, and recent developments in NAS assessment and treatment. RECENT FINDINGS: Apart from different pharmacological and nonpharmacological treatment modalities, maturity of the infant and genetic variations likely are (co)responsible for interpatient variability in NAS severity, despite similar maternal exposure. Recent efforts concerning the further development of NAS severity scoring systems focus on the development of brief screening measures; in addition, pupil diameter and skin conductance have been proposed as complements to observer-rated scales. The decrease in incidence of NAS begins in the appropriate management of medication assisted treatment of the mother. SUMMARY: Mitigating the negative outcomes for infants affected by NAS, their mothers and the healthcare system implies, first and foremost, developing and implementing an organized protocol for the management of NAS, and the homogenous use of a standardized scoring system utilizing interobserver reliability and a guide for medication initiation, maintenance, and weaning which is consistent with traditional methods of treatment for neonates.

Opioid dependence and pregnancy: minimizing stress on the fetal brain.

Increase in the number of opioid-dependent pregnant women delivering babies at risk for neonatal abstinence syndrome prompted a US Government Accountability Office report documenting deficits in research and provider knowledge about care of the maternal/fetal unit and the neonate. There are 3 general sources of dependence: untreated opioid use disorder, pain management, and medication-assisted treatment with methadone or buprenorphine. A survey of methadone patients' experiences when telling a physician of their pregnancy and opioid dependence demonstrated physician confusion about proper care, frequent negative interactions with the mother, and failures to provide appropriate referral. Patients in pain management were discharged without referral when the physician was told of the pregnancy. Methadone and buprenorphine were frequently seen negatively because they "caused" neonatal abstinence syndrome. Most mothers surveyed had to find opioid treatment on their own. How dependence is managed medically is a critical determinant of the level of stress on both mother and fetus, and therefore another determinant of neonatal health. The effects of both opioid withdrawal stress and maternal emotional stress on neonatal and developmental outcomes are reviewed. Currently, there have been efforts to criminalize maternal opioid dependence and to encourage or coerce pregnant women to undergo withdrawal. This practice poses both acute risks of fetal hypoxia and long-term risks of adverse epigenetic programming related to catecholamine and corticosteroid surges during withdrawal. Contemporary studies of the effects of withdrawal stress on the developing fetal brain are urgently needed to elucidate and quantify the risks of such practices. At birth, inconsistencies in the hospital management of neonates at risk for neonatal abstinence syndrome have been observed. Neglect of the critical role of maternal comforting in neonatal abstinence syndrome management is an iatrogenic and preventable cause of poor outcomes and long hospitalizations. Rooming-in allows for continuous care of the baby and maternal/neonatal attachment, often unwittingly disrupted by the neonatal intensive care unit environment. Recommendations are made for further research into physician/patient interactions and into optimal dosing of methadone and buprenorphine to minimize maternal/fetal withdrawal.

Methadone and buprenorphine for the management of opioid dependence in pregnancy.

This article provides an overview and discussion of the collective maternal, fetal and neonatal outcome research on women maintained on methadone or buprenorphine during pregnancy. Its focus is on an assessment of the comparative effectiveness of methadone and buprenorphine pharmacotherapy, with particular attention given to recent findings from the literature. Recommendations for clinical practice are outlined, and directions for future research are presented. Findings from comparative studies of methadone and buprenorphine underscore the efficacy of both medications in preventing relapse to illicit opioid use in the treatment of opioid-dependent pregnant patients, as well as the simplicity of induction onto methadone and patient retention while receiving such therapy. Fetal monitoring suggests that buprenorphine results in less fetal cardiac and movement suppression than does methadone. The clinical implications of these findings need future exploration. For the neonate, evidence from studies using a wide range of designs, including retrospective chart reviews, prospective observational studies, and randomized clinical trials, show consistent results, with prenatal exposure to buprenorphine resulting in less severe neonatal abstinence syndrome relative to methadone. Any medication given to pregnant women should be prescribed only after considering the risk : benefit ratio for the maternal-fetal dyad. Medication choices for each opioid-dependent patient during pregnancy need to be made on a patient-by-patient basis, taking into consideration the patient's opioid dependence history, previous and current treatment experiences, medical circumstances and treatment preferences. Moreover, for a full remission of opioid addiction to be sustainable, both post-partum and across the lifespan, treatment providers must not rely solely on medication to treat their patients but should also utilize women-specific comprehensive treatment models that address the underlying multifaceted complexities of their patient's lives.

Acute neonatal effects of cocaine exposure during pregnancy.

OBJECTIVE: To identify associations between cocaine exposure during pregnancy and medical conditions in newborn infants from birth through hospital discharge. DESIGN: Multisite, prospective, randomized study. SETTING: Brown University, University of Miami, University of Tennessee (Memphis), and Wayne State University. Subjects A total of 717 cocaine-exposed infants and 7442 nonexposed infants. MAIN OUTCOME MEASURES: Results of physical examination and conditions observed during hospitalization. RESULTS: Cocaine-exposed infants were about 1.2 weeks younger, weighed 536 g less, measured 2.6 cm shorter, and had head circumference 1.5 cm smaller than nonexposed infants (all P<.001). Results did not confirm previously reported abnormalities. Central and autonomic nervous system symptoms were more frequent in the exposed group: jittery/tremors (adjusted odds ratio, 2.17; 99% confidence interval, 1.44-3.29), high-pitched cry (2.44; 1.06-5.66), irritability (1.81; 1.18-2.80), excessive suck (3.58; 1.63-7.88), hyperalertness (7.78; 1.72-35.06), and autonomic instability (2.64; 1.17-5.95). No differences were detected in organ systems by ultrasound examination. Exposed infants had more infections (3.09; 1.76-5.45), including hepatitis (13.46; 7.46-24.29), syphilis (8.84; 3.74-20.88), and human immunodeficiency virus exposure (12.37; 2.20-69.51); were less often breastfed (0.26; 0.15-0.44); had more child protective services referrals (48.92; 28.77-83.20); and were more often not living with their biological mother (18.70; 10.53-33.20). CONCLUSIONS: Central and autonomic nervous system symptoms were more frequent in the exposed cohort and persisted in an adjusted analysis. They were usually transient and may be a true cocaine effect. Abnormal anatomic outcomes previously reported were not confirmed. Increased infections, particularly sexually transmitted diseases, pose a serious public health challenge. Exposure increased involvement of child protective services and out-of-home placement.

The Maternal Lifestyle Study (MLS): effects of prenatal cocaine and/or opiate exposure on auditory brain response at one month.

OBJECTIVE: To study absolute and interpeak latencies of the auditory brain response in infants exposed to cocaine and/or opiates in utero.Study design The sample included 477 exposed and 554 comparison infants matched for race, sex, and gestational age. Mothers were recruited at 4 urban university-based centers; most were black, receiving public assistance, and had received adequate prenatal care. Exposure was determined by meconium assay and self-report with alcohol, marijuana, and tobacco present in both groups. At 1 month, infants were tested by masked examiners with the auditory brain response. RESULTS: Analyses were conducted for exposed and comparison groups and for level of prenatal cocaine exposure with adjustment for covariates (alcohol, marijuana, tobacco, gestational age at birth, social class, and site). Heavy prenatal cocaine exposure (>/=3 days per week, first trimester) led to an increase in the I-III, I-V, and III-V interpeak latencies and to a shorter latency to peak I. Infants with prenatal opiate exposure showed a longer latency to peak V and a longer III-V interpeak latency. CONCLUSIONS: Prenatal cocaine and/or opiate exposure affects neural transmission. Detection of these effects requires a large sample with control for gestational age, other drugs, and level of cocaine use.

The maternal lifestyle study: effects of substance exposure during pregnancy on neurodevelopmental outcome in 1-month-old infants.

OBJECTIVE: This was a prospective longitudinal multisite study of the effects of prenatal cocaine and/or opiate exposure on neurodevelopmental outcome in term and preterm infants at 1 month of age. METHODS: The sample included 658 exposed and 730 comparison infants matched on race, gender, and gestational age (11.7% born <33 weeks' gestational age). Mothers were recruited at 4 urban university-based centers and were mostly black and on public assistance. Exposure was determined by meconium assay and self-report with alcohol, marijuana, and tobacco present in both groups. At 1 month corrected age, infants were tested by masked examiners with the NICU Network Neurobehavioral Scale and acoustical cry analysis. Exposed and comparison groups were compared adjusting for covariates (alcohol, marijuana, tobacco, birth weight, social class, and site). Separate analyses were conducted for level of cocaine exposure. RESULTS: On the NICU Network Neurobehavioral Scale, cocaine exposure was related to lower arousal, poorer quality of movement and self-regulation, higher excitability, more hypertonia, and more nonoptimal reflexes with most effects maintained after adjustment for covariates. Some effects were associated with heavy cocaine exposure, and effects were also found for opiates, alcohol, marijuana, and birth weight. Acoustic cry characteristics that reflect reactivity, respiratory, and neural control of the cry sound were also compromised by prenatal drug exposure, including cocaine, opiates, alcohol, and marijuana and by birth weight. Fewer cry effects remained after adjustment for covariates. CONCLUSIONS: Cocaine effects are subtle and can be detected when studied in the context of polydrug use and level of cocaine exposure. Effects of other drugs even at low thresholds can also be observed in the context of a polydrug model. The ability to detect these drug effects requires a large sample and neurobehavioral tests that are differentially sensitive to drug effects. Long-term follow-up is necessary to determine whether these differences develop into clinically significant deficits.

Gestational cocaine exposure and intrauterine growth: maternal lifestyle study.

OBJECTIVE: To estimate the effects of cocaine exposure on intrauterine growth and to investigate at what point in gestation growth deviation would be manifested. METHODS: This is a secondary analysis of data from a multicenter project, the Maternal Lifestyle Study, designed to determine infant outcomes of in utero cocaine or opiates exposure. Four centers of the National Institute of Child Health and Human Development Neonatal Research Network enrolled 11,811 maternal-infant dyads. A total of 1072 infants were cocaine exposed, 7565 were cocaine negative by maternal history and meconium results, and 3174 were excluded from analysis because of unconfirmed negative exposure. Outcome measures included birth weight, length, and head circumference. RESULTS: Percentile estimates for birth weight, length, and head circumference revealed growth deceleration in cocaine-exposed infants evident after 32 weeks' gestation. There was significant interaction between cocaine and gestational age. After controlling for confounders, at 40 weeks' gestation, cocaine exposure was estimated to be associated with a decrease of 151 g, 0.71 cm, and 0.43 cm in birth weight, length, and head circumference, respectively. Smoking had a negative impact on all growth measurements, with some indication of a dose-effect relationship. Heavy alcohol use was associated with decrease in weight and length only. Opiates had significant effect only on birth weight. CONCLUSION: In utero cocaine exposure is associated with growth deceleration involving all measurements, becoming more pronounced with advancing gestation.

The Maternal Lifestyle Study: drug exposure during pregnancy and short-term maternal outcomes.

OBJECTIVE: Reports of maternal effects resulting from drug exposure during pregnancy are inconsistent. The Maternal Lifestyle Study (MLS) is a multicenter, prospective, observational study that was initiated to better define the effects of exposure to illicit drugs during pregnancy on the mother, fetus, and infant. METHODS: Between May 1993 and May 1995, of 19,079 mother-infant dyads that were screened after delivery for cocaine and opiate exposure at four clinical centers (Brown University, University of Miami, University of Tennessee, Memphis, and Wayne State University), 16,988 (89%) met eligibility criteria and 11,811 (70%) of those eligible agreed to participate in the study. Exposure was defined as an admission of use of cocaine or opiates or both or the presence of cocaine or opiate metabolites in meconium as determined by use of gas chromatography-mass spectroscopy assay. Nonexposure was defined as a negative drug use history by interview and a negative immunoassay screen. When exposure could not be confirmed, such as when meconium was not obtained or was inadequate for confirmatory analysis, the mother-infant dyad was excluded (n = 3184). RESULTS: Of the mothers who consented to participate, 50% were African American, 38% were married, 64% were Medicaid recipients, and 95% had at least one prenatal care visit (median, 10 visits). Significant differences (P <.01) between cocaine-opiate exposed (n = 1185) and nonexposed (n = 7442) mothers included race (African American: 74.6% and 47.0%, respectively), mean age (29.6 and 26.1 years, respectively), and polydrug use including any combination of alcohol, tobacco, and/or marijuana (93% and 42%, respectively). Odds ratios (99% CI) indicate that exposed mothers had a significantly higher risk(P <.001) of medical complications including syphilis 6.7 (4.8-9.6), gonorrhea 1.9 (1.3-3.0), and hepatitis 4.8 (2.6-8.91); psychiatric, nervous, and emotional disorders 4.0 (2.2-7.4); and abruptio placenta 2.3 (1.4-3.9). The odds of a positive test for human immunodeficiency virus were higher (available on 28% of the cohort) in the exposed group 8.2 (14.3-15.4). Seventeen cases of maternal acquired immunodeficiency syndrome (AIDS) were identified. Opiate exposure with its attendant needle use significantly increased the risk of hepatitis and AIDS. The number of hospitalizations during pregnancy did not differ between the exposure groups because 11% of patients in each group were hospitalized at least once. However, violence as a cause of hospitalization was more common in the cocaine-exposed group, 19.6 (2.7-144.7). CONCLUSION: This observational study confirmed many of the reported adverse social and serious medical perinatal complications of mothers exposed to cocaine or opiates during pregnancy. The overall prevalence of these risk outcomes was lower than has been reported previously.