First Trimester Use of Buprenorphine or Methadone and the Risk of Congenital Malformations.

Importance: Use of buprenorphine or methadone to treat opioid use disorder is recommended in pregnancy; however, their teratogenic potential is largely unknown. Objective: To compare the risk of congenital malformations following in utero exposure to buprenorphine vs methadone. Design, Setting, and Participants: This population-based cohort study used health care utilization data from publicly insured Medicaid beneficiaries in the US from 2000 to 2018. A total of 13 360 pregnancies with enrollment from 90 days prior to pregnancy start through 1 month after delivery and first trimester use of buprenorphine or methadone were included and linked to infants. Data were analyzed from July to December 2022. Exposure: A pharmacy dispensing of buprenorphine or a code for administration of methadone in the first trimester. Main Outcomes and Measures: Primary outcomes included major malformations overall and malformations previously associated with opioids (any cardiac malformations, ventricular septal defect, secundum atrial septal defect/nonprematurity-related patent foramen ovale, neural tube defects, clubfoot, and oral clefts). Secondary outcomes included other organ system-specific malformations. Risk differences and risk ratios (RRs) were estimated comparing buprenorphine with methadone, adjusting for confounders with propensity score overlap weights. Results: The cohort included 9514 pregnancies with first-trimester buprenorphine exposure (mean [SD] maternal age, 28.4 [4.6] years) and 3846 with methadone exposure (mean [SD] maternal age, 28.8 [4.7] years). The risk of malformations overall was 50.9 (95% CI, 46.5-55.3) per 1000 pregnancies for buprenorphine and 60.6 (95% CI, 53.0-68.1) per 1000 pregnancies for methadone. After confounding adjustment, buprenorphine was associated with a lower risk of malformations compared with methadone (RR, 0.82; 95% CI, 0.69-0.97). Risk was lower with buprenorphine for cardiac malformations (RR, 0.63; 95% CI, 0.47-0.85), including both ventricular septal defect (RR, 0.62; 95% CI, 0.39-0.98) and secundum atrial septal defect/nonprematurity-related patent foramen ovale (RR, 0.54; 95% CI, 0.30-0.97), oral clefts (RR, 0.65; 95% CI, 0.35-1.19), and clubfoot (RR, 0.55; 95% CI, 0.32-0.94). Results for neural tube defects were uncertain given low event counts. In secondary analyses, buprenorphine was associated with a decreased risk of central nervous system, urinary, and limb malformations but a greater risk of gastrointestinal malformations compared with methadone. These findings were consistent in sensitivity and bias analyses. Conclusions and Relevance: In this cohort study, the risk of most malformations previously associated with opioid exposure was lower in buprenorphine-exposed infants compared with methadone-exposed infants, independent of measured confounders. Malformation risk is one factor that informs the individualized patient decision regarding medications for opioid use disorder in pregnancy.

Increasing knowledge about recovery-related life domains among pregnant and parenting women in comprehensive substance use disorder treatment: The Art of Addiction Recovery Program.

BACKGROUND: Group treatments designed specifically for pregnant and parenting women with substance use disorders are lacking. This study provides a preliminary assessment of the Art of Addiction Recovery Program, a manualized group treatment imbedded within a comprehensive substance use disorder treatment program for pregnant and parenting women. METHODS: The Program consists of 14 sessions, each focusing on a different topic, including health, social relationships, the recovery process, well-being, and introspection. Each session includes both the presentation of information by a facilitator, group discussions guided by the facilitator, and a creative project. A single-group pretest-posttest design provides an initial evaluation of the Art of Addiction Recovery Program. RESULTS: Participants were 51 women with an average age of 28.7 (SD = 5.0) with most (69%) having a primary opioid use disorder and 82% reporting tobacco use. Significant (ps < 0.001) pre- to post-session increases in session-specific knowledge occurred for all 14 sessions with a measure of multivariate association indicating that these changes were substantial. Ratings of learning and effectiveness were generally high, with 19/28 means at 3.7 or above (maximum score = 4). CONCLUSIONS: Findings suggest that The Art of Addiction Recovery Program was effective in conveying knowledge about substance use and recovery, and that participants increased their knowledge and generally strongly agreed that the sessions provided high levels of learning and were highly effective. The Art of Addiction Recovery Program provides an option for those seeking a manual-based group treatment program as an aid in the treatment process for this subpopulation.

Implementation and Evaluation of a Psychoactive Substance Use Intervention for Children in Afghanistan: Differences Between Girls and Boys at Treatment Entry and in Response to Treatment.

Psychoactive substance use among children in Afghanistan is an issue of concern. Somewhere around 300,000 children in the country have been exposed to opioids that either parents directly provided to them or by passive exposure. Evidence-based and culturally appropriate drug prevention and treatment programs are needed for children and families. The goals of this study were to: (1) examine lifetime psychoactive substance use in girls and boys at treatment entry; and (2) examine differential changes in substance use during and following treatment between girls and boys. Children ages 10-17 years old entering residential treatment were administered the Alcohol, Smoking and Substance Involvement Screening Test for Youth (ASSIST-Y) at pre- and post-treatment, and at three-month follow-up. Residential treatment was 45 days for children and 180 days for adolescents and consisted of a comprehensive psychosocial intervention that included education, life skills, individual and group counseling and, for older adolescents, vocational skills such as embroidery and tailoring. Girls and boys were significantly different regarding lifetime use of five substances at treatment entry, with girls less likely than boys to have used tobacco, cannabis, stimulants, and alcohol, and girls more likely than boys to have used sedatives. Differences between boys and girls were found for past-three-month use of four substances at treatment entry, with girls entering treatment with higher past-three-month use of opioids and sedatives, and boys with higher past-three-month use of tobacco, cannabis, and alcohol. Change over the course of treatment showed a general decline for both girls and boys in the use of these substances. Girls and boys in Afghanistan come to treatment with different substance use histories and differences in past-three-month use. Treatment of children for substance use problems must be sensitive to possible differences between girls and boys in substance use history.

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

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

Maternal buprenorphine treatment during pregnancy and maternal physiology.

BACKGROUND: Buprenorphine, used for opioid use disorder (OUD) treatment during pregnancy, provides unknown effects on maternal physiological activity. The primary aim of this report is to document acute effects of buprenorphine administration on indicators of maternal autonomic functioning. Effects of maternal buprenorphine dose and other substance exposures on maternal measures were examined, as were neonatal abstinence syndrome (NAS) outcomes. METHODS: Forty-nine pregnant, buprenorphine-maintained women yielded maternal physiologic information (heart rate and variability, electrodermal activity, and respiratory rate) at 24, 28, 32 and 36 weeks gestation. Monitoring at trough and peak maternal medication levels was implemented to ascertain acute physiologic effects of buprenorphine administration. RESULTS: Buprenorphine administration accelerated maternal heart rate and reduced variability at two gestational ages (24 and 36 weeks) and suppressed sympathetic (electrodermal) activation at 24, 28 and 32 weeks at times of peak maternal medication levels. Maternal autonomic parameters were unrelated to polysubstance exposure with the exception of cigarette smoking. Heavier smoking dampened maternal heart rate variability across gestation and potentiated reactivity to buprenorphine at 24 and 36 weeks. Heavier smoking was also associated with reduced electrodermal activity at 36 weeks. Buprenorphine dose was unrelated to observed effects. Larger degree of maternal heart rate reactivity to buprenorphine administration was related to more severe NAS expression. CONCLUSIONS: These findings detail the maternal autonomic response to buprenorphine administration but also illustrate the significant effect of concurrent cigarette use on maternal autonomic regulation. This suggests the importance of smoking-reduction strategies in the comprehensive, medication-assisted treatment of women with OUD.

The CHILD Intervention for Living Drug-free Comprehensive Assessment of Risk, Resilience, and Experience (CHILD CARRE) Measure: Initial Findings.

This paper summarizes the development and evaluation of an assessment instrument for children ages 7-12. The CHILD CARRE measure is a semi-structured interview with 7 domains. Children from the USA and Argentina (N=134) completed baseline and follow-up assessments. Substance use occurred at an average age of 8. Almost 33% of the children were taking medications for medical issues, more than 50% of them said that medical problem gets in the way of doing things they like to to do and almost 64% of the children stated that they would like to feel better. On average, children completed third grade in school, 56% of them knew how to read and 26% of the children started making money at age 8. Most children (74%) saw someone drunk or high and 23% of children reported alcohol or psychoactive substance use. Among these children using substances, such substance use occurred at an average age of 8, and in the past 30 days they used these substances an average for 5 days. The rating of level of risk on the part of the interviewer placed these children in the "risky" to "very risky" categories. Most children reported seeing their family members smoking (83%) or using alcohol (67%), and 49% reported seeing their family members high on drugs. Few children (10%) had conflicts with the law, while 46% of their family members had legal problems. Some children (30%) reported having serious problems getting along with family members, neighbors, or friends. These results suggest that this measure can serve as the first comprehensive measure to assess multiple life domains for young children at risk for or using psychoactive substances.

Neonatal abstinence syndrome.

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.

Maternal buprenorphine treatment and infant outcome.

BACKGROUND AND OBJECTIVES: Maternal buprenorphine maintenance predisposes the infant to exhibit neonatal abstinence syndrome (NAS), but there is insufficient published information regarding the nature of NAS and factors that contribute to its severity in buprenorphine-exposed infants. METHODS: The present study evaluated forty-one infants of buprenorphine-maintained women in comprehensive substance use disorder treatment who participated in an open-label study examining the effects of maternal buprenorphine maintenance on infant outcomes. Modifiers of the infant outcomes, including maternal treatment and substance use disorder parameters, were also evaluated. RESULTS: Fifty-nine percent of offspring exhibited NAS that required pharmacologic management. Both maternal buprenorphine dose as well as prenatal polysubstance exposure to illicit substance use/licit substance misuse were independently associated with NAS expression. Polysubstance exposure was associated with more severe NAS expression after controlling for the effects of buprenorphine dose. Other exposures, including cigarette smoking and SRI use, were not related to outcomes. Maternal buprenorphine dose was positively associated with lower birth weight and length. CONCLUSIONS: Polysubstance exposure was the most potent predictor of NAS severity in this sample of buprenorphine-exposed neonates. This finding suggests the need for interventions that reduce maternal polysubstance use during medication assisted treatment for opioid use disorder, and highlights the necessity of a comprehensive approach, beyond buprenorphine treatment alone, for the optimal care for pregnant women with opioid use disorders.

Maternal buprenorphine treatment and fetal neurobehavioral development.

BACKGROUND: Gestational opioid use/misuse is escalating in the United States; however, little is understood about the fetal effects of medications used to treat maternal opioid use disorders. OBJECTIVE: The purpose of this study was to determine the effect of maternal buprenorphine administration on longitudinal fetal neurobehavioral development. STUDY DESIGN: Forty-nine buprenorphine-maintained women who attended a substance use disorder treatment facility with generally uncomplicated pregnancies underwent fetal monitoring for 60 minutes at times of trough and peak maternal buprenorphine levels. Data were collected at 24, 28, 32, and 36 weeks gestation. Fetal neurobehavioral indicators (ie, heart rate, motor activity, and their integration [fetal movement-fetal heart rate coupling]) were collected via an actocardiograph, digitized and quantified. Longitudinal data analysis relied on hierarchic linear modeling. RESULTS: Fetal heart rate, heart rate variability, and heart rate accelerations were significantly reduced at peak vs trough maternal buprenorphine levels. Effects were significant either by or after 28 weeks gestation and tended to intensify with advancing gestation. Fetal motor activity and fetal movement-fetal heart rate coupling were depressed from peak to trough at 36 weeks gestation. Polysubstance exposure did not significantly affect fetal neurobehavioral parameters, with the exception that fetuses of heavier smokers moved significantly less than those of lighter smokers at 36 weeks gestation. By the end of gestation, higher maternal buprenorphine dose was related to depression of baseline fetal cardiac measures at trough. CONCLUSION: Maternal buprenorphine administration has acute suppressive effects on fetal heart rate and movement, and the magnitude of these effects increases as gestation progresses. Higher dose (≥13 mg) appears to exert greater depressive effects on measures of fetal heart rate and variability. These findings should be balanced against comparisons to gestational methadone effects, relatively good outcomes of buprenorphine-exposed infants, and recognition of the benefits of medication-assisted treatment for pregnant women with opioid use disorders in optimizing pregnancy outcomes.

A comparison of cigarette smoking profiles in opioid-dependent pregnant patients receiving methadone or buprenorphine.

INTRODUCTION: Little is known about the relationship between cigarette smoking and agonist treatment in opioid-dependent pregnant patients. The objective of this study is to examine the extent to which cigarette smoking profiles differentially changed during the course of pregnancy in opioid-dependent patients receiving either double-blind methadone or buprenorphine. Patients were participants in the international, randomized controlled Maternal Opioid Treatment: Human Experimental Research (MOTHER) study. METHODS: A sample of opioid-maintained pregnant patients (18-41 years old) with available smoking data who completed a multisite, double-blind, double-dummy, randomized controlled trial of methadone (n = 67) and buprenorphine (n = 57) between 2005 and 2008. Participants were compared on smoking variables based on opioid agonist treatment condition. RESULTS: Overall, 95% of the sample reported cigarette smoking at treatment entry. Participants in the two medication conditions were similar on pretreatment characteristics including smoking rates and daily cigarette amounts. Over the course of the pregnancy, no meaningful changes in cigarette smoking were observed for either medication condition. The fitted difference in change in adjusted cigarettes per day between the two conditions was small and nonsignificant (ß = -0.08, SE = 0.05, p = .132). CONCLUSIONS: Results support high rates of smoking with little change during pregnancy among opioid-dependent patients, regardless of the type of agonist medication received. These findings are consistent with evidence that suggests nicotine effects, and interactions may be similar for buprenorphine compared with methadone. The outcomes further highlight that aggressive efforts are needed to reduce/eliminate smoking in opioid-dependent pregnant women.

Cigarette smoking in opioid-dependent pregnant women: neonatal and maternal outcomes.

BACKGROUND: The relationship between cigarette smoking and neonatal and maternal clinical outcomes among opioid-agonist-treated pregnant patients is sparse. OBJECTIVES: (1) Is smoking measured at study entry related to neonatal and maternal outcomes in pregnant women receiving opioid-agonist medication? (2) Is it more informative to use a multi-item measure of smoking dependence or a single-item measure of daily smoking? (3) Is the relationship between smoking at study entry and outcomes different between methadone and buprenorphine? METHODS: Secondary analyses examined the ability of the tobacco dependence screener (TDS) and self-reported past 30-day daily average number of cigarettes smoked, both measured at study entry, to predict 12 neonatal and 9 maternal outcomes in 131 opioid-agonist-maintained pregnant participants. RESULTS: Past 30-day daily average number of cigarettes smoked was significantly positively associated with total amount of morphine (mg) needed to treat neonatal abstinence syndrome (NAS), Adjusted Odds Ratio (AOR)=1.06 (95% CI: 1.02, 1.09), number of days medicated for NAS, AOR=1.04 (95% CI: 1.01, 1.06), neonatal length of hospital stay in days, AOR=1.03 (95% CI: 1.01, 1.05), and negatively associated with 1-AOR=.995 (95% CI: .991,.999) and 5-min Apgar scores, AOR=.996 (95% CI: .994,.998). Simple effect tests of the two significant TDS×medication condition effects found TDS was unrelated to non-normal presentation and amount of voucher money earned in the methadone [AORs=.90 (95% CI: .74, 1.08, p>.24) and 1.0 (95% CI: .97, 1.03, p>.9)] but significant in the buprenorphine condition [AORs=1.57 (95% CI: 1.01, 2.45, p<.05) and 1.08 (95% CI: 1.04, 1.12, p<.01)]. CONCLUSIONS: Regardless of prenatal methadone or buprenorphine exposure, heavier cigarette smoking was associated with more compromised birth outcomes.

Neonatal outcomes following in utero exposure to methadone or buprenorphine: a National Cohort Study of opioid-agonist treatment of Pregnant Women in Norway from 1996 to 2009.

BACKGROUND: In Norway, most opioid-dependent women are in opioid maintenance treatment (OMT) with either methadone or buprenorphine throughout pregnancy. The inclusion criteria for both medications are the same and both medications are provided by the same health professionals in any part of the country. International studies comparing methadone and buprenorphine in pregnancy have shown differing neonatal outcomes for the two medications. METHOD: This study compared the neonatal outcomes following prenatal exposure to either methadone or buprenorphine in a national clinical cohort of 139 women/neonates from 1996 to 2009. RESULTS: After adjusting for relevant covariates, buprenorphine-exposed newborns had larger head circumferences and tended to be heavier and longer than methadone-exposed newborns. The incidence of neonatal abstinence syndrome (NAS) and length of treatment of NAS did not differ between methadone- and buprenorphine-exposed newborns. There was little use of illegal drugs and benzodiazepines during the pregnancies. However, the use of any drugs or benzodiazepines during pregnancy was associated with longer lasting NAS-treatment of the neonates. CONCLUSIONS: The clinical relevance of these findings is that both methadone and buprenorphine are acceptable medications for the use in pregnancy, in line with previous studies. If starting OMT in pregnancy, buprenorphine should be considered as the drug of choice, due to more favorable neonatal growth parameters. Early confirmation of the pregnancy and systematic follow-up throughout the pregnancy are of importance to encourage the women in OMT to abstain from the use of tobacco, alcohol, illegal drugs or misuse of prescribed drugs.

Predicting treatment for neonatal abstinence syndrome in infants born to women maintained on opioid agonist medication.

AIM: To identify factors that predict the expression of neonatal abstinence syndrome (NAS) in infants exposed to methadone or buprenorphine in utero. DESIGN AND SETTING: 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. PARTICIPANTS: A total of 131 infants born to opioid dependent mothers, 129 of whom were available for NAS assessment. MEASUREMENTS: 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. FINDINGS: 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. CONCLUSIONS: 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.

Contingent incentives reduce cigarette smoking among pregnant, methadone-maintained women: results of an initial feasibility and efficacy randomized clinical trial.

AIMS: This study examined the feasibility and efficacy of behavioral incentives for reducing cigarette smoking among pregnant methadone-maintained patients. DESIGN: Participants (n = 102) were assigned randomly to: (i) contingent behavioral incentives (CBI: n = 42); (ii) non-contingent behavioral incentives (NCBI: n = 28); or (iii) treatment as usual (TAU: n = 32). SETTING: Study procedures were implemented at the Center for Addiction and Pregnancy in Baltimore, MD. PARTICIPANTS: Study participants were pregnant, methadone-maintained women enrolled in substance use disorder treatment. MEASUREMENTS: Baseline carbon monoxide (CO) levels were calculated for each participant. Subsequently, breath samples were tested three times weekly to measure changes in smoking behavior. CBI participants received incentives for target reductions from baseline: any reduction (week 1); 10% reduction (weeks 2-4), 25% reduction (weeks 5-7), 50% reduction (weeks 8-9), 75% reduction (week 10-11); and abstinence [CO < 4 parts per million (p.p.m.)] (week 12 until delivery). NCBI participants received incentives independent of smoking CO measurement results. TAU participants received no incentives, the standard treatment at the program. FINDINGS: CBI condition participants submitted significantly lower mean CO values than the NCBI and TAU conditions over the course of the intervention (P < 0.0001). Nearly half (48%) of the CBI participants met the 75% smoking reduction target and one-third (31%) met the abstinence target at week 12. In contrast, none of the NCBI met either the 75% or abstinence targets. Only 2% of the TAU participants met the 75% reduction and none of the TAU participants met the abstinence targets. These smoking behavior reductions did not yield significant differences in birth outcomes. CONCLUSIONS: Cigarette smoking may be reduced significantly among pregnant, methadone-maintained women through the use of contingent reinforcement for gradual reductions in breath carbon monoxide levels.

Double jeopardy--drug and sex risks among Russian women who inject drugs: initial feasibility and efficacy results of a small randomized controlled trial.

BACKGROUND: With HIV prevalence estimated at 20% among female injecting drug users (IDUs) in St. Petersburg, Russia, there is a critical need to address the HIV risks of this at-risk population. This study characterized HIV risks associated with injecting drug use and sex behaviors and assessed the initial feasibility and efficacy of an adapted Woman-Focused intervention, the Women's CoOp, relative to a Nutrition control to reduce HIV risk behaviors among female IDUs in an inpatient detoxification drug treatment setting. METHOD: Women (N = 100) were randomized into one of two one-hour long intervention conditions--the Woman-Focused intervention (n = 51) or a time and attention-matched Nutrition control condition (n = 49). RESULTS: The results showed that 57% of the participants had been told that they were HIV-positive. At 3-month follow-up, both groups showed reduced levels of injecting frequency. However, participants in the Woman-Focused intervention reported, on average, a lower frequency of partner impairment at last sex act and a lower average number of unprotected vaginal sex acts with their main sex partner than the Nutrition condition. CONCLUSION: The findings suggest that improvements in sexual risk reduction are possible for these at-risk women and that more comprehensive treatment is needed to address HIV and drug risks in this vulnerable population.

Randomized controlled trials in pregnancy: scientific and ethical aspects. Exposure to different opioid medications during pregnancy in an intra-individual comparison.

BACKGROUND: Chronic medical conditions such as opioid dependence require evidence-based treatment recommendations. However, pregnant women are under-represented in clinical trials. We describe the first within-subject comparison of maternal and neonatal outcomes for methadone- versus buprenorphine-exposed pregnancies. Although methadone is the established treatment of pregnant opioid-dependent women, recent investigations have shown a trend for a milder neonatal abstinence syndrome (NAS) under buprenorphine. However, it is not only the choice of maintenance medication that determines the occurrence of NAS; other factors such as maternal metabolism, illicit substance abuse and nicotine consumption also influence its severity and duration and represent confounding factors in the assessment of randomized clinical trials. CASE SERIES DESCRIPTION: Three women who were part of the European cohort of a randomized, double-blind multi-center trial with a contingency management tool [the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study], each had two consecutive pregnancies and were maintained on either methadone or buprenorphine for their first and then the respective opposite, still-blinded medication for their second pregnancy. Birth measurements, the total neonatal abstinence score, the total amounts of medication used to treat NAS and the days of NAS treatment duration were assessed. RESULTS: Both medications were effective and safe in reducing illicit opioid relapse and avoiding preterm labor. Methadone maintenance yielded to a significantly higher neonatal birth weight. Data patterns suggest that buprenorphine exposure was associated with lower neonatal abstinence syndrome (NAS) scores. Findings from this unique case series are consistent with earlier reports using between-group analyses. CONCLUSIONS: Buprenorphine has the potential to become an established treatment alternative to methadone for pregnant opioid-dependent women. Under special consideration of ethical boundaries, psychopharmacological treatment during pregnancy must be addressed as an integral part of clinical research projects in order to optimize treatment for women and neonates.

Cigarette Smoking and Neonatal Outcomes in Depressed and Non-Depressed Opioid-Dependent Agonist-Maintained Pregnant Patients.

AIMS: To investigate whether cigarette smoking and/or depression contribute to neonatal abstinence syndrome (NAS) severity. DESIGN: Cohort study analyzing data from a randomized, controlled trial of methadone versus buprenorphine. SETTING: Seven study sites that randomized patients to study conditions and provided comprehensive addiction treatment to pregnant patients. PARTICIPANTS: 119 of 131 opioid-dependent pregnant patients who completed the MOTHER study. MEASUREMENTS: Smoking data and depression status were obtained from the Addiction Severity Index and Mini International Neuropsychiatric Interview, respectively. Neonatal outcomes (birth weight, preterm delivery and NAS pharmacologic treatment) were collected from the medical charts. Study site was a fixed-effect factor in all analyses. FINDINGS: Cigarette smoking was reported by 94% of participants and depression identified in 35%. Smoking was associated with low birth weight, preterm delivery, and NAS pharmacologic treatment in both depressed and non-depressed participants. The association between smoking and NAS treatment differed significantly between depressed and non-depressed participants. Among non-depressed participants, adjusting for site and illicit drug use, each additional average cigarette per day (CPD) increased the odds of NAS treatment by 12% [95%CI: (1.02-1.23), p=0.02]. Among depressed participants, each additional average CPD did not statistically increase the odds of NAS treatment [OR: 0.94, 95% CI: (0.84-1.04), p=0.23]. CONCLUSIONS: These results are consistent with the hypothesis that NAS expression is influenced by many factors. The relationship between CPD and NAS pharmacologic treatment is attenuated among depressed women in this study for reasons currently unknown. Further investigations are needed to clarify the complex relationships among maternal smoking, depression, and NAS.

Prenatal methadone exposure, meconium biomarker concentrations and neonatal abstinence syndrome.

AIMS: 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. DESIGN: Prospective clinical study. SETTING: An urban drug treatment facility treating pregnant and post-partum women and their children. PARTICIPANTS: Forty-nine opioid-dependent pregnant women received 30-110 mg methadone daily. MEASUREMENTS: 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. FINDINGS: 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. CONCLUSIONS: 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.