Neonatal opioid withdrawal syndrome (NOWS) is a condition that often occurs in neonates born to mothers who received methadone treatment for opioid use disorder during pregnancy. Early identification and treatment of infants at risk of NOWS may improve clinical outcomes. The purpose of this study was to evaluate whether maternal and umbilical cord plasma concentrations of methadone and its metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), could predict the need for NOWS treatment.

Single-center prospective study.

University of Michigan Neonatal Intensive Care Unit.

The study included 11 opioid-dependent mother-infant dyads, where the mothers were treated with methadone at 34 weeks' gestation or later.

Maternal and cord blood samples were collected from the study participants.

Maternal and cord plasma concentrations of methadone and EDDP were determined. Six out of the 11 infants required treatment for NOWS. Maternal methadone plasma concentrations were comparable between infants requiring and not requiring NOWS treatment (329.1 ± 229.7 ng/mL vs. 413.2 ± 329.8 ng/mL). However, the average cord plasma methadone concentration in infants who did not require NOWS treatment was 2.9-fold higher than in those who required the treatment (120.0 ± 88.6 ng/mL vs. 40.9 ± 24.4 ng/mL), although the difference was not statistically significant. The ratios of maternal-to-cord methadone plasma concentrations were significantly higher in patients who required treatment for NOWS compared with those who did not (7.7 ± 1.9 vs. 3.5 ± 1.6, p = 0.003). Maternal and cord plasma EDDP concentrations and the maternal-to-cord plasma EDDP concentration ratios did not differ between patients who required and did not require treatment for NOWS.

The results suggest that methadone permeability across the blood-placental barrier may affect in utero exposure to methadone, and the maternal-to-cord methadone plasma concentration ratio could be a potential biomarker for predicting the need for NOWS treatment.

The escalation in opioid pain relief (OPR) medications, heroin and fentanyl, has led to an increased use during pregnancy and a public health crisis. Methamphetamine use in women of childbearing age has now eclipsed the use of cocaine and other stimulants globally. Recent reports have shown increases in methamphetamine are selective to opioid use, particularly in rural regions in the US. This report compares the extent of our knowledge of the perinatal outcomes of OPRs, heroin, fentanyl, two long-acting substances used in the treatment of opioid use disorders (buprenorphine and methadone), and methamphetamine. The methodological limitations of the current research are examined, and two important initiatives that will address these limitations are reviewed. Current knowledge of the perinatal effects of short-acting opioids, OPRs, heroin, and fentanyl, is scarce. Most of what we know about the perinatal effects of opioids comes from research on the long-acting opioid agonist drugs used in the treatment of OUDs, methadone and buprenorphine. Both have better perinatal outcomes for the mother and newborn than heroin, but the uptake of these opioid substitution programs is poor (<50%). Current research on perinatal outcomes of methamphetamine is limited to retrospective epidemiological studies, chart reviews, one study from a treatment center in Hawaii, and the US and NZ cross-cultural infant Development, Environment And Lifestyle IDEAL studies. Characteristics of pregnant individuals in both opioid and MA studies were associated with poor maternal health, higher rates of mental illness, trauma, and poverty. Infant outcomes that differed between opioid and MA exposure included variations in neurobehavior at birth which could complicate the diagnosis and treatment of neonatal opioid withdrawal (NOWs). Given the complexity of OUDs in pregnant individuals and the increasing co-use of these opioids with MA, large studies are needed. These studies need to address the many confounders to perinatal outcomes and employ neurodevelopmental markers at birth that can help predict long-term neurodevelopmental outcomes. Two US initiatives that can provide critical research and treatment answers to this public health crisis are the US Environmental influences on Child Health Outcomes (ECHO) program and the Medication for Opioid Use Disorder During Pregnancy Network (MAT-LINK).

Recently, neonatal abstinence syndrome (NAS) emerged as a significant global concern with a dramatic increase in healthcare expenditures. The incidence of the NAS has increased notably in the past decade and emergence as a global public health problem.

To evaluate the development and trend of global NAS research from 1958 to 2019 by bibliometric analysis.

Analyzed aspects included publication output per year, language, document types, journals, countries/territories, h-index, authors, and top research priorities. The VOSviewer was used to determine the top research priorities, and trends, and to present bibliometric networks concerning various dimensions, such as co-authorship, authors, and countries.

A total of 1738 articles were retrieved in the Scopus database from 1958 to 2019. It was found that the great majority of the total NAS documents (n = 1295) were original articles followed by reviews (n = 268) and letters (n = 48). The most productive countries in the NAS field were the United States (n = 833), Canada (n = 112), the United Kingdom (n = 111), and Germany (n = 77). Treatment and hospital outcomes in NAS, evidence-based nurse-driven interventions for the care of newborns with NAS, and a systematic reviews and network meta-analysis for therapeutic approaches of NAS were found in recent years (after 2010), compared with terms such as pathophysiology, mechanisms of NAS, and signs and symptoms in the early years.

Treatment and pediatric outcomes and the effectiveness of pharmacological treatment may be frontiers in the NAS field, and continued efforts from researchers are needed in those topics.

To evaluate the severity of neonatal opioid withdrawal syndrome (NOWS) in infants prenatally exposed to medications for opioid use disorder (MOUD) and serotonin reuptake inhibitors (SRI).

A prospective cohort included 148 maternal-infant pairs categorized into MOUD (n = 127) and MOUD + SRI (n = 27) groups. NOWS severity was operationalized as the infant's need for pharmacologic treatment with opioids, duration of hospitalization, and duration of treatment. The association between prenatal SRI exposure and the need for pharmacologic treatment (logistic regression), time-to-discharge, and time-to-treatment discontinuation (Cox proportional hazards modeling) was examined after adjusting for the type of maternal MOUD, use of hydroxyzine, other opioids, benzodiazepines/sedatives, alcohol, tobacco, marijuana, gestational age, and breastfeeding.

Infants in the MOUD + SRI group were more likely to receive pharmacologic treatment for NOWS (OR = 3.58; 95% CI: 1.31; 9.76) and had a longer hospitalization (median: 11 vs. 6 days; HR = 0.54; 95% CI: 0.33; 0.89) compared to the MOUD group. With respect to time-to-treatment discontinuation, no association was observed in infants who received treatment (HR = 0.59; 95% CI: 0.26, 1.32); however, significant differences were observed in the entire sample (HR = 0.55; 95% CI: 0.34, 0.89).

Use of SRIs among pregnant women on MOUD might be associated with more severe NOWS.

A potential drug-drug interaction between maternal SRIs and opioid medications that inhibit the reuptake of serotonin has been hypothesized but not carefully evaluated in clinical studies. Results of this prospective cohort indicate that the use of SRIs among pregnant women on MOUD is associated with more severe neonatal opioid withdrawal syndrome. This is the first prospective study which carefully examined effect modification between the type of maternal MOUD and SRI use on neonatal outcomes. This report lays the foundation for treatment optimization in pregnant women with co-occurring mental health and substance use disorders.

This pilot study evaluated the relationship between maternal and neonatal R- and S-methadone and R- and S-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) exposure and the severity of neonatal abstinence syndrome (NAS). The use of dried blood spots (DBS) as an alternative for plasma in assessing methadone and EDDP was also assessed.

Women receiving methadone for medication assisted treatment of opioid use disorder during pregnancy were eligible for recruitment. Plasma and DBS samples were collected from mothers during labor, from cord blood, and from newborns during genetic screen. R-/S-methadone and EDDP were measured by high-performance liquid chromatography tandem mass spectrometry (HPLC/MS/MS). Associations between methadone exposure, neonatal morphine requirements, and severity of NAS were examined.

Twenty women and infants completed the study. Maternal methadone dose at delivery was 112 mg/day (range = 60-180 mg/day). Sixteen neonates experienced NAS requiring morphine; three also required phenobarbital. Higher cord blood concentrations of R-methadone, R- and S-EDDP were associated with higher maximum doses of morphine (p < 0.05).

Maternal methadone and cord blood concentration at delivery are variable and may be potential markers of neonatal abstinence syndrome.

Methadone use for the management of opioid dependency during pregnancy is commonplace. Methadone levels are altered during pregnancy due to changes in maternal physiology. Despite this, a paucity of data exist regarding the most appropriate optimal dosing regimens during pregnancy.

This study applied a pharmacokinetic modeling approach to examine gestational changes in R- and S-methadone concentrations in maternal plasma and fetal (cord) blood. This study did so to derive a theoretical optimal dosing regimen during pregnancy, and to identify the impact of Cytochromes P450 (CYP) 2B6 and 2C19 polymorphisms on methadone maternal and fetal pharmacokinetics.

The study noted significant decreases in maternal R- and S-methadone plasma concentrations during gestation, with concomitant increases in fetal levels. At a dose of 90 mg once daily, 75% (R-) and 94% (S-) of maternal methadone trough levels were below the lower therapeutic window at term (week 40). The developed optimal dosing regimen escalated doses to 110 mg by week 5, followed by 10 mg increments every 5 weeks up to a maximum of 180 mg once daily near term. This increase resulted in 27% (R-) and 11% (S-) of subjects with trough levels below the lower therapeutic window at term. CYP2B6 poor metabolizers (PM) and either CYP2C19 extensive metabolizers (EM), PM, or ultra-rapid (UM) metabolizer phenotypes demonstrated statistically significant increases in concentrations when compared to their matched CYP2B6 EM counterparts.

Specific and gestation-dependent dose titrations are required during pregnancy to reduce the risks associated with illicit drug use and to maintain fetal safety.

In methadone-exposed preterm neonates, early identification of those at risk of severe neonatal abstinence syndrome (NAS) and use of a methadone dosing regimen that can provide effective and safe drug exposure are two important aspects of optimal care. To this end, we reviewed 17 methadone dosing recommendations in the international guidelines and literature and explored their variability in key dosing strategies. We selected three of the reviewed dosing regimens for their pharmacokinetics (PK) characteristics and their exposure-response relationship in three gestational age groups of preterm neonates (28, 32 and 36 gestational age weeks) at risk for development of severe NAS (defined as an umbilical cord methadone concentration of ≤60 ng/mL, following fetal exposure). We applied early (12 h after birth) vs. typical (36 h after birth) initiation of treatment. We observed that use of universally recommended dosing regimens in preterm neonates can result in under- or over-exposure. Use of a PK-guided dosing regimen resulted in effective target exposures within 24 h after birth with early initiation of treatment (12 h after birth). Future prospective studies should explore the incorporation of umbilical cord methadone concentrations for early identification of preterm neonates at risk of developing severe NAS and investigate the use of a PK-guided methadone dosing regimen, so that treatment failure, prolonged length of stay and opioid over-exposure can be avoided.

Objective  This study examines methadone dose adjustment postpartum. Methods  A retrospective study of women with methadone for opioid use treatment (OUT) during pregnancy was performed. Patient charts were reviewed and data were extracted. Methadone doses from five temporal data points for each patient were used: starting dose, day of delivery, and 1, 2, and 6 months postpartum. Results  Over 26 months, 49 pregnancies to women using methadone for OUT were evaluated and 20 (41%) were included. The mean methadone starting dose was 47 mg, compared with 86 mg at the time of delivery. The mean dose postpartum remained unchanged from delivery and 75% of pregnancies required the same dose or higher 1 month postpartum. By 2 months postpartum, only 33% were able to decrease their methadone dose. Twelve pregnancies completed follow-up until 6 months postpartum; only 17% of patients were able to decrease their dose, with an overall mean dose decrease was 12%. There was no difference between the mean dose at delivery and the 6-month postpartum dose. Conclusion  Patients using methadone for OUT during pregnancy achieved minimal dose decreases postpartum. Patients should be counseled that postpartum dose tapers may be challenging and about alternatives to methadone for OUT.

In a number of countries, the prevalence of neonatal opioid withdrawal syndrome (NOWS) is increasing. While NOWS is ultimately the result of opioid exposure in utero, a wide range of risk factors have been associated with the prevalence of NOWS, extending beyond just drug exposure. This article reviews the available literature on factors associated with the incidence of NOWS in opioid-exposed neonates. A range of risk factors have been associated with NOWS, including features of neonatal drug exposure, maternal and neonatal characteristics, aspects of labor and delivery, and genetics. Increased length of gestation and higher birth weight were consistently associated with an increased risk of NOWS, while breast feeding and 'rooming-in' were associated with a reduced risk of NOWS. Additionally, several genetic factors have also been associated with NOWS severity. There is conflicting evidence on the association between NOWS and other risk factors including opioid dose, neonate sex, and the use of some medications during pregnancy. This may be in part attributable to differences in how NOWS is diagnosed and the variety of methodologies across studies. While a large number of risk factors associated with NOWS are non-modifiable, encouraging pregnant women to reduce other drug use (including smoking), breast feed their child, and the judicious use of medications during pregnancy may help reduce the prevalence of NOWS. The presence or absence of NOWS in an opioid-exposed neonate is associated with a wide range of factors. Some of these modifiable risk factors may be potential targets for the primary prevention of NOWS.

Neonatal abstinence syndrome refers to the signs and symptoms attributed to the cessation of prenatal exposure (via placental transfer) to various substances. This Primer focuses on neonatal abstinence syndrome caused by opioid use during pregnancy - neonatal opioid withdrawal syndrome (NOWS). As the global prevalence of opioid use has alarmingly increased, so has the incidence of NOWS. NOWS can manifest with varying severity or not at all, for unknown reasons, but is likely to be associated with multiple factors, both maternal (for example, smoking and additional substance exposures) and neonatal (gestational age, sex and genetics). Care for the infant with NOWS begins with addressing the issues experienced by pregnant women with opioid use disorder. Co-occurring mental illness, economic hardship, intimate partner violence, infectious diseases and limited access to care are common in these women and can result in poor maternal and neonatal outcomes. Although there is no consensus regarding optimal NOWS management, non-pharmacological interventions (such as breastfeeding and rooming-in of the mother and the baby) have become a priority, as they can ameliorate symptoms without the need for further opioid exposure. Untreated NOWS can be associated with morbidity in early infancy, and the long-term consequences of fetal opioid exposure are only beginning to be understood.

Neonatal abstinence syndrome (NAS) is an increasingly common disorder diagnosed in infants exposed to various drugs, causing immense financial and social burden. Recommendations from various bodies are for babies to be monitored for 4 to 7 days following birth so that prompt treatment can commence should symptoms develop. We aimed to determine the best post-natal observation period in babies at risk of NAS.

A retrospective review was undertaken of infants ≥35 weeks' gestation who received treatment for NAS in the period 2001-2010. During this time, the standard post-natal observation period was a minimum of 7 days. Data including drug exposure, day of admission and day of treatment were collected.

Two hundred and ten babies were included. Drug exposure was predominantly to opiates (99%); however, most infants (58%) were exposed to additional substances (benzodiazepines, cannabis or amphetamines). Ninety-five per cent of infants were admitted by day 5 of life. Of the babies treated by day 7, 98.5% had been admitted to the nursery by day 5. Infants with polydrug exposure were admitted significantly earlier; however, time to treatment was not significantly different to those exposed to opiate replacement therapy alone.

In our hospital, babies treated for NAS often required admission before day 5. This has implications for hospital resource allocation, suggesting that routine post-natal observation for NAS could be shortened to 5 days. Further research is needed to help identify neonates who require more careful post-natal observation.

Despite evidence of low transfer of methadone into breast milk and the potential physical and psychological benefits that breastfeeding offers for methadone-exposed mothers and infants, the rate of breastfeeding initiation in this population is about half that reported nationally. This study describes the perceptions surrounding breastfeeding decisions and management among pregnant and postpartum women taking methadone.

Seven pregnant women and 4 postpartum women enrolled in methadone maintenance programs participated in semistructured, audiotaped interviews and focus groups, respectively, about their breastfeeding experiences. Transcripts were analyzed and coded using qualitative content analysis.

Three major content categories were identified: (1) fears, barriers, and misconceptions about breastfeeding while taking methadone; (2) motivation and perceived benefits of breastfeeding; and (3) sources of information, support, and anxiety about general breastfeeding management and breastfeeding while taking methadone. Lack of support from the health care community and misinformation about the dangers of combining breastfeeding and methadone therapy represented significant, yet modifiable, barriers to breastfeeding success in methadone-exposed women.

Interventions to increase the prevalence of breastfeeding among women taking methadone should address identified logistical, educational, and psychological barriers and consider inclusion of women themselves, partners, peers, and clinicians. In particular, clinicians who care for methadone-exposed mothers and infants should be educated on therapeutic communication, up-to-date breastfeeding contraindications, and the health benefits of breastfeeding in this population.

Compared to untreated opioid dependence, methadone maintenance treatment of opioid-dependent pregnant women has been found to be associated with better maternal and neonatal outcomes. Secondary analysis of data from 73 maternal and neonatal participants in the MOTHER study (H. E. Jones et al., New England Journal of Medicine, 2010) found no relationship between maternal methadone dose at delivery and any of 9 neonatal outcomes--peak neonatal abstinence syndrome (NAS) score, total amount of morphine needed to treat NAS, duration of neonatal hospital stay, duration of treatment for NAS, estimated gestational age at delivery, Apgar score at 5 min, and neonatal head circumference, length, and weight at birth. These results are consistent with a recent systematic review and meta-analysis (B. J. Cleary et al., Addiction, 2010) and extend findings to outcomes other than NAS. Methodological and design issues that might have adversely impacted the ability of researchers to establish the existence or non-existence of these relationships are considered.

Opioids and clonidine, used in for sedation, analgesia and control of opioid withdrawal in neonates, directly or indirectly activate opioid receptors (OPRs) expressed in immune cells. Therefore, our objective is to study how clinically relevant concentrations of different opioids and clonidine change cytokine levels in cultured whole blood from preterm and full-term infants.

Using blood from preterm (≤ 30 weeks gestational age (GA), n=7) and full-term ( ≥ 37 weeks GA, n=19) infants, we investigated the changes in cytokine profile (IL-1β, IL-6, IL-8, IL-10, IL-12p70 and TNF-α), cyclic adenosine monophosphate (cAMP) levels and μ-, δ- and κ- opioid receptor (OPR) gene and protein expression, following in-vitro exposure to morphine, methadone, fentanyl or clonidine at increasing concentrations ranging from 0 to 1 mM.

Following lipopolysaccharide activation, IL-10 levels were 146-fold greater in cultured blood from full-term than from preterm infants. Morphine and methadone, but not fentanyl, at >10(-5) M decreased all tested cytokines except IL-8. In contrast, clonidine at <10(-9) M increased IL-6, while at >10(-5) M increased IL-1β and decreased TNF-α levels. All cytokine changes followed the same patterns in preterm and full-term infant cultured blood and matched increases in cAMP levels. All three μ-, δ- and κ-OPR genes were expressed in mononuclear cells (MNC) from preterm and full-term infants. Morphine, methadone and clonidine, but not fentanyl, at >10(-5)M decreased the expression of μ-OPR, but not δ- or κ-OPRs.

Generalized cytokine suppression along with downregulation of μ-OPR expression observed in neonatal MNC exposed to morphine and methadone at clinically relevant concentrations contrast with the modest effects observed with fentanyl and clonidine. Therefore, we speculate that fentanyl and clonidine may be safer therapeutic choices for sedation and control of opioid withdrawal and pain in neonates.

To identify factors that predict the expression of neonatal abstinence syndrome (NAS) in infants exposed to methadone or buprenorphine in utero.

Multi-site randomized clinical trial in which infants were observed for a minimum of 10 days following birth, and assessed for NAS symptoms by trained raters.

A total of 131 infants born to opioid dependent mothers, 129 of whom were available for NAS assessment.

Generalized linear modeling was performed using maternal and infant characteristics to predict: peak NAS score prior to treatment, whether an infant required NAS treatment, length of NAS treatment and total dose of morphine required for treatment of NAS symptoms.

Of the sample, 53% (68 infants) required treatment for NAS. Lower maternal weight at delivery, later estimated gestational age (EGA), maternal use of selective serotonin re-uptake inhibitors (SSRIs), vaginal delivery and higher infant birthweight predicted higher peak NAS scores. Higher infant birthweight and greater maternal nicotine use at delivery predicted receipt of NAS treatment for infants. Maternal use of SSRIs, higher nicotine use and fewer days of study medication received also predicted total dose of medication required to treat NAS symptoms. No variables predicted length of treatment for NAS.

Maternal weight at delivery, estimated gestational age, infant birthweight, delivery type, maternal nicotine use and days of maternal study medication received and the use of psychotropic medications in pregnancy may play a role in the expression of neonatal abstinence syndrome severity in infants exposed to either methadone or buprenorphine.

  Methadone use in pregnancy has been associated with adverse perinatal outcomes and neonatal abstinence syndrome (NAS). This study aimed to examine perinatal outcomes and NAS in relation to (i) concomitant drug use and (ii) methadone dose.

  Prospective cohort study.

  Two tertiary care maternity hospitals.

  A total of 117 pregnant women on methadone maintenance treatment recruited between July 2009 and July 2010.

  Information on concomitant drug use was recorded with the Addiction Severity Index. Perinatal outcomes included pre-term birth (<37 weeks' gestation), small-for-gestational-age (<10th centile) and neonatal unit admission. NAS outcomes included: incidence of medically treated NAS, peak Finnegan score, cumulative dose of NAS treatment and duration of hospitalization.

  Of the 114 liveborn infants 11 (9.6%) were born pre-term, 49 (42.9%) were small-for-gestational-age, 56 (49.1%) had a neonatal unit admission and 29 (25.4%) were treated medically for NAS. Neonates exposed to methadone-only had a shorter hospitalization than those exposed to methadone and concomitant drugs (median 5.0 days versus 6.0 days, P = 0.03). Neonates exposed to methadone doses ≥80 mg required higher cumulative doses of morphine treatment for NAS (median 13.2 mg versus 19.3 mg, P = 0.03). The incidence and duration of NAS did not differ between the two dosage groups.

  The incidence and duration of the neonatal abstinence syndrome is not associated with maternal methadone dose, but maternal opiate, benzodiazepine or cocaine use is associated with longer neonatal hospitalization.

To examine opioid replacement therapy in pregnancy and effect on neonatal outcomes, including length of hospital stay for neonatal abstinence syndrome.

Retrospective descriptive study.

Labor and delivery unit and neonatal intensive care unit (NICU), Eastern Maine Medical Center, Bangor, Maine.

One hundred fifty-two opioid-dependent pregnant women on methadone maintenance therapy (MMT) (n = 136) or buprenorphine maintenance therapy (BMT) (n = 16) during pregnancy and their neonates. The neonates were born between January 1, 2005 and December 31, 2007.

A review of the electronic medical record (EMR) was conducted of all opioid-dependent women who were maintained on MMT or BMT at the time of admission for labor and delivery and their neonates.

Maternal methadone dose and concomitant in-utero exposure to benzodiazepines prolonged the length of hospital stay for neonates. Length of stay was shorter in breastfed neonates than formula-fed neonates or neonates who received formula and breast milk. Neonates with prenatal exposure to MMT spent more days in the hospital (21 vs. 14 days) for treatment of neonatal abstinence syndrome (NAS) than infants with prenatal exposure to BMT.

These findings are consistent with previous research on the simultaneous use of methadone and benzodiazepines during pregnancy and provide further direction for the treatment of opioid dependency during pregnancy. Harm reduction strategies for opioid-dependent pregnant women in substance abuse treatment with MMT may one day include guidance on daily treatment doses and recommendations to avoid the concomitant use of benzodiazepines to lessen NAS. Breastfeeding should be recommended to shorten length of stay. Understanding perinatal and neonatal outcomes of pregnant women on methadone or buprenorphine will help to identify optimal treatment for opioid dependency in pregnancy.

Maternal use of certain drugs during pregnancy can result in transient neonatal signs consistent with withdrawal or acute toxicity or cause sustained signs consistent with a lasting drug effect. In addition, hospitalized infants who are treated with opioids or benzodiazepines to provide analgesia or sedation may be at risk for manifesting signs of withdrawal. This statement updates information about the clinical presentation of infants exposed to intrauterine drugs and the therapeutic options for treatment of withdrawal and is expanded to include evidence-based approaches to the management of the hospitalized infant who requires weaning from analgesics or sedatives.

The purpose was to explore methadone and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) umbilical cord disposition, correlate with maternal methadone dose and neonatal outcomes, and evaluate the window of drug detection in umbilical cord of in utero illicit drug exposure.

Subjects comprised 19 opioid-dependent pregnant women from 2 clinical studies, one comparing methadone and buprenorphine pharmacotherapy for opioid-dependence treatment and the second examining monetary reinforcement schedules to maintain drug abstinence. Correlations were calculated for methadone and EDDP umbilical cord concentrations and maternal methadone dose, and neonatal outcomes. Cocaine- and opiate-positive umbilical cord concentrations were compared with those in placenta and meconium, and urine specimens collected throughout gestation.

Significant positive correlations were found for umbilical cord methadone concentrations and methadone mean daily dose, mean dose during the third trimester, and methadone cumulative daily dose. Umbilical cord EDDP concentrations and EDDP/methadone concentration ratios were positively correlated to newborn length, peak neonatal abstinence syndrome (NAS) score, and time-to-peak NAS score. Methadone concentrations and EDDP/methadone ratios in umbilical cord and placenta were positively correlated. Meconium identified many more cocaine- and opiate-positive specimens than did umbilical cord.

Umbilical cord methadone concentrations were correlated to methadone doses. Also, our results indicate that methadone and EDDP concentrations might help to predict the NAS severity. Meconium proved to be more suitable than umbilical cord to detect in utero exposure to cocaine and opiates; however, umbilical cord could be useful when meconium is unavailable due to in utero or delayed expulsion.

Few investigations have used placenta as an alternative matrix to detect in utero drug exposure, despite its availability at the time of birth and the large amount of sample. Methadone-maintained opioid-dependent pregnant women provide a unique opportunity to examine the placental disposition of methadone and metabolite [2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)], to explore their correlations with maternal methadone dose and neonatal outcomes, and to test the ability to detect in utero exposure to illicit drugs.

We calculated the correlations of placental methadone and EDDP concentrations and their correlations with maternal methadone doses and neonatal outcomes. Cocaine- and opiate-positive placenta results were compared with the results for meconium samples and for urine samples collected throughout gestation.

Positive correlations were found between placental methadone and EDDP concentrations (r=0.685), and between methadone concentration and methadone dose at delivery (r=0.542), mean daily dose (r=0.554), mean third-trimester dose (r=0.591), and cumulative daily dose (r=0.639). The EDDP/methadone concentration ratio was negatively correlated with cumulative daily dose (r=-0.541) and positively correlated with peak neonatal abstinence syndrome (NAS) score (r=0.513). Placental EDDP concentration was negatively correlated with newborn head circumference (r=-0.579). Cocaine and opiate use was detected in far fewer placenta samples than in thrice-weekly urine and meconium samples, a result suggesting a short detection window for placenta.

Quantitative methadone and EDDP measurement may predict NAS severity. The placenta reflects in utero drug exposure for a shorter time than meconium but may be useful when meconium is unavailable or if documentation of recent exposure is needed.

Human infants may be exposed to opiates through placental transfer from an opiate-using mother or through the direct administration of such drugs to relieve pain (e.g., due to illness or neonatal surgery). Infants of many species show physical dependence and tolerance to opiates. The magnitude of tolerance and the nature of withdrawal differ from those of the adult. Moreover, the mechanisms that contribute to the chronic effects of opiates are not well understood in the infant but include biological processes that are both common to and distinct from those of the adult. We review the animal research literature on the effects of chronic and acute opiate exposure in infants and identify mechanisms of withdrawal and tolerance that are similar to and different from those understood in adults. These mechanisms include opioid pharmacology, underlying neural substrates, and the involvement of other neurotransmitter systems. It appears that brain circuitry and opioid receptor types are similar but that NMDA receptor function is immature in the infant. Intracellular signaling cascades may differ but data are complicated by differences between the effects of chronic versus acute morphine treatment. Given the limited treatment options for the dependent infant patient, further study of the biological functions that are altered by chronic opiate treatment is necessary to guide evidenced-based treatment modalities.

To identify maternal and neonatal factors that impact response to methadone therapy for neonatal abstinence syndrome.

This is a retrospective review of 128 infants that received pharmacotherapy for opiate withdrawal to identify factors associated with favorable response to methadone therapy. Maternal and neonatal data were analyzed with univariate statistics and multivariate logistic regression.

Maternal methadone maintenance dose during pregnancy correlated with length of stay (P=0.009). There was an inverse correlation between the amount of mother's breast milk ingested and length of stay (β=-0.03, P=0.02). Methadone was initiated later, tapered more rapidly and was more successful as monotherapy in preterm infants. Five percent of infants were admitted to hospital again for rebound withdrawal following reduction of breast milk intake.

Severity of neonatal abstinence syndrome may be mitigated by titrating methadone to the lowest effective dose during pregnancy and by encouraging breast milk feeds, which should be weaned gradually.

To determine if there is a relationship between maternal methadone dose in pregnancy and the diagnosis or medical treatment of neonatal abstinence syndrome (NAS).

PubMed, EMBASE, the Cochrane Library and PsychINFO were searched for studies reporting on methadone use in pregnancy and NAS (1966-2009). The relative risk (RR) of NAS was compared for methadone doses above versus below a range of cut-off points. Summary RRs and 95% confidence intervals (CI) were estimated using random effects meta-analysis. Sensitivity analyses explored the impact of limiting meta-analyses to prospective studies or studies using an objective scoring system to diagnose NAS.

A total of 67 studies met inclusion criteria for the systematic review; 29 were included in the meta-analysis. Any differences in the incidence of NAS in infants of women on higher compared with lower doses were statistically non-significant in analyses restricted to prospective studies or to those using an objective scoring system to diagnose NAS.

Severity of the neonatal abstinence syndrome does not appear to differ according to whether mothers are on high- or low-dose methadone maintenance therapy.

Methadone is standard pharmacotherapy for opioid-dependent pregnant women, yet the relationship between maternal methadone dose and neonatal abstinence syndrome (NAS) severity is still unclear. This research evaluated whether quantification of fetal methadone and drug exposure via meconium would reflect maternal dose and predict neonatal outcomes.

Prospective clinical study.

An urban drug treatment facility treating pregnant and post-partum women and their children.

Forty-nine opioid-dependent pregnant women received 30-110 mg methadone daily.

Maternal methadone dose, infant birth parameters and NAS assessments were extracted from medical records. Thrice-weekly urine specimens were screened for opioids and cocaine. Newborn meconium specimens were quantified for methadone, opioid, cocaine and tobacco biomarkers.

There was no relationship between meconium methadone concentrations, presence of opioids, cocaine and/or tobacco in meconium, maternal methadone dose or NAS severity. Opioid and cocaine were also found in 36.7 and 38.8 of meconium specimens, respectively, and were associated with positive urine specimens in the third trimester. The presence of opioids other than methadone in meconium correlated with increased rates of preterm birth, longer infant hospital stays and decreased maternal time in drug treatment.

Methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) concentrations in meconium did not predict infant birth parameters or NAS severity. Prospective urine testing defined meconium drug detection windows for opiates and cocaine as 3 months, rather than the currently accepted 6 months. The presence of opioids in meconium could be used as a biomarker for infants at elevated risk in the newborn period.

To estimate the relationship between maternal methadone dose and the incidence of neonatal abstinence syndrome (NAS).

We performed a retrospective cohort study of pregnant women treated with methadone for opiate addiction who delivered live-born neonates between 1996 and 2006. Four dose groups, on the basis of total daily methadone dose, were compared (<or=80 mg/d, 81-120 mg/d, 121-160 mg/d, and >160 mg/d). The primary outcome was treatment for NAS. Symptoms of NAS were objectively measured with the Finnegan scoring system, and treatment was initiated for a score>24 during the prior 24 hours.

A total of 330 women treated with methadone and their 388 offspring were included. Average methadone dose at delivery was 117+/-50 mg/d (range, 20-340 mg/d). Overall, 68% of infants were treated for NAS. Of infants exposed to methadone doses<or=80 mg/d, 81-120 mg/d, 121-160 mg/d, and >160 mg/d, treatment for NAS was initiated for 68%, 63%, 70%, and 73% of neonates, respectively (P=.48). The rate of maternal illicit opiate abuse at delivery was 26%, 28%, 19%, and 11%, respectively (P=.04).

No correlation was found between maternal methadone dose and rate of NAS. However, higher doses of methadone were associated with decreased illicit opiate abuse at delivery.

The objective of this retrospective study is to compare the medical treatment of neonatal narcotic abstinence syndrome with clonidine and chloral hydrate with the commonly used combination therapy of morphine and phenobarbital.

From 1998 to 2008, a total of 133 newborns suffering from neonatal narcotic abstinence syndrome were treated at our clinic. All of these patients were born to mothers who had received methadone substitution for drug addiction during the course of pregnancy.

Twenty-nine patients received clonidine and chloral hydrate, and 64 patients were treated with morphine and phenobarbital for abstinence syndrome. The duration of treatment was significantly shorter in the clonidine/chloral hydrate group (median: 14 days vs. 35 days). Correspondingly, the period of hospitalization was also considerably shorter in the clonidine/chloral hydrate group (median: 32 days vs. 44 days). In addition, patients in the clonidine/chloral hydrate group exhibited markedly reduced withdrawal symptoms.

This study suggests that a treatment of neonatal abstinence syndrome with clonidine in omission of opiates is possible without causing short-term adverse cardiovascular effects. Considering the retrospective design of the study, controlled and prospective trials are needed.

The management of the infant exposed to drugs in utero poses significant challenges. Symptoms and signs of neonatal abstinence syndrome (NAS) are non-specific but most commonly associated with withdrawal from maternal opioids. A high index of suspicion is required when presented with an infant who could be manifesting symptoms of NAS. In the absence of a reliable history of maternal drug exposure, analysis of neonatal meconium or urine may be indicated. Approximately 90% of infants exposed to opioids will exhibit signs of NAS, although a smaller proportion will require pharmacological treatment. Although few studies have evaluated the advantages of different therapeutic agents and strategies, opioid withdrawal is best treated initially with opioid medication. Supportive care of the infant should include assessment of the adequacy of feeding, evaluation of social circumstances (particularly child protection issues) and surveillance for transmission of viral infection.

Illicit drug use during pregnancy is common and probably underestimated in the majority of published studies. The infant exposed to opiates or other drugs of dependency during intrauterine development is at risk for post-natal withdrawal as well as to long-term problems that are associated with drug-effects and often, adverse social circumstances. This article examines the early management of the infant and mother for detection and monitoring of drug-exposure, pharmacological intervention for withdrawal and the management of associated, particularly infective and psychosocial, problems. Practical concerns surrounding these issues are discussed and further research on psychosocial intervention to improve long-term outcome are much needed.

Neonatal opioid withdrawal often requires treatment but there have been few recent studies of current pharmacological interventions to guide treatment. This retrospective chart review provides an exploratory examination of newborns treated with either methadone or paregoric for opioid withdrawal and outlines dosage ranges and intervals, side effects, and clinical outcomes of the two regimens. The outcome variables examined were time to resolution of withdrawal symptoms, rate of decrease in symptom severity, and length of hospital stay. There were no observed differences in outcome variables between the two treatment groups and side effect profiles were similar. Dosages, dosage intervals, and tapering regimens were consistent with American Academy of Pediatrics recommendations. Although the sample size is small and standardized regimens were not used, this study provides preliminary data about dosing levels and dosing intervals of these two pharmacologic treatment agents. Both groups of infants had favorable outcomes, although given the variation in treatment regimens it is difficult to draw an equation of equivalency. These results are applicable to the design of future studies of pharmacological interventions.

To evaluate the efficacy and safety of methadone versus buprenorphine treatment in pregnant opioid-dependent women.

Randomized, double-dummy, double-blind, flexible-dosing comparison study.

Addiction Clinic at the Medical University of Vienna, Austria.

Eighteen women were assigned randomly to receive either methadone (n = 9) or buprenorphine (n = 9) during weeks 24-29 of pregnancy. After dropouts, data were available from 14 cases (six in the methadone and eight in the buprenorphine group).

Sublingual buprenorphine tablets (8-24 mg/day) or oral methadone solution (40-100 mg/day), with matched placebos.

Mothers: retention in treatment, urine toxicology and nicotine use. Neonates: Routine birth data, neonatal abstinence syndrome (NAS) in severity and duration.

There was somewhat greater retention in the buprenorphine group but significantly lowered use of additional opioids in the methadone group (P = 0.047).Neonates: There was earlier onset of NAS in neonates born to the methadone (mean 60 hours) than to the buprenorphine groups (mean 72 hours after last medication); 43% did not require NAS-treatment with short treatment duration in both groups (mean 5 days).

This preliminary study had limited power to detect differences but the trends observed suggest this kind of research is practicable and that further studies are warranted.

This study assesses the effect of higher doses of methadone during pregnancy on maternal and fetal outcomes.

We retrospectively reviewed clinical data for 81 mothers who received methadone and their 81 offspring. The cohort was divided into high-dose (>/=100 mg) and low-dose (<100 mg) groups.

There were no differences in the rate of medication treatment for neonatal abstinence symptoms or days of infant hospitalization between the high-dose (mean, 132 mg) and low-dose (mean, 62 mg) groups. Despite longer histories of opiate abuse, the high-dose group had less illicit drug use at delivery. The whole cohort, which received an average of 101 mg/d, had an 81% rate of negative toxicology screens at delivery.

High doses of methadone were not associated with increased risks of neonatal abstinence symptoms but had a positive effect on maternal drug abuse. Arbitrarily limiting methadone dose as a way of minimizing the risks of neonatal abstinence symptoms may be unwarranted.