BACKGROUND-Methadone, a full mu-opioid agonist, is the recommended treatment for opioid dependence during pregnancy. However, prenatal exposure to methadone is associated with a neonatal abstinence syndrome (NAS) characterized by central nervous system hyperirritability and autonomic nervous system dysfunction, which often requires medication and extended hospitalization. Buprenorphine, a partial mu-opioid agonist, is an alternative treatment for opioid dependence but has not been extensively studied in pregnancy.

The aim of the present study was to estimate the prevalence of unintended pregnancy and its three subtypes (mistimed, unwanted, ambivalent) among opioid-abusing women. In the general population, 31–47% of pregnancies are unintended; data on unintended pregnancy in opioid- and other drug-abusing women are lacking. Pregnant opioid-abusing women (N=946) screened for possible enrollment in a multi-site randomized controlled trial comparing opioid maintenance medications completed a standardized interview assessing sociodemographic characteristics, current and past drug use, and pregnancy intention. Almost 9 of every 10 pregnancies were unintended (86%), with comparable percentages mistimed (34%), unwanted (27%), and ambivalent (26%). Irrespective of pregnancy intention, more than 90% of the total sample had a history of drug abuse treatment, averaging more than 3 treatment episodes. Interventions are sorely needed to address the extremely high rate of unintended pregnancy among opioid-abusing women. Drug treatment programs are likely to be an important setting for such interventions.

This article addresses common questions that clinicians face when treating pregnant women with opioid dependence. Guidance, based on both research evidence and the collective clinical experience of the authors, which include investigators in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) project, is provided to aid clinical decision making. The MOTHER project is a double-blind, double-dummy, flexible-dosing, parallel-group clinical trial examining the comparative safety and efficacy of methadone and buprenorphine for the treatment of opioid dependence in pregnant women and their neonates. The article begins with a discussion of appropriate assessment during pregnancy and then addresses clinical management stages including maintenance medication selection, induction, and stabilization; opioid agonist medication management before, during, and after delivery; pain management; breast-feeding; and transfer to aftercare. Lastly, other important clinical issues including managing co-occurring psychiatric disorders and medication interactions are discussed.

Aims This paper reviews the published literature regarding outcomes following maternal treatment with buprenorphine in five areas: maternal efficacy, fetal effects, neonatal effects, effects on breast milk, and longer-term developmental effects. Methods Within each outcome area, findings are summarized first for the 3 randomized controlled trials and then for the 44 non-randomized studies (i.e., prospective studies, case reports and series, and retrospective chart reviews), only 28 of which involve independent samples. Results Results indicate that maternal treatment with buprenorphine has comparable efficacy to methadone, although difficulties may exist with current buprenorphine induction methods. The available fetal data suggest buprenorphine results in less physiologic suppression of fetal heart rate and movements than methadone. Regarding neonatal effects, perhaps the single definitive conclusion is that prenatal buprenorphine treatment results in a clinically significant less severe neonatal abstinence syndrome (NAS) than treatment with methadone. The limited research suggests that, like methadone, buprenorphine is compatible with breastfeeding. Data available thus far suggest that there are no deleterious effects of in utero buprenorphine exposure on infant development. Conclusions Buprenorphine produces a less severe neonatal abstinence syndrome than methadone, but there is still a role for methadone in the treatment of opioid dependence during pregnancy.

Aims The Maternal Opioid Treatment: Human Experimental Research (MOTHER) project, an eight-site randomized, double-blind, double-dummy, flexible-dosing, parallel-group clinical trial is described. This study is the most current – and single most comprehensive – research effort to investigate the safety and efficacy of maternal and prenatal exposure to methadone and buprenorphine. Methods The MOTHER study design is outlined, and its basic features are presented. Conclusions At least seven important lessons have been learned from the MOTHER study: (1) an interdisciplinary focus improves the design and methods of a randomized clinical trial; (2) multiple sites in a clinical trial present continuing challenges to the investigative team due to variations in recruitment goals, patient populations, and hospital practices that in turn differentially impact recruitment rates, treatment compliance, and attrition; (3) study design and protocols must be flexible in order to meet the unforeseen demands of both research and clinical management; (4) staff turnover needs to be addressed with a proactive focus on both hiring and training; (5) the implementation of a protocol for the treatment of a particular disorder may identify important ancillary clinical issues worthy of investigation; (6) timely tracking of data in a multi-site trial is both demanding and unforgiving; and, (7) complex multi-site trials pose unanticipated challenges that complicate the choice of statistical methods, thereby placing added demands on investigators to effectively communicate their results.

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 n = 131 infants born to opioid dependent mothers, 129 of which 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 53% of the sample (68 infants) required treatment for NAS. Lower maternal weight at delivery, later estimated gestational age (EGA), maternal use of selective serotonin reuptake inhibitors (SSRIs), vaginal delivery, and higher infant birth weight predicted higher peak NAS scores. Higher infant birth weight 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 birth weight, 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.

cians can impress upon their local health systems the importance of this issue, which should lead to changes in messaging to patients themselves. The use of social media on the internet should not be undervalued in these efforts as well. Finally, all women with gestational diabetes mellitus and T1 and T2 diabetes deserve careful follow-up after a first pregnancy, preparing for a second pregnancy. These women are likely to understand the importance of tight prepregnancy control and will benefit from programs designed to keep them up-to-date and educated regarding the current standards.As we face an increasing epidemic of T2 diabetes, there will be even more pregnant women with this disease. We must draw upon the resources of the entire health care system to ensure these women are in tight control and on the correct medications before pregnancy. In doing so, we are likely to not only improve health outcomes, but also to lower the high health care costs from complications of pregnancy.-ABC) ABSTRACTThe recommended treatment for opioid dependence in pregnant women is methadone, a full mu-opioid agonist. However, in utero exposure to methadone is associated with neonatal abstinence syndrome (NAS) that is characterized by hyperirritability of the central nervous system and a dysfunctional autonomic nervous system. Management of NAS often requires prolonged hospitalization and pharmacologic intervention. A partial mu-opioid agonist, buprenorphine, has been investigated as an alternative treatment for opioid dependence but relatively few studies of this drug have been conducted in pregnant women. Some prospective open-label and controlled studies suggest that NAS occurring in neonates treated prenatally with buprenorphine was less likely to require treatment than NAS in neonates exposed to prenatal methadone. However, the results of these studies have been inconsistent.This double-blind, randomized, controlled study compared the use of buprenorphine and methadone for management of pregnant women with opioid dependency. The study subjects were 175 pregnant opioid-dependent women enrolled at 8 international sites. A total of 131 of these women completed the trial; 58 (44%) were patients receiving buprenorphine and 73 (56%) were women treated with methadone. The 5 primary neonatal outcomes included the number of neonates requiring treatment for NAS, the peak NAS score, the total amount of morphine needed to treat NAS, length of hospital stay, and head circumference. The P values for all group comparisons were calculated according to prespecified thresholds for significance. Neonatal Complications 191

The interaction of psychiatric symptoms with drug dependence during pregnancy is not well understood. This study examines the relationship of psychiatric symptoms to severity of drug use and drug related problems among participants in a clinical trial of pharmacologic treatment of opioid dependence during pregnancy (N=174). 64.6% reported additional psychiatric symptoms (48.6% mood symptoms, 40.0% anxiety symptoms, and 12.6% suicidal thinking). Women who endorsed co-occurring psychiatric symptoms showed more severe impairment on the Addiction Severity Index (ASI). Further investigation is warranted to understand the effect of psychiatric symptoms on long-term maternal and neonatal outcomes.