consultants on the reviews of the harm of substance use in pregnancy and breastfeeding); Margaret Harris (consultant in WHO guideline methodology, who prepared the guideline document and advised at the GDG meeting in Geneva); Keryn Murphy (who wrote the meeting report of the meeting in Washington DC); Nandi Siegfried (WHO consultant on systematic review, GRADE and WHO guideline methodology, and advisor at the GDG meeting in Washington DC, who conducted the reviews and prepared the GRADE tables on the effectiveness of interventions for substance use disorders).# Objectives and scope of these guidelines
Use of alcohol, illicit drugs and other psychoactive substances during pregnancy is common and can lead to multiple health and social problems for both mother and child.
Use of alcohol during pregnancy can lead to fetal alcohol syndrome and other harms such as spontaneous abortion, stillbirth, low birthweight, prematurity and birth defects. Use of alcohol and other drugs can also severely impair an individual's functioning as a parent, spouse or partner, and trigger gender-based and domestic violence, thus significantly affecting the physical, mental and emotional development of children. Injecting drug use is also associated with an increased risk of transmission of HIV and viral hepatitis to pregnant women and their infants.
Alcohol and other substance use by expectant mothers and other people living in their households is not only detrimental to maternal and child health -the topics of UN Millennium Development Goals 2, 4, 5 and 6 -but can also undermine the social and health gains achieved in many low-and middle-income countries.
Pregnancy may be an opportunity for women, their partners and other people living in their household to change their patterns of alcohol and other substance use. Health workers providing care for women with substance use disorders during pregnancy need to understand the complexity of the woman's social, mental and physical problems and to provide the right advice and support throughout pregnancy and the postpartum period.

# WHY THESE GUIDELINES WERE DEVELOPED
These guidelines have been developed to enable professionals to assist pregnant women who use alcohol or drugs or with substance use disorders to achieve healthy outcomes. There are currently no global guidelines providing evidence-based recommendations for identifying and managing substance use and substance use disorders in pregnancy. While several high-income countries have developed national guidelines covering these issues, low-and middle-income countries currently lack such guidance.
The project was initiated in response to requests from organizations, institutions and individuals for technical guidance on the identification and management of alcohol and other substance use disorders in pregnant women. These recommendations have been developed in tandem with the WHO recommendations for the prevention and management of tobacco use and second-hand smoke exposure in pregnancy. Development of these guidelines is part of a range of activities carried out by the WHO Department of Mental Health and Substance Abuse (MSD). These include the development and dissemination of the ASSIST tool for screening for substance use in health-care settings; the ASSIST-linked brief intervention manual; the WHO mhGAP intervention package for management of priority mental health and behavioural disorders; the WHO guidelines for the psychosocially assisted pharmacological treatment of opioid dependence; the UNODC/WHO discussion paper on the principles of drug dependence treatment; and the UNODC/WHO programme on drug dependence treatment and care.

# WHO SHOULD USE THESE GUIDELINES
These guidelines have been primarily written for health-care providers managing women from conception to birth and the postnatal period, and their infants.

# OBJECTIVES AND SCOPE OF THE DOCUMENT
These guidelines aim to provide evidence-based technical advice to health-care providers on identifying and managing substance use in pregnant women, which enables users to apply the scientific principles of a public health approach in their own countries. An equally important objective is to enable pregnant women to make healthy decisions about alcohol and other substance use in the context of pregnancy, breastfeeding and the postnatal period.
After a broad search of the needs of this population and challenges faced by health-care providers working with pregnant women with substance use disorders, it was agreed by the Guideline Development Group (GDG) that these guidelines should focus on six areas:
- screening and brief intervention 2. psychosocial interventions 3. detoxification 4. dependence management 5. infant feeding 6. management of neonatal withdrawal.

# INDIVIDUALS AND PARTNERS INVOLVED IN DEVELOPMENT OF THE GUIDELINES

# WHO steering group
An internal steering group was drawn from the WHO departments of Mental Health and Substance Abuse, Reproductive Health and Research, Gender Equity and Human Rights, and the Tobacco Free Initiative. The full list of names is provided in Annex 4.

# Guideline Development Group
The Guideline Development Group was made up of people with content expertise, relevant experience in health care in low-and middle-income countries and expertise in evidence-based guideline methodology. The Guideline Development Group selection also ensured gender balance and regional diversity. Members have been drawn from all WHO regions.
Consultants with expertise in evidence search and GRADE methodology supported the Guideline Development Group. The full list of the Guideline Development Group members and consultants along with their expertise, affiliations and geographical base is provided in Annex 4.

# External review group
External reviewers were drawn from end-users, agencies and partners working in the subject area of the guidelines. Their names, affiliations, areas of interest and geographical base are given in Annex 4.
External reviewers were asked to evaluate and comment at different stages of development of the guidelines. Some members of the external review group attended the initial scoping meeting and the final recommendation decision meeting as 'special invitees' where they acted as observers providing comments but had no involvement in decision-making. They reviewed the scoping questions, outcomes of interest, evidence profiles, and the final guideline document. Reviewer response was compiled and comments used to refine the scope of the guidelines, the outcomes of interest, and the final recommendations.

# Management of conflicts of interest
All Guideline Development Group members, external reviewers and consultants completed the WHO declaration of interest forms. Several Guideline Development Group members declared academic and financial interests. These were then reviewed by the secretariat for potential conflicts of interest (see summary in Annex 5). Hendree Jones had received funding from Reckitt Benckiser, a manufacturer of buprenorphine. She received small honoraria for presenting at conferences, and received free buprenorphine for use in her clinical trials. Gabriele Fischer received a small amount of consultancy funding from Reckitt Benckiser, a manufacturer of buprenorphine, Mundipharma, a manufacturer of morphine, and Lannacher, a manufacturer of psychiatric medication. Anju Dhawan had received funding for a clinical trial from Rusan Pharmaceuticals, a manufacturer of both methadone and buprenorphine. As these members are well-recognized researchers and clinicians in this field and, taking into consideration the level of funding, it was agreed that they should not be excluded from the GDG but that these potential competing interests should be managed by excluding them from active discussion and decision-making related to the pharmaceuticals produced by companies from which they had received funds. Both meetings began with an open declaration of interests. It was made clear that those Guideline Development Group members with pharmaceutical industry funding could not participate in discussions on questions related to the medications associated with such companies.

# HOW THE GUIDELINES WERE DEVELOPED
The development of these guidelines began in mid 2012 as a collaborative effort between the WHO departments of Mental Health and Substance Abuse and the Tobacco Free Initiative with production of the guidelines proposal, a virtual meeting of the Guideline Development Group (GDG), and subsequent approval of the guidelines proposal by the WHO Guideline Review Committee. The GDG has conferred through teleconferences and virtual meetings, as well as at two face-to-face meetings. At the first meeting, held at the WHO offices in Washington DC, USA (29 January to 1 February 2013), the evidence for the harms of different patterns of alcohol and drug use in pregnancy was reviewed, and the scope and areas of evidence retrieval were established. At the second and final meeting, held at the WHO headquarters in Geneva, Switzerland (11-13 September 2013), the evidence retrieved was presented using evidence profiles and GRADE tables (see annex), and final recommendations were formulated. These were then reviewed by the external review group and finalized by the GDG using online discussions and a final teleconference.

# EVIDENCE SEARCH AND RETRIEVAL
The six focus areas agreed upon by the GDG were used to generate appropriate evidence questions to govern systematic searches for evidence. In April 2013, the GDG were asked to select and rate outcomes on a scale from 1 to 9, where 9 is most important (critical) and 1 is least important. Means were calculated for each outcome and the top seven outcomes used for the evidence review, except where the GDG agreed that more than seven outcomes were necessary (see evidence profiles and GRADE tables in Annex 1).
Four investigators (two consultants, two WHO interns) managed the evidence retrieval. The database search was conducted by Tomas Allen, WHO information specialist, who searched multiple databases: PubMed, EmBase, CENTRAL, Psychinfo, CINAHL (see Annex 2 for details of MeSH terms, etc). Essentially, the search strategy was to identify all randomized controlled trials (RCTs) and systematic reviews conducted in pregnant women using alcohol or drugs, and then to allocate these to the different areas of evidence retrieval. The search identified approximately 6000 articles, which were screened on the basis of title and abstract, then on the full paper (see Figure 1, and Tables 1 & 2, below). Where a recent Cochrane review or other high-quality systematic review was identified, this was used as the evidence base and results presented in GRADE tables.
Where a Cochrane review or equivalent was not available, RCTs were identified and a systematic review
SCREENED 5632 conducted using Cochrane methods, including meta-analysis, where appropriate, to generate results that were then evaluated using GRADE.
To supplement gaps in the RCT literature, the other studies identified in the systematic literature search were also allocated to each area of evidence retrieval used to provide supplementary information in the GRADE profiles. There were 598 such articles that were not RCTs but still considered relevant to the key issues covered by the guidelines.
A values and preferences survey was conducted over three weeks in August 2013. Respondents -many of them health-care workers or pregnant (or recently pregnant) women -were asked to rate their preference for each draft recommendation and to provide comments on how it might affect them. At the final face-to-face guideline development group meeting, held in September 2013, an analysis of the responses was presented during discussion of each recommendation. These results were used by the GDG to weigh values and preferences when setting the strength of each recommendation. The form can be accessed at: . enketo.formhub.org/webform

# EVIDENCE TO RECOMMENDATIONS
The GRADE system for assessing quality of evidence and using evidence to inform decisions was applied by the GDG when drafting the final recommendations. For each of the six areas of scoping focus, an evidence profile was provided summarizing the evidence retrieved, including evidence on values, preferences, benefits, harms and feasibility. Wherever possible, the evidence retrieved was evaluated using GRADE and GRADE tables were provided. Evidence of effectiveness was rated as high, moderate, low or very low depending on the certainty of effect measured in the studies evaluated. For many of the EVIDENCE questions the evidence was either lacking or very limited, leading to a rating of very low quality evidence.
The GDG recognized that extensive research needs to be done to provide a solid evidence base for management of pregnant women with substance use and substance use disorders. A decision table was used by the Guideline Development Group to assess and agree on the quality of evidence and certainty about harms and benefits, values and preferences, feasibility and resource implications (see annex for details of each decision, presented in Evidence Profiles 1-6).
The strength of the recommendation was set as either:
'strong': meaning that the Guideline Development Group was confident that the quality of the evidence of effect, combined with certainty about the values, preferences, benefits and feasibility, made this a recommendation that should be done in most circumstances and settings;
-r 'conditional': meaning there was less certainty about the quality of the evidence and values, preferences, benefits and feasibility of this recommendation. Thus, there may be circumstances or settings in which it should not apply.
Decisions were usually made by consensus but where there was disagreement, the GDG members voted and a two-thirds majority was required for a decision to be carried. Where a two-thirds majority was not achieved initially, it was agreed that the recommendation should be reworded and a vote taken again. This was necessary in only one instance -for recommendation 8, concerning management of stimulant withdrawal.
Following an extensive review of the evidence in each of the six scoping areas, the GDG agreed on the following recommendations for the identification and management of substance use and substance use disorders during pregnancy. Each recommendation is followed by remarks clarifying contextual issues and relevant aspects of management. During development of the recommendations, the GDG identified considerable research gaps and agreed on a list of research priorities and questions, which are listed after the recommendations.
prevention strategies and supports healthy choices about substance use among women of childbearing age, and health promotion efforts encouraging a healthy home and social environment, supporting pregnant women and their partners in making healthy choices about their substance use and protecting from pressures to drink alcohol or use drugs.

# II. Ensuring access to prevention and treatment services.
All pregnant women and their families affected by substance use disorders should have access to affordable prevention and treatment services and interventions delivered with a special attention to confidentiality, national legislation and international human rights standards; women should not be excluded from accessing health care because of their substance use.
Health-care services should be able to identify and manage substance use and substance use disorders in pregnancy. Substance use disorders should be identified by the health-care system at the earliest opportunity and quality, affordable and accessible treatment offered. Specialized services for women with substance use disorders should be recognized as an important component of the health system and need to be available proportional to the clinical need. Health-care services for women with substance use disorders should take into consideration the childcare needs of women when considering the accessibility of their services. Confidentiality, a fundamental right of every health-care user, is also affected by the organization of services.
III. Respecting patient autonomy. The autonomy of pregnant and breastfeeding women should always be respected; women with substance use disorders need to be fully informed about the risks and benefits, for themselves and for their fetuses or infants, of available treatment options, when making decisions about their health care.
Patient autonomy and patient-centred care are crucial components of health-care services for pregnant women.
Treatment decisions should be based on accepted principles of medical-care ethics, respecting a women's autonomy in decisions related to her care and the health of her fetus, and her right to privacy and confidentiality when discussing treatment options. It is essential to provide clear, accurate and consistent information to pregnant and breastfeeding women about the risks of alcohol and drug use, and all women with substance use disorders should have access to information about effective contraception.
IV. Providing comprehensive care. Services for pregnant and breastfeeding women with substance use disorders should have a level of comprehensiveness that matches the complexity and multifaceted nature of substance use disorders and their antecedents.
Comprehensive services for pregnant and breastfeeding women include a range of gender-sensitive prevention and treatment interventions that can respond to multiple needs, including childcare needs, comorbid mental and concurrent medical conditions, bloodborne and other infectious diseases, poor diet and psychosocial problems such as relationships with a partner/other people living in the same household, homelessness, poverty and violence. Comprehensive services that offer a continuity of care are generally much easier for vulnerable groups to access.
V. Safeguarding against discrimination and stigmatization. Prevention and treatment interventions should be provided to pregnant and breastfeeding women in ways that prevent stigmatization, discrimination, marginalization, and promote family, community and social support as well as social inclusion by fostering strong links with available childcare, employment, education, housing and other relevant services.
Health-care providers should seek to establish a clinician-patient relationship without discrimination or stigmatization. All important information about the risks of substance use and the benefits of treatment should be communicated in a non-judgemental, respectful, non-stigmatizing and empathic manner, sensitive to age, culture and language differences. All important information has to be provided verbally, as well as in writing, at reading and comprehension levels that are congruent with the patient's level of literacy. Health-care providers should respond to disclosure of private and distressing information (e.g. gender-based violence or self-harm) with sensitivity.
Screening and brief interventions for hazardous and harmful substance use during pregnancy (Evidence Profile 1: see Annex 1, page 22)
Much of the evidence underlying the effectiveness of screening and brief interventions during pregnancy comes from a period when reporting standards and measures of bias were not in standard use, hence the evidence quality is graded as low or very low. However, the evidence retrieved indicated that being asked about alcohol and other substance use in a detailed and comprehensive manner may increase a woman's awareness of the risks associated with alcohol and drug use and may function to modify her behaviour.
A brief motivational intervention has been found to reduce the number of drinks and the number of heavy drinking days during the postpartum period. Pregnant women with higher levels of alcohol use may reduce their alcohol use following a brief intervention that includes their partner.
Pregnant adolescent girls with a substance use disorder have been shown to reduce their substance use after a single-session, standardized brief intervention. Full details of studies evaluated, harms and benefits, feasibility and resource use are provided in Annex 1, page 22.

# RECOMMENDATION 
Health-care providers should ask all pregnant women about their use of alcohol and other substances (past and present) as early as possible in the pregnancy and at every antenatal visit.

# Strength of recommendation: Strong
Quality of evidence: Low
- Asking at every visit is important as some women are more likely to report sensitive information only after a trusting relationship has been solidly established. - Pregnant women should be advised of the potential health risks to themselves and to their babies posed by alcohol and drug use. - Validated screening instruments for alcohol and other substance use and use disorders are available (see Annex 3).
- Health-care providers should be prepared to intervene or refer all pregnant women who are identified as using alcohol and/or drugs (past and present). - It was decided that despite the low quality of evidence of effect, the benefit -potential reduction of alcohol and substance use -outweighed any potential harms of a brief psychosocial intervention, which were considered minimal. Therefore the balance of benefits versus harms was clearly positive despite uncertainty about the degree of benefit. In addition, the burden of implementation was minimal.

# RECOMMENDATION 2
Health-care providers should offer a brief intervention to all pregnant women using alcohol or drugs.

# Strength of recommendation: Strong
Quality of evidence: Low
- Brief intervention is a structured therapy of short duration (typically 5-30 minutes) offered with the aim of assisting an individual to cease or reduce the use of a psychoactive substance. It is designed in particular for general practitioners and other primary health-care workers. - Health-care providers should be given appropriate training and resource materials.
- The brief intervention should be individualized, and include feedback and advice on ceasing or reducing alcohol and other substance use during pregnancy. There may need to be follow-up with the patient, with the possibility of referral to treatment for those patients who are unable to reduce or eliminate such use. - The approach/attitude of health-care providers is an important contributor to the effectiveness of brief interventions.
- As for recommendation 1, it was decided that, despite the low quality of evidence of effectiveness, this should be a strong recommendation because the potential benefit -reduction of alcohol and/other substance use -likely outweighs any potential harms of a brief psychosocial intervention which were considered minimal. Therefore the balance of benefits versus harms was clearly positive, although there was uncertainty about the degree of benefit. In addition the burden of implementation was minimal.
Psychosocial interventions for substance use disorders in pregnancy (Evidence Profile 2: see Annex 1, page 44)
The concept of "substance use disorders" includes dependence syndrome and harmful use of psychoactive substances such as alcohol, cannabis, amphetamine-type stimulants (ATS), cocaine, opioids and benzodiazepines. The evidence review sought trials evaluating the effectiveness of psychosocial interventions, including trials of cognitive behavioural therapy (CBT), motivational interviewing (MI), contingency management (CM), and home visits. All the trials were conducted in services specializing in the management of substance use in pregnancy. "Treatment-as-usual" in this context is best considered a form of unstructured psychosocial intervention rather than the absence of psychosocial support.
- Findings suggest that CBT may be superior to treatment-as-usual in terms of treatment retention, reductions in risky sex and needle use, and occurrence of preterm birth. o Findings support the superiority of contingency management (CM) to treatment-as-usual in terms of retention in treatment, percentage of negative urines, and weeks of continuous cocaine abstinence. o Findings do not support the superiority of MI to treatment-as-usual or educational control, with similar results for maternal retention in treatment and maternal substance abuse. o A review of randomized trials suggests that increased home visits following delivery are not effective in reducing maternal substance use, or alcohol use, nor in improving adherence to treatment of substance use disorders.

# RECOMMENDATION 3
Health-care providers managing pregnant or postpartum women with alcohol or other substance use disorders should offer comprehensive assessment and individualized care.

# Strength of recommendation: Conditional
Quality of evidence: Very low
- A comprehensive assessment of women using alcohol or drugs in pregnancy and the postpartum period includes an assessment of patterns of substance use, medical or psychiatric comorbidity, family context, as well as social problems. - Individualized care involves selecting appropriate psychosocial interventions of different intensity based on the particular needs of the pregnant women and the resources available. Psychosocial interventions include a number of psychological treatments and social supports, ranging from lesser to higher intensity. The psychosocial treatment and support referred to in this section is a more intensive set of interventions typically delivered by people with specific training in the management of substance use disorders, and usually includes repeated contact with the patient. The kinds of specific psychological techniques considered in this category include cognitive behavioural therapy, contingency management and motivational interviewing/enhancement. The kinds of social support referred to in this section include assistance with accommodation, vocational training, parenting training, life-skills training, legal advice, home-visiting and outreach. - Despite the benefits of psychosocial treatment outweighing the harms, this recommendation was considered to be conditional given the absence of strong evidence and the potential resource implications.
Detoxification or quitting programmes for alcohol and other substance dependence in pregnancy (Evidence Profile 3: see Annex 1, page 93)
A withdrawal syndrome requiring pharmacological treatment in pregnancy can be said to occur for three substances: benzodiazepines, alcohol, and opioids. The withdrawal syndrome associated with the cessation of other substances (such as psychostimulants) has not been considered to justify the use of psychotropic medication. For those pregnant women for whom medication-assisted withdrawal is successful, there does not appear to be any evidence of significant fetal distress during detoxification, no increased risk of fetal demise or premature delivery.
For opioid dependence, in addition to recommending cessation of opioid use, there is the option of prescribing long-acting opioids such as methadone and buprenorphine to maintain stable opioid levels (see also Evidence Profile 4 in Annex 1). Although this treatment approach includes a risk of neonatal opioid withdrawal symptoms, opioids are essentially non-toxic at stable levels. Cessation of opioids, on the other hand carries a higher risk of relapse to unstable patterns of short-acting opioid use (such as heroin). The decision, therefore, is between opioid maintenance treatment approach with a known risk of neonatal withdrawal but a low risk of relapse, and opioid detoxification, which, if successful, carries no risk of neonatal withdrawal, but, if unsuccessful, has a high risk of adverse neonatal outcomes, including neonatal opioid withdrawal and intrauterine growth retardation (IUGR) and also adverse maternal outcomes such as overdose.
For dependence on other substances, there was considered to be no feasible maintenance treatment option.

# RECOMMENDATION 4
Health-care providers should, at the earliest opportunity, advise pregnant women dependent on alcohol or drugs to cease their alcohol or drug use and offer, or refer to, detoxification services under medical supervision where necessary and applicable.

# Strength of recommendation: Strong
Quality of evidence: Very low
- Pregnant women dependent on alcohol or drugs who agree to undergo detoxification should be offered the supported withdrawal from substance use in an inpatient or hospital facility, if medically indicated. - Detoxification can be undertaken at any stage in pregnancy, but at no stage should antagonists (such as naloxone, or naltrexone -in the case of opioid withdrawal) be used to accelerate the detoxification process. - Equal attention should be paid to the health of mother and fetus during detoxification and treatment adjusted accordingly. - The exceptions to this recommendation are opioid and benzodiazepine dependence, which are covered by recommendations 5 and 6 separately. - It was decided that this recommendation should be strong, despite the very low quality of evidence of the effectiveness of the health-care intervention because there is clear evidence of harm to the fetus of ongoing maternal substance use, and the benefit to both mother and fetus of ceasing alcohol and/or substance use under medical supervision strongly outweighs any potential harms.

# RECOMMENDATION 5
Pregnant women dependent on opioids should be encouraged to use opioid maintenance treatment whenever available rather than to attempt opioid detoxification.

# Strength of recommendation: Strong
Quality of evidence: Very low
- Opioid maintenance treatment in this context refers to either methadone maintenance treatment or buprenorphine maintenance treatment. - Pregnant patients with opioid dependence who wish to undergo detoxification should be advised that relapse to opioid use is more likely following medication-assisted withdrawal than while undertaking opioid maintenance treatment. - Such medication-assisted withdrawal from opioids should be attempted only in an inpatient unit, using a gradual reduction in methadone or buprenorphine doses. Inpatient care should also be considered for the initiation and optimization of maintenance treatment. - Psychosocial treatment should be an integral component of such treatment.
- Pregnant women who fail to complete medication-assisted withdrawal should be offered opioid agonist pharmacotherapy. - It was decided that this recommendation should be strong despite the low quality of evidence of effectiveness from randomized controlled trials, as the rate of relapse to opioid use following detoxification has been shown to be high and the risks of harm to both mother and fetus from failed detoxification are catastrophic compared to the very low risks of harm from opioid maintenance treatment.

# RECOMMENDATION 6
Pregnant women with benzodiazepine dependence should undergo a gradual dose reduction, using long-acting benzodiazepines.

# Strength of recommendation: Strong
Quality of evidence: Very low
- Long-acting benzodiazepines should only be used for as short a time as is medically feasible in managing benzodiazepine withdrawal. - Psychosocial interventions should be offered throughout the period of benzodiazepine withdrawal.
- Inpatient care should be considered in the withdrawal management of pregnant women with benzodiazepine dependence. - It was decided that this recommendation should be strong despite the very low quality of evidence of effectiveness because ongoing benzodiazepine use in pregnancy is associated with significant risk of harm. At the same time, abrupt cessation of benzodiazepines can result in a severe withdrawal syndrome including seizures and psychosis. This leaves gradual reduction as the only practicable alternative. Significant clinical experience indicates that this approach is feasible and safe. Hence the GDG was in agreement that the benefits of gradual dose reduction outweigh the harms of both ongoing use and abrupt cessation.

# RECOMMENDATION 7
Pregnant women who develop withdrawal symptoms following the cessation of alcohol consumption should be managed with the short-term use of a long-acting benzodiazepine.

# Strength of recommendation: Strong

# Quality of evidence: Very low
- Management of alcohol withdrawal usually also includes administration of thiamine.
- Alcohol withdrawal management may be facilitated by the use of an alcohol-withdrawal scale such as the CIWA-Ar.
- Inpatient care should be considered in the withdrawal management of pregnant women with alcohol dependence.
- Alcohol withdrawal can be a severe and even life-threatening condition, provoking seizures and delirium. Evidence from non-pregnant populations has demonstrated the effectiveness of long-acting benzodiazepines for preventing seizures and delirium in alcohol withdrawal. Given the severity of alcohol withdrawal, and the lack of significant harm from short-term benzodiazepine use, and the evidence supporting the use of benzodiazepines in the management of alcohol withdrawal in the general population, the GDG decided that this recommendation should be strong despite the low quality of evidence in pregnant women.

# RECOMMENDATION 8
In withdrawal management for pregnant women with stimulant dependence, psychopharmacological medications may be useful to assist with symptoms of psychiatric disorders but are not routinely required.

# Strength of recommendation: Strong
Quality of evidence: Very low
- Except for the management of acute intoxication, withdrawal management in amphetamine-type stimulants (ATS) dependence or cocaine dependence does not include psychopharmacological medications as a primary approach to treatment in pregnant patients. There is no evidence that medication-assisted withdrawal would benefit pregnant women with these respective disorders. - Inpatient care should be considered in the withdrawal management of pregnant women with stimulant dependence.
- It was decided that this recommendation should be strong despite the very low quality of evidence because the harms to mother and fetus of ongoing use of psychostimulants have been shown to be high. The risks of providing short-term appropriate non-teratogenic medications for short-term management of psychologically distressing symptoms in pregnancy are very low. Therefore, the potential benefits of this approach strongly outweigh the harms of providing psychopharmacological treatment of symptoms, if required, during psychostimulant withdrawal.
Pharmacological treatment (maintenance and relapse prevention) for alcohol and other substance dependence in pregnancy (Evidence Profile 4: see Annex 1, page 100)
Systematic reviews of psychopharmacological treatments, methadone versus buprenorphine and methadone compared to slow-release morphine for pregnant women with substance use disorders were performed and the evidence of effect evaluated (see GRADE tables and summary of findings tables in Annex 1 for full details). Findings in brief: o Pharmacotherapy has been shown to be successful in the treatment of opioid dependence and benzodiazepine dependence. Methadone and buprenorphine have similar efficacy in the management of opioid dependence. While methadone may result in better maternal retention in treatment, buprenorphine may result in milder NAS, less preterm delivery and higher birthweight. o Combining psychosocial interventions with pharmacotherapy has been shown to be superior to pharmacotherapy alone. o No evidence was found on the use of medications for relapse prevention for alcohol dependence in pregnancy (acamprosate, disulfiram, nalmefene, naltrexone). o No RCT evidence was found on the use of naltrexone in relapse prevention from opioid dependence in pregnancy. o No evidence was found on the use of benzodiazepine maintenance for benzodiazepine dependence in pregnancy.

# RECOMMENDATION 9
Pharmacotherapy is not recommended for routine treatment of dependence on amphetamine-type stimulants, cannabis, cocaine or volatile agents in pregnant patients.

# Strength of recommendation: Conditional
Quality of evidence: Very low
- For pregnant patients who use cannabis, amphetamine-type stimulants, cocaine, and volatile agents, the focus of treatment should be on psychosocial interventions. - The recommendation was considered conditional given the complete lack of research on this issue.

# RECOMMENDATION 
Given that the safety and efficacy of medications for the treatment of alcohol dependence has not been established in pregnancy, an individual risk benefit analysis should be conducted for each woman.

# Strength of recommendation: Conditional
Quality of evidence: Very low
- Pregnant patients with alcohol dependence should be offered psychosocial interventions.
- The recommendation was considered conditional given the complete lack of research on this issue.

# RECOMMENDATION 
Pregnant patients with opioid dependence should be advised to continue or commence opioid maintenance therapy with either methadone or buprenorphine.

# Strength of recommendation: Strong
Quality of evidence: Very low
- Pregnant patients with opioid dependence should be encouraged to commence opioid agonist pharmacotherapy, which should be combined with psychosocial interventions. - Opioid-dependent pregnant women who are already taking opioid maintenance therapy with methadone should not be advised to switch to buprenorphine due to the risk of opioid withdrawal. Pregnant opioid-dependent women taking buprenorphine should not be advised to switch to methadone unless they are not responding well to their current treatment. - In opioid-dependent pregnant women, the buprenorphine mono formulation should be used in preference to the buprenorphine/naloxone formulation. - Regardless of the choice of medication, psychosocial interventions should be an integral component of treatment.
- Opioid-dependent pregnant patients who wish to receive opioid antagonist pharmacotherapy should be discouraged from such a choice. - It was decided that this recommendation should be strong despite the low quality of evidence as the rate of relapse to opioid use following detoxification is high and the risks of harm from failed detoxification are catastrophic compared to the small risks of harm from opioid maintenance treatment.
Breastfeeding and maternal substance use (Evidence Profile 5: see Annex 1, page 122)
Enhanced maternal-infant attachment through breastfeeding is especially important, particularly for women feeling guilty about their prenatal substance use and those who lack self-confidence in parenting skills. Breastfeeding and/or breast milk may reduce the incidence and/or severity of neonatal withdrawal syndrome in opioid-exposed infants.
Evidence of decreased stress response and increased vagal tone, indicating better autonomic regulation, in lactating compared to non-lactating women is salient for drug-dependent women. Stress can be a major factor in the development of psychiatric symptoms, and has been linked to relapse to substance use. Alcohol use, binge drinking, tobacco and cannabis use rates rebound substantially in the postpartum period compared with use during pregnancy. Depression correlates with substance use, and new mothers with postpartum depression may be at high risk for substance use or return to substance use. Maternal psychopathology is more common in substance-dependent women than in the general population, and is not infrequently related to poor judgment, enhancing the physical risk to the breastfed infant. Maternal somnolence, lack of adequate sleep-wake cycling, or decreased reaction times due to alcohol or drug use may increase the risk of infant injury injury, including smothering the child by falling asleep while breastfeeding.

# RECOMMENDATION 
A. Mothers with substance use disorders should be encouraged to breastfeed unless the risks clearly outweigh the benefits. B. Breastfeeding women using alcohol or drugs should be advised and supported to cease alcohol or drug use; however, substance use is not necessarily a contraindication to breastfeeding.

# Strength of recommendation: Conditional

# Quality of evidence: Low
- A risk assessment should take into account the risks of exposure to alcohol and drugs in breast milk, HIV status, the specific pattern of substance use in each case, the availability of safe and affordable breast milk substitutes, as well as access to clean water, sterilizing equipment, and the age of the infant/child. Heavy daily alcohol consumption, such as in alcohol dependence, would constitute high risk to the infant, for example, and in the presence of safe breast milk alternatives, it would be preferable not to breastfeed. - The message to breastfeeding women who have used alcohol and drugs to cease using alcohol and drugs while breastfeeding should be given in such a way that it does not undermine the potential benefits of breastfeeding. - It is possible to reduce the risk of exposure through breastfeeding by altering the timing of breastfeeding, or by the use of temporary alternatives, such as stored (frozen) breast milk or breast milk substitutes where they are available and can be safely used. Women who use alcohol intermittently should be discouraged from breastfeeding for 2 hours after consuming one standard drink (10 g of pure alcohol), and 4-8 hours after consuming more than one drink in a single occasion. Breastfeeding advice for women with HIV should also take into consideration the risk of HIV transmission (refer to the WHO guidelines on breastfeeding and HIV). - Mothers of infants with a neonatal withdrawal syndrome should be offered appropriate breastfeeding information and support. - This recommendation was considered conditional because the different values and preferences of women and the lack of strong evidence of harms of low levels of substance use in pregnancy.

# RECOMMENDATION 
Skin-to-skin contact is important regardless of feeding choice and needs to be actively encouraged for a mother with a substance use disorder who is able to respond to her baby's needs.

# Strength of recommendation: Strong

# Quality of evidence: Low
- It was decided that the recommendation should be strong despite the very low quality evidence as the risk of harm is minimal, it consumes no resources, the values and preferences were in favour of the recommendation, and there was considered to be certainty about the balance between benefits and harms.

# RECOMMENDATION 
Mothers who are stable on opioid maintenance treatment with either methadone or buprenorphine should be encouraged to breastfeed unless the risks clearly outweigh the benefits.

# Strength of recommendation: Strong

# Quality of evidence: Low
- Women prescribed opioids such as methadone and buprenorphine and wishing to stop breastfeeding may wean their children off breast milk gradually to reduce the risk of developing withdrawal symptoms. - It was decided that the recommendation should be strong, as, despite the low quality of evidence of effect, it was considered highly likely that the benefit of avoiding withdrawal symptoms in the infant strongly outweighed any potential harms. The values and preferences expressed by end-users surveyed were strongly in favour of the recommendation and there was certainty about the balance between benefits and resources being consumed.
Management of infants exposed to alcohol and other psychoactive substances (Evidence Profile 6: see Annex 1, page 135)
Note: The term "neonatal withdrawal syndrome" is used here to remain consistent with WHO nomenclature, but the term "neonatal abstinence syndrome (NAS)" is commonly used with the same meaning.
The small study size and risk of bias in the studies evaluated mean that the evidence of treatment effectiveness is very uncertain. Protocols for the management of neonatal withdrawal syndrome have changed considerably over the last 40+ years. Initial treatment guidelines were weight-based, and tables for treatment with phenobarbital and paregoric were published. Current treatment involves use of an opioid such as morphine sulfate or tincture of opium, or a sedative, typically phenobarbital, with infrequent use of a benzodiazepine. Systems for scoring withdrawal are usually used to guide treatment initiation, maintenance and weaning.
Because there is neither a uniform assessment method for measuring neonatal withdrawal nor an established treatment protocol, and health-care practices worldwide are variable, it is difficult to state with any precision how neonatal withdrawal is treated across the globe.

# RECOMMENDATION 
Health-care facilities providing obstetric care should have a protocol in place for identifying, assessing, monitoring and intervening, using non-pharmacological and pharmacological methods, for neonates prenatally exposed to opioids.

# Strength of recommendation: Strong

# Quality of evidence: Low
- Evidence of a dose-response relationship between opioid maintenance treatment and neonatal withdrawal syndrome has been inconsistent, which implies that all infants should be assessed. - Infants exposed to opioids during pregnancy should remain in the hospital at least 4-7 days following birth and be monitored for neonatal withdrawal symptoms using a validated assessment instrument, which should be first administered 2 hours after birth and then every 4 hours thereafter. - Non-pharmacological interventions including low lights, quiet environments, swaddling and skin-to-skin contact should be used with all neonates prenatally exposed to alcohol and drugs. - It was decided that the recommendation should be strong despite the low quality of evidence of effect, as the GDG agreed that the benefits of such an approach strongly outweighed any potential harms. The values and preferences of end-users were in favour of the recommendation, and there was certainty that while resources would be consumed, the benefits strongly outweighed costs. There was a high value placed on identifying preventable suffering in affected neonates.

# RECOMMENDATION 
An opioid should be used as initial treatment for an infant with neonatal opioid withdrawal syndrome if required.

# Strength of recommendation: Strong
Quality of evidence: Very low
- Prolonged treatment of neonatal opioid withdrawal syndrome with opioids is generally not necessary and aiming for shorter treatment is preferable. - Phenobarbital can be considered as an additional therapy if there has been concurrent use of other drugs in pregnancy, particularly benzodiazepines, and if symptoms of neonatal opioid withdrawal are not adequately suppressed by an opioid alone. If opioids are unavailable, phenobarbital can be used as an alternative therapy. - Infants with signs of a neonatal withdrawal syndrome in the absence of known maternal opioid use should be fully assessed for possible benzodiazepine, sedative or alcohol exposure. - The strong recommendation to use opioids rather than phenobarbital despite the very low quality of evidence of effectiveness was based on vast clinical experience with opioids in the management of both adult and neonatal opioid withdrawal. There has only been very limited clinical experience with phenobarbital use. In addition, the values and preferences of end-users were in favour of the recommendation, and the GDG agreed that there was certainty about the balance between benefits and resources being consumed.

# RECOMMENDATION 
If an infant has signs of a neonatal withdrawal syndrome due to withdrawal from sedatives or alcohol or the substance the infant was exposed to is unknown, then phenobarbital may be a preferable initial treatment option.

# Strength of recommendation: Conditional
Quality of evidence: Very low
- Infants with signs of a neonatal withdrawal syndrome in the absence of known maternal opioid use should be fully assessed for possible benzodiazepine, sedative, or alcohol exposure. - This recommendation was considered conditional because of the lack of high-quality evidence and the lack of certainty of the balance between benefits and harms.

# RECOMMENDATION 
All infants born to women with alcohol use disorders should be assessed for signs of fetal alcohol syndrome.

# Strength of recommendation: Conditional
Quality of evidence: Very low
- Signs of fetal alcohol syndrome (FAS) include growth impairment, dysmorphic facial features (short palpebral fissures, smooth or flattened philtrum, thin upper lip) and central nervous system abnormalities, including microcephaly.
- When assessing such infants the following information should be recorded:
-birthweight and length -head circumference -dysmorphic facial features -gestation -prenatal exposure to alcohol -follow-up of infants with signs of FAS should be provided - This recommendation was considered conditional because of the lack of high-quality evidence, and questions about the feasibility of implementation in all settings.

# RESEARCH PRIORITIES AND GAPS
The extensive search for evidence of effective interventions for managing alcohol and other substance disorders in pregnancy yielded useful baseline information but also highlighted considerable gaps in knowledge. The GDG identified priority areas and questions that need to be researched in order to increase certainty about what works most effectively when managing pregnant women with these disorders.

# General Remarks
The GDG calls upon the research community to: o improve descriptions of current clinical practices -including routine clinical outcome data; o agree on standardized outcomes; o perform observational studies on risks and benefits of pharmacotherapies in pregnancy; o conduct a global cohort study with standardized patient-centred outcome measurements and data repository; o conduct qualitative research on ethical issues; o encourage more research in low-income countries; o evaluate the benefits of comprehensive-care models (e.g. psychosocial, spiritual support, programmes for very young children affected by maternal substance use in utero); o provide better prevalence data on prescription opioid use.

# Exposure to different drugs and medications in utero
The GDG calls upon the research community to conduct further research on the impact of substance use upon: o maternal outcomes o fetal outcomes o neonatal outcomes o long-term outcomes for the exposed children.
A number of critical questions on the optimal use of specific interventions in pregnancy remain unanswered. Pharmacological treatment o a confidential case registry of pregnancies exposed to different substances, including psychotropic medications used for the treatment of substance use disorders in pregnancy, could help explore the potential risks and benefits of pharmacotherapy in substance use disorders in pregnancy. o further studies could explore the optimal method of treatment with methadone and buprenorphine in pregnancy (including further dose/response studies). o data on the safety of pharmacotherapy for alcohol dependence in pregnancy is lacking.
Breastfeeding o effects of breastfeeding and substance use on the neonate still need to be better understood. o how best to promote the initiation and continuation of breastfeeding in appropriate situations, such as in mothers receiving opioid maintenance treatment? o to what degree are different drugs and medications excreted in human milk? o what is the safety of breastfeeding while the mother is using different drugs and psychoactive medications? o what is the effect of breastfeeding on neonatal withdrawal for mothers receiving methadone or buprenorphine treatment.

# Birth and labour
- what is the optimal treatment during labour, including pain management?

# Management of infants exposed to alcohol or drugs in utero
- what is the sensitivity and specificity of screening for FAS in the neonatal period and what are the risks and benefits of early identification and intervention, including in low resource settings?
PLANS FOR DISSEMINATING, ADAPTING AND IMPLEMENTING THESE RECOMMENDATIONS These recommendations will be used to provide guidance on the identification and management of substance use and substance use disorders in pregnancy through a range of derivative publications including training materials and a manual describing how best to put these recommendations into practice. This will be widely disseminated through the WHO regional and country offices, collaborating centres, professional organizations and partner agencies.

# Local adaptation/implementation of these recommendations
These recommendations will be adapted for the field by developing suitable training materials in consultation with regional, national and local stakeholders. Adaptation will include translation into appropriate languages and ensuring that the interventions are acceptable in local sociocultural contexts suitable for local health systems.

# EVALUATING THE IMPACT OF THESE RECOMMENDATIONS
The impact of these recommendations will be measured in the following ways: o use of maternal and child health indicators to assess improvement in maternal and child health outcomes in this population; o measurement of inclusion of alcohol and drugs into the routine screening protocols in different countries/ guidelines; o WHO survey of resources for the prevention and treatment of substance use disorders; o assessment of any increase in specialized services for pregnant women with substance use disorders; and o assessment of number of references to the WHO guidelines in the medical literature.

# REVIEW BY DATE
It is not expected that these recommendations will need to be reviewed until 2016. However, developments in the field will be continually monitored and should there be significant changes in practice and/or the evidence base that affect any of the recommendations, review may be undertaken earlier.

# ANNEX 1: EVIDENCE PROFILES

# Evidence Profile 1: Screening and brief interventions Evidence question:
In pregnant or postpartum women using alcohol or drugs, does screening for alcohol or drug use, followed by a brief intervention (or referral to treatment for those with possible dependence), result in better maternal, fetal or neonatal outcomes (see separate outcome list) than treatment-as-usual (generally the absence of screening, or brief interventions and the occasional referral to treatment)?
Selection criteria for the systematic review:

# Study design: RCTs
Population: Pregnant or postpartum women using alcohol or drugs (some studies included women who had alcohol or drug use only in the past; studies with up to one third of participants in this category were still eligible for inclusion).
Intervention: Systematic screening of all patients followed by a brief intervention. The Cochrane Review definition of brief intervention in the general population review was used (anything beyond simple advice or information up to 4 sessions), accepting any referral of more severe patients for treatment.
Control: Brief advice or information or no intervention.
Outcomes: The outcomes ranked as important were:
Outcome Importance (0-9) Summary of the Evidence: For GRADING of evidence see summary of findings and GRADE tables below RCT evidence -10 studies were included in the review. Most studies were underpowered and there were differences in study design and outcome measures used which limited the capacity for meta-analysis. As a result, the level of evidence for most outcomes was low or very low. Nonetheless, there was a small but consistent effect in favour of screening and brief interventions for both alcohol and, to a lesser extent, drugs.
- Simply asking about alcohol and other substance use may result in a change in behaviour (Goler et al., 2008;Klesges et al., 2001;Nilsen, 2009). - Being asked about alcohol or other substance use in a detailed and comprehensive manner may increase a woman's awareness of actual levels of consumption and may function to modify her behavior (Delrahim-Howlett, 2011). - A brief motivational intervention has been shown to reduce the risk of an alcohol-exposed pregnancy (Floyd, 2007).
- A brief alcohol intervention has been found to reduce the number of drinks and the number of heavy drinking days during the postpartum period (Fleming et al., 2008). Pregnant women with higher levels of alcohol use may reduce their alcohol use following a brief intervention that includes their partner (e.g., Chang, 2005). - Pregnant adolescent girls with a substance use disorder have been shown to reduce their substance use after a single-session, standardized brief intervention (Whicher et al., 2012).

# Benefits and harms
- Discussion of alcohol and illicit substance use during pregnancy is a teachable moment (Chang et al., 2000 Prevention, 1993) contains an excellent review in regard to all such instruments], which vary in length from 4 questions to more than 100, and which can be administered by the clinician or require paper-and-pencil administration - HCW may resent difficulties of interaction when identifying a substance user - HCW may resent extra time and difficulty imposed by need to refer - HCW may be unwilling to provide intervention - HCW may believe they are not competent to screen: Gassman (2003) found that the biggest barrier to the implementation of screening and brief intervention among obstetricians was selfrated competence to deliver the intervention.

# Costs and feasibility

# Costs and resource use
- Additional cost in terms of staff time should be minimal if integrated into routine care. However, there are no good estimates of cost for either the screening or the brief intervention, given the fact that a brief intervention may be no more than guidance provided in the office or a structured and standardized administration of a behavioural intervention by a counsellor - Appropriate staff training requires resource use - Appropriate intensive treatment needs to be made available for referral when substance use/ alcohol use is identified and long-term, sustainable support is required. - Brief interventions have been assessed as highly cost-effective (Windsor, 1985;Ershoff, 1989;Dornelas, 2006: Parker, 2007)

# EVIDENCE TO RECOMMENDATIONS TABLE
(including economic consequences)
- Self-report screening has been shown to be accurate. Yonkers et al. (2011) found a high degree of agreement between urine toxicology and self-report results for cannabis and cocaine testing in 168 pregnant women. Moreover, self-report was found to lead to more positive reporting of use when a larger window was available for such reporting than was available for toxicology screening, leading to the conclusion that self-report may be a better indicator of use. - Some time is needed for the care provider to either complete and/or review the screening results. Diekman et al. (2000) have reported than only 23% of obstetricians in the USA used a standardized screening tool for the detection of substance use, yet research (e.g. Bailey & Sokol, 2008;Svikis & Reid-Quinones, 2003) has shown that such tools substantially increase the rate of detection of such use. Oser et al. (2011) found that less than 50% of USA obstetricians were using a standardized screening instrument, and of those using such an instrument, most were using the CAGE, which was not specifically developed for use with a pregnant population. - Effective interventions are labour intensive. Providing reading material is not as effective as a brief intervention. Face-to-face counselling about abstaining from alcohol (and other substances) is needed (Calabro, 1996). - Other research has shown that non-mental-health specialists can be trained to perform brief interventions in general health-care settings.

# Draft recommendations:
- Screening for use of alcohol and other substance use among all pregnant women is recommended in all health-care settings (e.g., primary care, obstetrical care). o Pregnant women reporting hazardous or harmful alcohol or other substance use should receive a brief intervention. o Pregnant women found to be dependent on alcohol or other substances should be referred to specialist services, where such services exist.

# Final recommendations:

# RECOMMENDATION 
Health-care providers should ask all pregnant women about their use of alcohol and other substances (past and present) as early as possible in the pregnancy and at every antenatal visit.

# Strength of recommendation: Strong
Quality of evidence: Low
- Asking at every visit is important as some women are more likely to report sensitive information only after a trusting relationship has been solidly established. - Pregnant women should be advised of the potential health risks to themselves and to their babies posed by alcohol and drug use. - Validated screening instruments for alcohol and other substance use and use disorders are available (see Annex 3).
- Health-care providers should be prepared to intervene or refer all pregnant women who are identified as using alcohol and/or drugs (past and present). - It was decided that despite the low quality of evidence of effect, the benefit -potential reduction of alcohol and substance use -outweighed any potential harms of a brief psychosocial intervention, which were considered minimal. Therefore the balance of benefits versus harms was clearly positive despite uncertainty about the degree of benefit. In addition, the burden of implementation was minimal.

# RECOMMENDATION 2
Health-care providers should offer a brief intervention to all pregnant women using alcohol or drugs.

# Strength of recommendation: Strong

# Quality of evidence: Low
- Brief intervention is a structured therapy of short duration (typically 5-30 minutes) offered with the aim of assisting an individual to cease or reduce the use of a psychoactive substance. It is designed in particular for general practitioners and other primary health-care workers. - Health-care providers should be given appropriate training and resource materials.
- The brief intervention should be individualized, and include feedback and advice on ceasing or reducing alcohol and other substance use during pregnancy. There may need to be follow-up with the patient, with the possibility of referral to treatment for those patients who are unable to reduce or eliminate such use. - The approach/attitude of health-care providers is an important contributor to the effectiveness of brief interventions.
- As for recommendation 1, it was decided that despite the low quality of evidence of effectiveness, this should be a strong recommendation because the potential benefit -reduction of alcohol and/other substance use -likely outweighs any potential harms of a brief psychosocial intervention which were considered minimal. Therefore the balance of benefits versus harms was clearly positive, although there was uncertainty about the degree of benefit. In addition the burden of implementation was minimal.
Factors in considering the strength of the recommendations (recommendations 1 & 2):

# Research gaps
More evidence is needed from low-income countries. Topics in need of further research include training on sceening and brief interventions, how to screen (which instrument), cost-effectiveness, whether to screen for alcohol or drugs together, whether to ask about tobacco at the same time, and whether or not to combine with other issues (such as depression). There is a need for more real-world effectiveness studies, and a systematic review of screening instruments.

# Factor Decision
Is there high-or moderate-quality evidence?
The higher the quality of evidence, the more likely is a strong recommendation.
Is there certainty about the balance of benefits versus harms and burdens?
In case of positive recommendations (a recommendation to do something), do the benefits outweigh harms? In case of negative recommendations (a recommendation not to do something), do the harms outweigh benefits?
Are the expected values and preferences clearly in favour of the recommendation? Yes
Is there certainty about the balance between benefits and resources being consumed?
In case of positive recommendations (recommending to do something) is there certainty that the benefits are worth the costs of the resources being consumed? In case of negative recommendations (recommending not to do something) is there certainty that the costs of the resources being consumed outweigh any benefit gained?  4,6,7 Birthweightall participants
  VERY LOW 1,
The mean birthweight -all participants in the control groups was 3240 grams
The mean birthweight -all participants in the intervention groups was 57.8 higher (77.26 lower to 192.86 higher)
(3 studies) 2,3,4,6,8,9 Attending substance abuse treatment  The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 The control group received a screening session 2 Up to a third of the participants were not heavy drinkers 3 Wide confidence interval 4 Cluster randomized trial not analysed as such 5 High dropout rate 6 Outcome assessment was not blinded 7 Post-hoc analysis, selective outcome reporting 8 No explanation was provided 9 Suggestion on funnel plot of publication bias 10 Post-hoc analysis
  VERY LOW 1,
miscarriage in the time between survey completion and telephone interview (14%), ( 4) intention to receive prenatal care elsewhere (7%), ( 5) non-English-speaking (3%), ( 6) intended abortion or false pregnancy (3%), ( 7) current substance abuse treatment (1%) and ( 8 3) request that the subject articulate her drinking goals while pregnant and their reason, ( 4) have the subject identify circumstances when she might be tempted to drink, ( 5) identify alternatives to drinking when she is tempted to drink, and ( 6) summarize the session by emphasizing four key points (drinking goal, motivation, risk situations for drinking and alternatives to alcohol) and noting them in the take-home manual, "How to prevent alcohol-related problems", given to the subject. This manual was based on materials provided by the WHO Amethyst Project (Babor et al., 1987;Babor & Grant, 1992;WHO Brief Intervention Study Group, 1996). All subjects receiving the BI were informed of the recommendation of the  Selzer, Vinokur & van Rooijen, 1975); ( 5) the Timeline Follow-back interview for the quantity and frequency of alcohol consumption for the 90 days immediately before study assessment (Sobell & Sobell, 1992); (6) the Alcohol Craving Scale, a visual analog scale to measure the desire to drink at the moment and in the past week (Wewers, Rachfal & Ahijevych, 1990); (7) the Global Assessment of Functioning (GAF, Endicott et al., 1976); and (8) the Situational Confidence Questionnaire, a measure of the subject's confidence in managing drinking situations (Annis, 1981). Subjects were asked to report any alcohol consumed, even a sip, when completing the Timeline Follow-back interview (Allen & Columbus, 1995). In this study, alcohol consumption was quantified by drinks per drinking day, since few pregnant women drink daily (Jacobson et al., 1991). Drinking episodes, defined with each episode beginning with a drinking day and ending with 7 consecutive days of abstinence, were also calculated. Additional details about the alcohol assessment are available elsewhere (Chang et al., 1998 42 (20 randomized to intervention group and 22 to control group). It was not stated if there were any significant statistical differences in baseline data between the two groups. All participants were initially assessed using the Brief Drinker Profile (BDP), supplemented by calendar for timeline reconstruction of drinking during the previous 2 months. Subsequently, the interviewer privately opened a prepared envelope to determine the randomized group assignment. INTERVENTION: Pregnant women in the treatment group completed SOCRATES, a measure of motivation for change.
The motivational interview lasted for 1 hour, starting with ascertaining participant's knowledge of the effects of alcohol on pregnancy, feedback on severity of participant's drinking, and showing chart of fetal development by gestational week. They were followed-up 2 months later. CONTROL: Those assigned to the control group were sent letters informing them about the potential risks of drinking during pregnancy and referring them to their healthcare provide and were followed up at 2 months. COMPLIANCE: Not stated CO-INTERVENTIONS: To corroborate self-report, participants' significant others were interviewed (with the participant's permission) at intake and follow-up, using a Collateral Information Form. All participants were paid $20.00 for completing baseline assessment, were entered into a lottery drawing for a $50 cash prize upon completing follow-up sessions, and those in the intervention group were paid $ 10 upon completing SOCRATES again after the interview. These interviews lasted 20 minutes on average.
3) The last follow-up interview before the birth comprised a BI and feedback on drinking behaviour, completing a questionnaire on changes in drinking behaviour, and completing a second AUDIT. Interviews were conducted by two trained fieldworkers. Incentives in the form of a food parcel were given to all participants in the trial. CONTROL: Involvement with respondents was kept to the minimum that was allowed ethically: 1) The initial assessment interview included the consent form, the personal questionnaire, the AUDIT, written material, i.e. the take-home alcohol booklet, and appointment for the follow-up interview, 2) the last followup interview just before the birth consisted of a second AUDIT and a questionnaire on changes in drinking behaviour. The software tailored content based on the current drinking status of each participant. For women who reported they already quit, the narrator presented a section that focused on relapse prevention (''My plan to remain abstinent'') while asking the participant to provide the reasons/benefits to them of having made this change.
The remaining women were asked about their current interest in quitting. Those reporting a goal of immediate abstinence moved more quickly to a section consistent with phase 2 of MI (primarily goal setting), whereas those who did not wish to quit received elements consistent with phase 1 of MI (e.g. pros and cons, feedback). CONTROL: Participants were administered series of questions about TV shows, videos of popular entertainers/shows, followed by requests for ratings of subjective preference. Duration was equivalent to that of intervention group. CO-INTERVENTIONS: All eligible participants received gift cards (equivalent to $30) for their participation at the baseline visit.
.Women who completed the follow-up session received an additional gift card (equivalent to $5) by mail.
Evidence Profile 2: Psychosocial interventions for harmful use and dependence on alcohol and other substances in pregnancy Evidence question:
For pregnant and postpartum women with harmful alcohol or drug use, do some psychosocial interventions result in better maternal, fetal and infant outcomes than other psychosocial interventions or usual care?
Selection criteria for the systematic review:

# Study design: RCTs
Population: Pregnant or postpartum women with harmful use of alcohol or drugs.
Interventions: Psychological or social interventions longer in duration and intensity than brief interventions.
Other psychosocial interventions or usual care (usual obstetric care or usual specialist care).
The key outcomes selected were:
Outcome Importance (0-9)

# Psychosocial interventions for harmful use and dependence on alcohol and other substances in pregnancy
Summary of evidence: see also summary of findings and GRADE tables below

# Summary of RCT evidence:
With the exception of home visits, all RCTs compared a specific form of psychosocial intervention to treatment-asusual in the specialist drug and alcohol treatment service, not usual obstetric care. As such, they are comparing one form of psychosocial intervention with another, since all specialist treatment is considered to include a component of psychosocial care.

# Motivational Interviewing (MI)
Two randomized clinical trials have compared motivational interviewing (MI) to treatment-as-usual or educational control. Findings do not support the superiority of MI to treatment-as-usual or educational control, with similar results for maternal retention in treatment and maternal substance abuse. Data are absent regarding neonatal outcomes. Both samples were identified as needing substance-abuse treatment.

# Cognitive Behavioural Therapy (CBT)
Two randomized clinical trials compared cognitive behavioural therapy (CBT) to treatment-as-usual. Findings suggest that CBT may be superior to treatment-as-usual in terms of treatment retention, reductions in sex and needle risk, and occurrence of preterm birth. One sample was in methadone treatment and the other sample was using alcohol or another illicit substance exclusive of opiates.

# Contingency Management (CM)
Five randomized clinical trials compared contingency management (CM) to treatment-as-usual. Findings support the superiority of CM to treatment-as-usual in terms of retention in treatment, percentage of negative urines, and weeks of continuous cocaine abstinence. Three of the samples met requirements for methadone maintenance, one sample met requirements for opioid or cocaine dependence, and one met criteria for cocaine dependence.
Standard management home visits have been shown not to be effective. A review of randomized trials (Turnbull & Osborn, 2012) suggests that home visits following delivery are not effective in reducing maternal retention in treatment, substance use or alcohol use. Findings from 4 other studies (Butz et al., 1998;Grant et al., 1996;Quinlivan et al., 2000;Schuler et al., 2000) omitted by Turnbull and Osborn (2013) are consistent with their conclusion.
Educational and counselling interventions may encourage women to cease alcohol use or reduce the amount of alcohol consumed during pregnancy (Stade, 2009).

# Benefits and harms
- Pregnancy presents a unique opportunity to help support women to reduce and ideally cease alcohol and/or illicit substance use (Chang et al., 2000) - Depending on the substance of use, psychosocial interventions are considered to be superior to usual care in terms of: -reduction in harmful consumption -reduction in risk to fetus -increase in birthweight -improved general health of pregnant women -improved maternal psychological well-being -less risk of fetotoxicity -improved perinatal outcomes (e.g. reduction in preterm births, increased overall birthweights, reduction in number of low-birthweight infants) -reductions in congenital defects or anomalies (Lui, Terplan, & Smith, 2008;Terplan & Lui, 2007) - There is a high incidence of mental health disorders in opioid-dependent pregnant women and psychosocial interventions may be appropriate in many instances (Martin et al., 2009) - Considerable research supports a variety of psychosocial interventions for substance use and co-occurring mental disorders in non-pregnant populations (Drake, O'Neal, & Wallach, 2008) - Retention in substance abuse treatment is an important factor in reducing illicit substance use (Laken, 1997)

# EVIDENCE TO RECOMMENDATIONS TABLE
- Physical and mental symptoms associated with reduction or cessation of alcohol or substance use - Possible development of depression or anxiety as a result of cessation or reduction of alcohol or illicit substance use - Possible verbal and/or physical abuse by the partner as a result of the pregnant woman's behaviour change - Possible risk of switching from one substance to another substance - Between 7% and 15% of individuals participating in psychosocial interventions to treat substance use disorders may be worse off after treatment than before treatment. This decline in functioning may be due to a lack of bonding with the provider, lack of goal direction and monitoring, confrontation, criticism, and high emotional arousal and stigma (Moos, 2012

# Costs and feasibility
- Additional costs beyond routine care - Trained staff and a sustainable programme are required. Training for management of substance use disorders on the part of obstetricians and their staff can increase their self-efficacy regarding the treatment of patients who use substances (Schumacher, 2000).

# Feasibility (including economic consequences)
- Inconvenient for women - Requires patient monitoring to ensure patient remains enrolled in and engaged in the psychosocial intervention - A comprehensive care model in which obstetrical care is part of a women-centered, traumainformed program would be the best model of care -and also potentially the costliest - A therapeutic workplace has been shown to be superior to usual care in reducing opioid and cocaine use in pregnant women with substance use disorders (Silverman et al., 2001) - Well-child care visits may not be sufficient to prevent deterioration in competence and social isolation in postpartum women who use substances (Taylor, 1998) Draft recommendations:
- Pregnant women with dependent alcohol or other substance use (or harmful alcohol or other substance use not responding to brief interventions) should be offered intensive psychosocial support and treatment. o Postpartum women with substance dependence should be offered intensive psychosocial support and treatment including home visits, parenting support, psychotherapy and social assistance.

# RECOMMENDATION 3
Health-care providers managing pregnant or postpartum women with alcohol or other substance use disorders should offer comprehensive assessment and individualized care.

# Strength of recommendation: Conditional
Quality of evidence: Very low
- A comprehensive assessment of women using alcohol or drugs in pregnancy and the postpartum period includes an assessment of patterns of substance use, medical or psychiatric comorbidity, family context, as well as social problems. - Individualized care involves selecting appropriate psychosocial interventions of different intensity based on the particular needs of the pregnant women and the resources available. Psychosocial interventions include a number of psychological treatments and social supports, ranging from lesser to higher intensity. The psychosocial treatment and support referred to in this section is a more intensive set of interventions typically delivered by people with specific training in the management of substance use disorders, and usually includes repeated contact with the patient. The kinds of specific psychological techniques considered in this category include cognitive behavioural therapy, contingency management and motivational enhancement. The kinds of social support referred to in this section include assistance with accommodation, vocational training, parenting training, life-skills training, legal advice, home visiting and outreach. - Despite the benefits of psychosocial treatment outweighing the harms, this recommendation was considered to be conditional given the absence of strong evidence and the potential resource implications.
Factors in considering the strength of the recommendation (recommendation 3):

# Research recommendations
- Better reporting and agreement on standardized designs and outcomes is needed. o Stronger RCT evidence of effect is needed, in particular comparing interventions with different levels of intensity and models of care with different levels of comprehensiveness, and including cost-effectiveness analyses.

# Factor Decision
Is there high or moderate quality evidence?
The higher the quality of evidence, the more likely is a strong recommendation.
Is there certainty about the balance of benefits versus harms and burdens?
In case of positive recommendations (a recommendation to do something), do the benefits outweigh harms? In case of negative recommendations (a recommendation not to do something), do the harms outweigh benefits?
Are the expected values and preferences clearly in favour of the recommendation? Yes
Is there certainty about the balance between benefits and resources being consumed?
In case of positive recommendations (recommending to do something) is there certainty that the benefits are worth the costs of the resources being consumed? In case of negative recommendations (recommending not to do something) is there certainty that the costs of the resources being consumed outweigh any benefit gained?
No CASE MANAGEMENT during pregnancy and after birth for women with an alcohol or drug problem

# INTERVENTION DURING AND AFTER PREGNANCY
No trials were identified from these settings.

# INTERVENTION AFTER PREGNANCY ONLY Generalised treatment settings
No trials were identified from these settings.

# Specialist treatment settings

# GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Risk of bias: rated as very serious. Randomization did not result in similar numbers in each group indicating a possible effect of chance or selection bias. Random generation and allocation concealment methods were not reported. Blinding was not possible for participants or providers and attrition was high. 2 Imprecision: The sample size is small and the confidence interval wide.
Guidelines for the identification and management of substance use and substance use disorders in pregnancy  Risk of bias: rated as very serious. Randomization did not result in similar numbers in each group indicating a possible effect of chance or selection bias. Random generation and allocation concealment methods were not reported. Blinding was not possible for participants or providers and attrition was high.
2 Imprecision: The sample size is small and the confidence interval wide.
COGNITIVE BEHAVIOURAL THERAPY during pregnancy and after birth for women with an alcohol or drug problem

# Specialist treatment settings
No trials were identified from these settings.

# INTERVENTION AFTER PREGNANCY ONLY Generalised treatment settings
No trials were identified from these settings.

# Specialist treatment settings
No trials were identified from these settings.

# GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Risk of bias: Rated as Serious: Lack of reporting of sequence generation and allocation concealment in O'Neill 1996 and the loss-to-follow up > 10% resulted in down-grading for risk of bias. A likely lack of blinding for providers and participants in both trials may have introduced performance bias. 2 Indirectness: Rated as Serious. The measurement for treatment retention used in the analysis is a proxy measure for both trials. In O'Neill 1996 completion and availability for 6 week follow-up is used but not all sessions would have been attended as appointments were missed at an average of mean 2.9 (SD 6.45) with a range of 0-11. In Yonkers 2012 the proxy measure is attending at least one of 6 session during the entire study period which continued to 3 months postpartum.

# Quality assessment
No. of patients  Risk of bias: Rated as Serious: Lack of reporting of sequence generation and allocation concealment in O'Neill 1996 and the loss-to-follow up > 10% resulted in down-grading for risk of bias. A likely lack of blinding for providers and participants in both trials may have introduced performance bias.
2 Indirectness: Rated as Serious. The measurement for treatment retention used in the analysis is a proxy measure for both trials. In O'Neill 1996 completion and availability for 6 week follow-up is used but not all sessions would have been attended as appointments were missed at an average of mean 2.9 (SD 6.45) with a range of 0-11. In Yonkers 2012 the proxy measure is attending at least one of 6 session during the entire study period which continued to 3 months postpartum.
Inclusion criteria was women of < 28 weeks pregnant. The mean duration of follow-up was calculated as from 28 weeks to delivery although women may have been in treatment for longer if enrolled before 28 weeks.
Risk of Bias: Rated as Serious. This well-conducted trial Yonkers 2012 was down-graded on the basis of a likely lack of blinding which may have introduced performance bias.
5 Imprecision: The event rate is very low < 300.

# Quality assessment

# No. of patients

# GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Jones 2001 reported a significant effect of CM on the rate of opioid positive urine samples in day 8 -14 (outpatient) (F (1.78) = 5.76; p =< 0.05) and this effect disappeared after vouchers were no longer provided after week 2. Jones 2011 reported that there was no statistically significant difference between heroin positive urines in the last 30 days between the groups. Tuten 2012 reported no statistically significant difference in the first opioid-positive assessment time point between the fixed combined with escalating voucher group compared with the control group (F(1,78.0) = 1.05; p = 0.31) and between the fixed and escalating groups (F(1,92.4) = 1.23; p = 0.27). 2 Risk of Bias: Rated as Very serious. No reporting of randomization sequence, no blinding and high attrition. 3 Imprecision: Rated as Very Serious. This is a very small trial (N = 20) with 14 analysed. The risk of imprecision is very high. 4 Tuten 2012 reported no statistically significant differences in the the number of cocaine-negative urine tests between the combined fixed with escalating voucher group compared with the control group (F1,54.3) = 0.01; p = 0.91) and between the fixed and escalating voucher groups (F(1,88.7) = 0.09; p = 0.76). 5 Risk of bias: Rated as Very Serious. The high rate of attrition and lack of blinding resulted in down-grading this trial. 6 Imprecision: Rated as VERY SERIOUS. The 95% confidence interval is very wide. 7 Jones 2001 reported a statistically significant favourable effect of CM on the rate of cocaine-positive urine from day 8 to 14 (F(1,78) -7.05); p =< 0.05). This effect disappeared after the vouchers were stopped at the end of week 2. Jones 2011 reported no statistically significant effect between groups for cocaine-positive urine. 8 The results from the three trials favoured contingency management over usual care for maternal retention in treatment. Carroll 1995 (N = 14 analysed) found no of prenatal visits was statistically significantly higher (CM: Mean = 14.7; SD: 5.9)(Usual Care: Mean = 5.1; SD: 3.6). In Jones 2001 (N = 80 analysed) participants in CM attended statistically significant more treatment days (CM: Mean = 12.1; SD: 2.3)(Usual Care: Mean = 10.6; SD: 2.4). In Schottenfeld 2011 (N = 71 analysed) participants in CM attended statistically significantly more therapy sessions (CM: Mean: 25.3; SD: 13.7)(Usual Care: Mean = 19.9; SD: 12.8). 9 Risk of bias: Rated as Very Serious. Jones 2001 and Schottenfeld 2001 randomized adequately. However the lack of provider blinding across all three trials and the high attrition in two of the three trials, resulted in overall downgrading. 10 Indirectness: Rated as Serious. Treatment duration was varying across trials and different proxy measures were used for retention e.g. no of prenatal visits versus no of groups attended 11 Imprecision: Rated as Serious. This was difficult to rate as the measures were varying, but within each trial the 95% confidence intervals were large and so overall it was down-graded for imprecision. 12 Risk of Bias: Rated as Very Serious. The high rate of attrition in Jones 2011 and Carroll 1995 resulted in the risk of bias rated as very serious. In addition, lack of blinding may result in a high risk of performance bias. 13 Inconsistency: Rated as Serious. There was unexplained heterogeneity present. 14 Imprecision: The confidence interval was wide and the overall sample size small.  Jones 2001 reported a significant effect of CM on the rate of opioid positive urine samples in day 8 -14 (outpatient) (F (1.78) = 5.76; p =< 0.05) and this effect disappeared after vouchers were no longer provided after week 2. Jones 2011 reported that there was no statistically significant difference between heroin positive urines in the last 30 days between the groups. Tuten 2012 reported no statistically significant difference in the first opioid-positive assessment time point between the fixed combined with escalating voucher group compared with the control group (F(1,78.0) = 1.05; p = 0.31) and between the fixed and escalating groups ((F(1,92.4) = 1.23; p = 0.27).
2 Risk of Bias: Rated as Very serious. No reporting of randomization sequence, no blinding and high attrition.
3 Imprecision: Rated as Very Serious. This is a very small trial (N = 20) with 14 analysed. The risk of imprecision is very high.
Tuten 2012 reported no statistically significant differences in the the number of cocaine-negative urine tests between the combined fixed with escalating voucher group compared with the control group (F(1,54.3) = 0.01; p = 0.91) and between the fixed and escalating voucher groups ((F(1,88.7) = 0.09; p = 0.76).
Risk of bias: Rated as Very Serious. The high rate of attrition and lack of blinding resulted in down-grading this trial.
Imprecision: Rated as VERY SERIOUS. The 95% confidence interval is very wide.
Jones 2001 reported a statistically significant favourable effect of CM on the rate of cocaine-positive urine from day 8 to 14 (F(1,78) -7.05); p =< 0.05). This effect disappeared after the vouchers were stopped at the end of week 2. Jones 2011 reported no statistically significant effect between groups for cocaine-positive urine.
The results from the three trials favoured contingency management over usual care for maternal retention in treatment. Carroll 1995 (N = 14 analysed) found no of prenatal visits was statistically significantly higher (CM: Mean = 14.7; SD: 5.9)(Usual Care: Mean = 5.1; SD: 3. Indirectness: Rated as Serious. Treatment duration was varying across trials and different proxy measures were used for retention e.g. no of prenatal visits versus no of groups attended 11 Imprecision: Rated as Serious. This was difficult to rate as the measures were varying, but within each trial the 95% confidence intervals were large and so overall it was down-graded for imprecision.
12 Risk of Bias: Rated as Very Serious. The high rate of attrition in Jones 2011 and Carroll 1995 resulted in the risk of bias rated as very serious. In addition, lack of blinding may result in a high risk of performance bias.
Inconsistency: Rated as Serious. There was unexplained heterogeneity present 14Imprecision: The confidence interval was wide and the overall sample size small. HOME VISITS during pregnancy and after birth for women with an alcohol or drug problem

# RISK OF BIAS IN EACH TRIAL INCLUDED IN THE CONTINGENCY MANAGEMENT COMPARISON

# GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
The meta-analysis included three RCTs (Black 1994, Bartu 2006, andDakof 2003). Two were judged to be at low risk of selection bias (although allocation concealment was unclear in Bartu 2006) and Black 1994 was judged to be at unclear risk of selection bias. All trials were judged to be at high risk of performance bias as blinding was not possible for the intervention. All trials were judged for this outcome (failure of retention in program) to be at high or unclear risk of detection bias. Attrition bias was a high risk for Black 1994 at 28% loss-to-follow-up.
Heterogeneity is present (I-squared = 49%). There are multiple sources of heterogeneity including differences in the type of home visitor, frequency and duration of the home visit and differences in content of visit. These subgroups are explored in additional analyses and may explain some of the heterogeneity; however, given the uncertainty and extent of the heterogeneity, the analysis was downgraded for inconsistency. The sample size is small, and the event rate is less than 300. This meta-analysis includes three RCTs (Bartu 2006, Butz 1998and Schuler 2000. Two trials were judged to be at low risk of selection bias and one was of unclear risk. All three trials were judged to be at high risk of performance bias as the visits could not be blinded. Two of three trials ensured outcome assessment was blinded reducing the risk of detection bias. Two trials had very high loss-to-follow-up (> 40%) at 18 months and are therefore at high risk of attrition bias.
Heterogeneity is present (I-squared = 64%). As there is moderate heterogeneity, it may be more appropriate to use a random effects model. This provides a RR = 1.04 (95% CI: 0.78, 1.38). This does not differ qualitatively from the fixed effects model. However, there are multiple sources of heterogeneity including differences in the type of home visitor, frequency and duration of the home visit and differences in content of visit. These sub-groups are explored in additional analyses and may explain some of the heterogeneity; however, given the uncertainty and extent of the heterogeneity, the analysis was downgraded for inconsistency. The event rate is less than 300. However, given the relatively large event rate and narrow confidence interval, the analysis was not downgraded for imprecision.
There was no statistical heterogeneity in the results. However, there are multiple potential causes of clinical heterogeneity including differences in the type of home visitor, frequency and duration of the home visit and differences in content of visit. These subgroups are explored in additional analyses but given the uncertainty regarding heterogeneity, the analysis was downgraded for inconsistency.

# Quality assessment
No. of patients  The meta-analysis included three RCTs (Black 1994, Bartu 2006, andDakof 2003). Two were judged to be at low risk of selection bias (although allocation concealment was unclear in Bartu 2006) and Black 1994 was judged to be at unclear risk of selection bias. All trials were judged to be at high risk of performance bias as blinding was not possible for the intervention. All trials were judged for this outcome (failure of retention in program) to be at high or unclear risk of detection bias. Attrition bias was a high risk for Black 1994 at 28% loss-to-follow-up.
Heterogeneity is present (I-squared = 49%). There are multiple sources of heterogeneity including differences in the type of home visitor, frequency and duration of the home visit and differences in content of visit. These sub-groups are explored in additional analyses and may explain some of the heterogeneity; however, given the uncertainty and extent of the heterogeneity, the analysis was downgraded for inconsistency.
The sample size is small, and the event rate is less than 300.
This meta-analysis includes three RCTs (Bartu 2006, Butz 1998and Schuler 2000. Two trials were judged to be at low risk of selection bias and one was of unclear risk. All three trials were judged to be at high risk of performance bias as the visits could not be blinded. Two of three trials ensured outcome assessment was blinded reducing the risk of detection bias. Two trials had very high loss-to-follow-up (> 40%) at 18 months and are therefore at high risk of attrition bias.
Heterogeneity is present (I-squared = 64%). As there is moderate heterogeneity, it may be more appropriate to use a random effects model. This provides a RR = 1.04 (95% CI: 0.78, 1.38). This does not differ qualitatively from the fixed effects model.
However, there are multiple sources of heterogeneity including differences in the type of home visitor, frequency and duration of the home visit and differences in content of visit. These sub-groups are explored in additional analyses and may explain some of the heterogeneity; however, given the uncertainty and extent of the heterogeneity, the analysis was downgraded for inconsistency.
The event rate is less than 300. However, given the relatively large event rate and narrow confidence interval, the analysis was not downgraded for imprecision.
There was no statistical heterogeneity in the results. However, there are multiple potential causes of clinical heterogeneity including differences in the type of home visitor, frequency and duration of the home visit and differences in content of visit. These sub-groups are explored in additional analyses but given the uncertainty regarding heterogeneity, the analysis was downgraded for inconsistency.
MOTIVATIONAL INTERVIEWING during pregnancy and after birth for women with an alcohol or drug problem

# General treatment settings
No trials were identified from these settings.  The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect.

# Specialist treatment settings
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Risk of Bias: Serious. Both trials were unblinded so the risk of performance bias is high. Attrition bias is also likely to be present due to the loss-to-follow-up. 2 Imprecision: Rated as Serious. The number of events is less than 300. 3 Risk of Bias: Serious. The trial was unblinded so the risk of performance bias is high. Attrition bias is also likely to be present due to the differential loss-to-followup between the groups. 4 Imprecision: Rated as Very Serious. The sample size is very small.  Risk of Bias: Rated as Serious. Both trials were unblinded so the risk of performance bias is high. Attrition bias is also likely to be present due to the loss-to-follow-up.

# Quality assessment

# No. of patients
2 Imprecision: Rated as Serious. The number of events is less than 300.
3 Risk of Bias: Rated as Serious. The trial was unblinded so the risk of performance bias is high. Attrition bias is also likely to be present due to the differential loss-to-follow-up between the groups.
4 Imprecision: Rated as Very Serious. The sample size is very small.
THERAPEUTIC WORKPLACE during pregnancy and after birth for women with an alcohol or drug problem

# General treatment settings
No trials were identified from these settings.

# Specialist treatment settings

# INTERVENTION DURING AND AFTER PREGNANCY ONLY

# General treatment settings
No trials were identified from these settings.

# Specialist treatment settings
No trials were identified from these settings.

# INTERVENTION AFTER PREGNANCY ONLY

# General treatment settings
No trials were identified from these settings.

# Specialist treatment settings
No trials were identified from these settings.

# GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Risk of bias: Rated as Very Serious. There was no blinding which may introduce performance bias. Detection bias is less likely as the primary outcome was objectively measured: urine screens. The high rate of attrition across the study period and the differential between the groups resulted in a very serious risk of bias rating. 2 Imprecision: Rated as Very Serious. The confidence interval is very wide and the sample size is very small (N = 40). 3 Imprecision: Rated as Serious. The data is presented as a t test and 95% Confidence intervals (CI) are not reported so imprecision cannot be interpreted from the CI.
The very small sample size of the participants (N = 40) indicates that imprecision is likely, despite this measurement being for 24 weeks of urine specimens per each participant.  Risk of bias: Rated as Very Serious. There was no blinding which may introduce performance bias. Detection bias is less likely as the primary outcome was objectively measured: urine screens. The high rate of attrition across the study period and the differential between the groups resulted in a very serious risk of bias rating.
2 Imprecision: Rated as Very Serious. The confidence interval is very wide and the sample size is very small (N = 40).
3 Imprecision: Rated as Serious. The data is presented as a t test and 95% Confidence intervals (CI) are not reported so imprecision cannot be interpreted from the CI. The very small sample size of the participants (N = 40) indicates that imprecision is likely, despite this measurement being for 24 weeks of urine specimens per each participant.
Evidence Profile 3: Detoxification or quitting programmes for alcohol and other substance dependence in pregnancy Evidence question:
For pregnant women with alcohol or other substance dependence, do detoxification or quitting programmes result in better maternal, fetal or infant outcomes compared to treatment-as-usual, maintenance treatment (in the case of opioids), or other methods of detoxification?
Selection criteria for the systematic review:

# Study design: RCTs
Population: Pregnant women with alcohol or other substance dependence.
Interventions: Detoxification, either inpatient or outpatient.
Control: Non-detoxification, delayed detoxification, gradual detoxification, maintenance treatment (in the case of opioids), treatment-as-usual.
The following outcomes were selected by the guidelines group:

# Summary of evidence
A withdrawal syndrome requiring pharmacological treatment in pregnancy can be said to occur for three substances: benzodiazepines, alcohol and opioids. The withdrawal syndrome associated with the cessation of other substances (such as psychostimulants) has not been considered severe enough to justify the routine use of psychotropic medication. For those pregnant women for whom medication-assisted withdrawal is successful, there does not appear to be any evidence of fetal distress during detoxification, nor any increased, no increased risk of fetal demise or premature delivery (Dashe et al., 1998). However, the nature and extent of withdrawal of the fetus from opioids or other substances is largely unknown, because there have been no methods developed to measure such withdrawal directly, and there is insufficient information available to distinguish the effects of fetal withdrawal from fetotoxicity.
Medication-assisted withdrawal for benzodiazepines typically consists of a gradual withdrawal regimen with the goal of having the women benzodiazepine-free at the time of delivery, or later in the postpartum period. Withdrawal from benzodiazepines has typically been managed by transfer to a long-acting benzodiazepine (e.g. diazepam) followed by a gradual dose reduction, with the goal of being benzodiazepine-free at birth, or earlier if possible, without provoking significant withdrawal symptoms for the pregnant woman. There are no reliable data regarding the relative success or failure of such an approach in pregnant women, although the general belief is that relapse to use is common, particularly if the taper is too fast or too short.
Medication-assisted withdrawal for alcohol use in pregnant women typically uses a benzodiazepine, often diazepam, as primary pharmacotherapy. There are no reliable data related to outcome following detoxification during the different trimesters.
Medication-assisted withdrawal from opioids typically involves tapered doses of methadone over a period of 3 to 14 days. Withdrawal from opioids is typically managed by tapered doses of methadone. The safety profile of methadone is well known but both conflicting and incomplete. Methadone maintenance pharmacotherapy has been found superior to detoxification in terms of treatment retention and heroin use (Mattick, Breen, Kimber, & Davoli, 2009). During pregnancy, methadone-maintenance pharmacotherapy has been found superior to detoxification for treatment retention, attending more obstetrical visits, and more often delivering at the program hospital.
Although there are considerable data regarding the failure of medication-assisted withdrawal for opioids, there are few data specific to trimester.

# EVIDENCE TO RECOMMENDATIONS TABLE

# Benefits and harms
- Pregnancy presents a unique opportunity to support women to reduce and ideally cease alcohol and/or illicit substance use (Chang et al., 1992) - Depending on the substance of use, medication-assisted withdrawal that results in continued non-use of substances following medication-assisted withdrawal is considered to be superior to usual care in terms of: -reduction in harmful consumption -reduction in risk to the fetus -increase in birthweight -improved general health of pregnant women -improved maternal psychological well-being -less risk of fetotoxicity -improved perinatal outcomes (e.g. reduction in preterm births, increased overall birthweights, reduction in number of low-birthweight infants -reductions in congenital defects or anomalies noting that: a meta-analysis by Enato et al. (2011) suggests that benzodiazepines are unrelated to an increased risk of major congenital abnormalities. However, research on the longer-term effects of benzodiazepines on the child exposed to benzodiazepines is largely lacking. - Improved general health of pregnant women - Improved maternal psychological well-being - Shorter hospitalizations, lower peak neonatal abstinence syndrome scores, and less likelihood of withdrawal treatment for neonates of mothers who had successfully completed medicationassisted withdrawal than for neonates of mothers who had been unsuccessful (Stewart, 2013) - Medication-assisted withdrawal has been associated with a significantly lower mean NAS peak score, a significantly lower mean amount of morphine to treat NAS, significantly fewer days medicated for NAS, significantly fewer number of days in the hospital relative to methadone, and significantly lower mean amount of morphine to treat NAS and significantly fewer days medicated for NAS than buprenorphine (Lund et al., 2012)
- The success of medication-assisted withdrawal during pregnancy is generally considered to be poor, with estimates of failure as low as 41% (Dashe et al., 1998) and as high as 96% (e.g., Luty et al., 2003). Failure rate is difficult to estimate precisely, because some authors have defined failure as failure to complete detoxification, while others have defined failure as return to substance use. This failure is associated with a number of negative outcomes, including increased fetal exposure to illicit substances and other maternal risk behaviors, reduced compliance with obstetrical care, and poorer neonatal birth parameters  summarized in Kaltenbach et al., 1998 - Inconvenient for women - Likely to fail any other goal beyond being drug-free at the completion of detoxification

# Draft recommendations:
- Pregnant women dependent on alcohol, amphetamine type stimulants, cocaine, cannabis, volatile agents, (everything except opioids and benzodiazepines), should be advised and encouraged to cease their alcohol or other substance use, and provided with the opportunity to do so in a safe and supportive manner, both for the health of the pregnant woman and to reduce the possibility of damage to the fetus. o Pregnant women dependent on opioids should be advised to use opioid-agonist maintenance treatment (such as methadone or buprenorphine) rather than to attempt opioid detoxification. o Pregnant patients with benzodiazepine-use disorder should be transferred to a long-acting benzodiazepine (e.g., diazepam) and undergo a gradual dose reduction, with the goal of being benzodiazepine-free at birth, if possible. Psychosocial treatment should serve as an integral component of any dose-reduction strategy. o Pregnant women who wish to undergo detoxification should be invited to withdraw from substance use in an inpatient or hospital facility to increase the chances of successful completion of substance withdrawal and to monitor the health of the fetus. o The health of the fetus should be monitored during detoxification by fetal heart monitoring, and by the monitoring of fetal movements. If there are signs of fetal distress associated with the detoxification, then medication should be used to reduce the severity of withdrawal and the process of withdrawal should be slowed or temporarily halted. o Withdrawal symptoms from the cessation of alcohol consumption should be managed with a long-acting benzodiazepine, titrated to the severity of withdrawal. o Psychotropic medication should not be routinely used in pregnant women to assist detoxification from stimulants (including cocaine), cannabis and volatile agents, but should be reserved for specific symptoms which emerge. o Given the high risk of relapse in opioid dependence, detoxification from opioids should be advised only for carefully selected patients. Such pregnant women who make an informed choice to cease opioid use should be supported to do so either with gradual tapering of opioids in an ambulatory treatment setting or with more rapid tapering in a residential treatment facility.

# Final recommendations:

# RECOMMENDATION 4
Health-care providers should, at the earliest opportunity, advise pregnant women dependent on alcohol or drugs to cease their alcohol or drug use and offer, or refer to, detoxification services under medical supervision where necessary and applicable.

# Strength of recommendation: Strong

# Quality of evidence: Very low
- Pregnant women dependent on alcohol or drugs who agree to undergo detoxification should be offered the supported withdrawal from substance use in an inpatient or hospital facility, if medically indicated. - Detoxification can be undertaken at any stage in pregnancy, but at no stage should antagonists (such as naloxone, or naltrexone -in the case of opioid withdrawal) be used to accelerate the detoxification process. - Equal attention should be paid to the health of mother and fetus during detoxification and treatment adjusted accordingly. - The exceptions to this recommendation are opioid and benzodiazepine dependence, which are covered by recommendations 5 and 6 separately. - It was decided that this recommendation should be strong, despite the very low quality of evidence of the effectiveness of the health-care intervention because there is clear evidence of harm to the fetus of ongoing maternal substance use, and the benefit to both mother and fetus of ceasing alcohol and/or substance use under medical supervision strongly outweighs any potential harms.

# RECOMMENDATION 5
Pregnant women dependent on opioids should be encouraged to use opioid maintenance treatment whenever available rather than to attempt opioid detoxification.

# Strength of recommendation: Strong

# Quality of evidence: Very low
- Opioid maintenance treatment in this context refers to either methadone maintenance treatment or buprenorphine maintenance treatment. - Pregnant patients with opioid dependence who wish to undergo detoxification should be advised that relapse to opioid use is more likely following medication-assisted withdrawal than while undertaking opioid maintenance treatment. - Such medication-assisted withdrawal from opioids should be attempted only in an inpatient unit, using a gradual reduction in methadone or buprenorphine doses. Inpatient care should also be considered for the initiation and optimization of maintenance treatment. - Psychosocial treatment should be an integral component of such treatment.
- Pregnant women who fail to complete medication-assisted withdrawal should be offered opioid agonist pharmacotherapy. - It was decided that this recommendation should be strong despite the low quality of evidence of effectiveness from randomized controlled trials, as the rate of relapse to opioid use following detoxification has been shown to be high and the risks of harm to both mother and fetus from failed detoxification are catastrophic compared to the very low risks of harm from opioid maintenance treatment.

# RECOMMENDATION 6
Pregnant women with benzodiazepine dependence should undergo a gradual dose reduction, using long-acting benzodiazepines.

# Strength of recommendation: Strong
Quality of evidence: Very low
- Long-acting benzodiazepines should only be used for as short a time as is medically feasible in managing benzodiazepine withdrawal. - Psychosocial interventions should be offered throughout the period of benzodiazepine withdrawal.
- Inpatient care should be considered in the withdrawal management of pregnant women with benzodiazepine dependence. - It was decided that this recommendation should be strong despite the very low quality of evidence of effectiveness because ongoing benzodiazepine use in pregnancy is associated with significant risk of harm. At the same time, abrupt cessation of benzodiazepines can result in a severe withdrawal syndrome including seizures and psychosis. This leaves gradual reduction as the only practicable alternative. Significant clinical experience indicates that this approach is feasible and safe. Hence the GDG was in agreement that the benefits of gradual dose reduction outweigh the harms of both ongoing use and abrupt cessation.

# RECOMMENDATION 7
Pregnant women who develop withdrawal symptoms following the cessation of alcohol consumption should be managed with the short-term use of a long-acting benzodiazepine.

# Strength of recommendation: Strong

# Quality of evidence: Very low
- Management of alcohol withdrawal usually also includes administration of thiamine.
- Alcohol withdrawal management may be facilitated by the use of an alcohol withdrawal scale such as the CIWA-Ar.
- Inpatient care should be considered in the withdrawal management of pregnant women with alcohol dependence.
- Alcohol withdrawal can be a severe and even life-threatening condition, provoking seizures and delirium. Evidence from non-pregnant populations has demonstrated the effectiveness of long-acting benzodiazepines for preventing seizures and delirium in alcohol withdrawal. Given the severity of alcohol withdrawal, and the lack of significant harm from short-term benzodiazepine use, and the evidence supporting the use of benzodiazepines in the management of alcohol withdrawal in the general population, the GDG decided that this recommendation should be strong despite the low quality of evidence in pregnant women.

# RECOMMENDATION 8
In withdrawal management for pregnant women with stimulant dependence, psychopharmacological medications may be useful to assist with symptoms of psychiatric disorders but are not routinely required.

# Strength of recommendation: Strong

# Quality of evidence: Very low
- Except for the management of acute intoxication, withdrawal management in amphetamine-type stimulants (ATS) dependence or cocaine dependence does not include psychopharmacological medications as a primary approach to treatment in pregnant patients. There is no evidence that medication-assisted withdrawal would benefit pregnant women with these respective disorders. - Inpatient care should be considered in the withdrawal management of pregnant women with stimulant dependence.
- It was decided that this recommendation should be strong despite the very low quality of evidence because the harms to mother and fetus of ongoing use of psychostimulants use have been shown to be high. The risks of providing short-term appropriate non-teratogenic medications for short-term management of psychologically distressing symptoms in pregnancy are very low. Therefore, the potential benefits of this approach strongly outweigh the harms of providing psychopharmacological treatment of symptoms, if required, during psychostimulant withdrawal.

# Factors in considering the strength of the recommendations (recommendations 4-8):
Research gaps o What type of benzodiazepine tapers work best for which types of patients? o What medications are the safest and most effective for mother and fetus being withdrawn from alcohol? o What intensity of fetal monitoring is needed to determine the relative safety of detoxification during pregnancy? o What are the best withdrawal-severity assessment tools to measure withdrawal in pregnant women? o What are the best ways to manage withdrawal from cocaine, cannabis, amphetamine, alcohol or volatile solvents in pregnant women?

# Factor Decision
Is there high or moderate quality evidence?
The higher the quality of evidence, the more likely is a strong recommendation.
Is there certainty about the balance of benefits versus harms and burdens?
In case of positive recommendations (a recommendation to do something), do the benefits outweigh harms? In case of negative recommendations (a recommendation not to do something), do the harms outweigh benefits?

# Are the expected values and preferences clearly in favour of the recommendation? Yes
Is there certainty about the balance between benefits and resources being consumed?
In case of positive recommendations (recommending to do something) is there certainty that the benefits are worth the costs of the resources being consumed? In case of negative recommendations (recommending not to do something) is there certainty that the costs of the resources being consumed outweigh any benefit gained?
Evidence profile 4: Pharmacological treatment (maintenance and relapse prevention) for alcohol and other substance dependence in pregnancy Evidence question:
In pregnant women dependent on alcohol or other substances, does pharmacological treatment (either maintenance or relapse prevention) result in better maternal, fetal or infant outcomes than no pharmacological treatment or other pharmacological treatment?
Study selection criteria for the systematic review:

# Study design: RCTs
Population: Pregnant women dependent on alcohol or other substances.
Interventions: Any pharmacotherapy used for agonist maintenance treatment (such as methadone or buprenorphine in opioid dependence) or relapse prevention treatment (such as naltrexone in opioid or alcohol dependence).
No pharmacotherapy or other pharmacotherapy.
Outcomes: The outcomes of interest were:
Outcome Importance (0-9)  2013) have performed systematic reviews of psychopharmacological treatments: methadone versus buprenorphine and a single study of methadone compared to slow-release morphine for pregnant women with a substance use disorder. See GRADE tables and summary of findings tables (below) for full details. Pharmacotherapy has been shown to be successful in the treatment of opioid use disorder. Methadone and buprenorphine have similar efficacy. Methadone appears to result in better maternal retention in treatment.
Buprenorphine is associated with a number of better neonatal outcomes, specifically increased birthweight, reduced prematurity, and possibly a milder NAS. There is a lack of data on the safety and efficacy of the buprenorphine/naloxone combination in pregnancy. - Psychosocial interventions in addition to pharmacotherapy have been shown to be superior to pharmacotherapy alone (Amato et al., 2011). - There was no evidence found on the use of medications for relapse prevention for alcohol dependence in pregnancy (acamprosate, disulfiram, nalmefene, naltrexone). - There was no RCT evidence on the use of naltrexone in relapse prevention from opioid dependence in pregnancy.
- There was no evidence found on the use of benzodiazepine maintenance for benzodiazepine dependence in pregnancy.

# EVIDENCE TO RECOMMENDATIONS TABLE

# Benefits and harms
- Pregnancy presents a unique opportunity to support women to reduce and ideally cease alcohol and/or illicit substance use - Although research in this area is extremely limited, given the history of exclusion of women from pharmacotherapy trials, and depending on the substance of use, pharmacotherapeutic interventions (specifically opioid agonist treatment in opioid dependence) are thought to be superior to usual care (e.g., Rayburn & Bogenschutz, 2004) in terms of: -reduction in harmful consumption -reduction in risk to the fetus -increase in birthweight -increase in the detection of harmful use and referral to treatment -improved general health of pregnant women -improved maternal psychological well-being -less risk of fetotoxicity -improved perinatal outcomes (e.g., reduction in preterm births, increased overall birthweights, reduction in number of low-birthweight infants) -reductions in congenital defects or anomalies
- Unpleasant side effects due to the pharmacological intervention or uncovered withdrawal from alcohol or substance use - Possible development of depression or anxiety as a result of cessation or reduction of alcohol or illicit substance use - Methadone and buprenorphine both reduce additional opioid use in pregnancy, but the neonate often develops a withdrawal syndrome referred to as neonatal abstinence syndrome (NAS) - Possible risk of drug substitution - Increased risk of fetotoxicity - Possible increased risk of congenital defects and anomalies related to exposure to the pharmacological intervention (particularly for acamprosate, naltrexone, nalmefene, disulfiram, benzodiazepines) - Inconvenient for women, particularly maintenance treatment requiring daily dosing - There are some suggestions in the literature that pregnant and postpartum women maintained on opioid agonists may have pain management needs different from those of non-opioidagonist-maintained women (Jones et al., 2009;Hoflich et al., 2012) - Requires patient monitoring to ensure patient continues taking her medication - A comprehensive care model in which pharmacotherapy is part of a women-centred, traumainformed programme would be the best model of care -and also the costliest

# Values and preferences

# Draft recommendations:
- Pharmacotherapy is not recommended for routine treatment of dependence on amphetamine-type stimulants, cannabis, cocaine, or volatile agents in pregnant patients o Medications for the treatment of alcohol dependence (acamprosate, naltrexone and disulfiram) should generally not be used in pregnancy. o Pregnant patients with benzodiazepine dependence should undergo a gradual taper. o Pregnant patients with an opioid use disorder should be encouraged to commence opioid agonist pharmacotherapy with either methadone or buprenorphine, in preference to detoxification, or detoxification followed by naltrexone.
Pharmacotherapy is not recommended for routine treatment of dependence on amphetamine-type stimulants, cannabis, cocaine or volatile agents in pregnant patients.

# Strength of recommendation: Conditional
Quality of evidence: Very low
- For pregnant patients who use cannabis, amphetamine-type stimulants, cocaine, and volatile agents, the focus of treatment should be on psychosocial interventions. - The recommendation was considered conditional given the complete lack of research on this issue.

# RECOMMENDATION 
Given that the safety and efficacy of medications for the treatment of alcohol dependence has not been established in pregnancy, an individual risk benefit analysis should be conducted for each woman.

# Strength of recommendation: Conditional
Quality of evidence: Very low
- Pregnant patients with alcohol dependence should be offered psychosocial interventions.
- The recommendation was considered conditional given the complete lack of research on this issue.

# RECOMMENDATION 
Pregnant patients with opioid dependence should be advised to continue or commence opioid maintenance therapy with either methadone or buprenorphine.

# Strength of recommendation: Strong

# Quality of evidence: Very low
- Pregnant patients with opioid dependence should be encouraged to commence opioid agonist pharmacotherapy, which should be combined with psychosocial interventions. - Opioid-dependent pregnant women who are already taking opioid maintenance therapy with methadone should not be advised to switch to buprenorphine due to the risk of opioid withdrawal. Pregnant opioid-dependent women taking buprenorphine should not be advised to switch to methadone unless they are not responding well to their current treatment. - In opioid-dependent pregnant women, the buprenorphine mono formulation should be used in preference to the buprenorphine/naloxone formulation. - Regardless of the choice of medication, psychosocial interventions should be an integral component of treatment.
- Opioid-dependent pregnant patients who wish to receive opioid antagonist pharmacotherapy should be discouraged from such a choice. - It was decided that this recommendation should be strong despite the low quality of evidence as the rate of relapse to opioid use following detoxification is high and the risks of harm from failed detoxification are catastrophic compared to the small risks of harm from opioid maintenance treatment.

# Factors in considering the strength of the recommendations (recommendations 9-11):

# Recommendations 9 & 10 Recommendation 11
Is there high or moderate quality evidence?
The higher the quality of evidence, the more likely is a strong recommendation.

# No No
Is there certainty about the balance of benefits versus harms and burdens?
In case of positive recommendations (a recommendation to do something), do the benefits outweigh harms? In case of negative recommendations (a recommendation not to do something), do the harms outweigh benefits?

# No Yes

# Are the expected values and preferences clearly in favour of the recommendation? Yes Yes
Is there certainty about the balance between benefits and resources being consumed?
In case of positive recommendations (recommending to do something) is there certainty that the benefits are worth the costs of the resources being consumed? In case of negative recommendations (recommending not to do something) is there certainty that the costs of the resources being consumed outweigh any benefit gained?

# Yes Yes

# Research recommendations
- A potential case registry of pregnancies exposed to different substances, including psychotropic medication used for the treatment of substance use disorders in pregnancy, which can help explore the potential risks and benefits of pharmacotherapy in substance use disorders in pregnancy. o The optimal treatment with methadone and buprenorphine in pregnancy (including further dose/response studies). o Safety of pharmacotherapy for alcohol dependence in pregnancy.

# METHADONE vs BUPRENORPHINE during pregnancy for women with opioid dependence

# INTERVENTION DURING PREGNANCY ONLY

# General treatment settings
No trials were identified from these settings. Medications were administered double-blind and double-dummy (i.e., each dosing day 12 sublingual tablets followed by 40 ml of oral liquid were administered). The first dose of double-blind medication was given at least 6 hours after the last immediate-release morphine and was split and separated by 2 hours. Buprenorphine: Participants were started with a dose of buprenorphine ranging from 4-24 mg. A participant assigned to active buprenorphine received 12 sublingual buprenorphine HCl (SubutexTM 2 mg) tablets followed by 40 ml of placebo liquid. Dose conversion was derived from first converting immediate-release morphine into methadone milligrams and then an equivalent buprenorphine dose was selected based on clinical experience and literature demonstrating similar outcomes for 8mg of buprenorphine and 60 mg of methadone.

# Specialist treatment settings
On the subsequent 2 days, doses of buprenorphine were systematically increased on an individual basis (2-4 mg of buprenorphine/day) that was dependent on patient report and clinician assessment until day 4 when patients achieved an individual stabilization dose.
Methadone: Participants were started on the first day with a total dose of methadone which ranged from 20-60 mg. A participant assigned to active methadone received 12 sublingual placebo tablets followed by her dose of methadone HCl (20-100 mg) in 40 ml liquid. The dose conversion ratio used for the transition was 6 mg morphine for every 1mg methadone.
On the subsequent 2 days, doses of methadone were systematically increased on an individual basis (5-10 mg methadone/day) that was dependent on patient report and clinician assessment until day 4 when patients achieved an individual stabilization dose. but admitted for at least 3 days during induction period Participants were admitted to the clinic for a minimum of 3 days induction. All participants were maintained on oral slow-release morphine hydrochloride. Participants received a mean daily dose of 330.56mg (range: 90-600mg) over 24 hours; the final dose of slow-release morphine (mean: 164.44mg SD: 95.50; range: 30-460mg) a mean of 17 hours prior to the first dose of medication. Buprenorphine: Participants were started on 8 mg buprenorphine at the onset of moderate withdrawal symptoms on day 1 (Wang score between 5 and 10). Participants who received more than 400mg/day of oral slow-release morphine, commenced treatment with 12 mg buprenorphine. Doses were titrated for 5 days according to a predefined titration algorithm: day 1 dosing was followed by 12 mg buprenorphine if withdrawal was present. Dose titration increments to 16, 20 and 24 mg per day were available during buprenorphine induction.
Participants received placebo syrup comprising 30mg dextramethorphan oral solution tastematched to methadone. Doses of buprenorphine were between 8 and 24 mg/day throughout the study. Methadone: Participants were started on 40 mg methadone at the onset of moderate withdrawal symptoms on day 1 (Wang score between 5 and 10). Participants who received more than 400mgday of oral slow-release morphine, commenced treatment with 55 mg methadone. Doses were titrated for 5 days according to a predefined titration algorithm: day 1 dosing was followed by 55 mg methadone if withdrawal was present. Dose titration increments to 70, 85 and 100 mg per day were available during induction onto methadone (depending on clinical status).
Participants received sub-lingual placebo tablets to taste-matched to buprenorphine. Doses of methadone ranged between 40 and 100 mg/day throughout the study.
All participants received food vouchers as compensation (the maximum amount possible was the equivalent of 1000 euros for 20 weeks participation). Before randomization, all participants received rapid-release morphine sulfate as inpatients to achieve medical stabilization and to ease the transition to the double-blind medication.
A blinded individualised dosing schedule was used to implement dose-unit increases or decreases with dose adjustments of 2mg for buprenorphine and 5 or 10 mg for methadone.
Dose adjustments were based on clinical decisions, participant request, urine toxicology and self-reported withdrawal symptoms. Buprenorphine: Daily seven tablets (three in the size of an 8-mg tablet and four in the size of a 2-mg tablet) to place under the tongue for 5 minutes, or until the tablets dissolved. Each tablet contained buprenorphine or placebo. A flexible dose range of 2 to 32 mg of buprenorphine in sublingual tablets was estimated to be equivalent to 20 to 140 mg of methadone on the basis of previously published data from clinical trials. After receiving these tablets, participants received liquid containing methadone placebo. Oral methadone placebo was given in the same fixed volume and included the same flavour-masking concentrates as the active drug concentrate. Methadone: Daily seven tablets of placebo buprenorphine followed by methadone dose in liquid preparation diluted to provide the dose in a fixed volume (e.g., 40 ml at U.S. sites and 50 ml in Vienna).
Monetary vouchers in exchange for providing urine samples that were negative for opioids (other than buprenorphine and methadone), other illicit drugs, and misuse of prescription medications.
INFANT:  (Jones 2005 andJones 2010) were well-conducted with appropriate randomization and blinding. However, the high rate of attrition in Jones 2010 and the magnitude of the differential between the groups (18% in methadone and 33% in the buprenorphine groups) results in the overall risk of bias rated as serious 2 Imprecision: The event rate is low and the confidence interval is wide. 3 Risk of Bias: Attrition was high and poses a serious risk of bias. 4 Imprecision: Two trial reported withdrawal data (Jones 2005 andFischer 2006). Trial samples sizes were very small (18 in each trial) and there is a high likelihood of imprecision in the results although confidence intervals are not reported for the estimates. 5 Risk of Bias: All three trials were well-conducted but attrition was high in all three trials. In the larger trial (Jones 2010) the magnitude of the differential attrition between the groups (18% in methadone and 33% in the buprenorphine groups) results in the overall risk of bias rated as serious. 6 Indirectness: Retention in the trial was deemed a suitable proxy measure for retention in substance use treatment. The evidence was not downgraded for indirectness. 7 Imprecision: The confidence interval is wide and the sample size is less than 400 (GRADE guideline for assessing continuous data) 8 Imprecision: Event rate was very low and the confidence interval was wide. 9 Imprecision: Event rate is very low and the confidence interval is very wide. VERY LOW 5,9 There were zero events in the buprenorphine group and 3 events in the methadone group.

# Quality assessment
No. of patients  (Jones 2005 andJones 2010) were well-conducted with appropriate randomization and blinding. However, the high rate of attrition in Jones 2010 and the magnitude of the differential between the groups (18% in methadone and 33% in the buprenorphine groups) results in the overall risk of bias rated as serious 2Imprecision: The event rate is low and the confidence interval is wide.
3 Risk of Bias: Attrition was high and poses a serious risk of bias. 4Imprecision: Two trial reported withdrawal data (Jones 2005 andFischer 2006). Trial samples sizes were very small (18 in each trial) and there is a high likelihood of imprecision in the results although confidence intervals are not reported for the estimates.
Risk of Bias: All three trials were well-conducted but attrition was high in all three trials. In the larger trial (Jones 2010) the magnitude of the differential attrition between the groups (18% in methadone and 33% in the buprenorphine groups) results in the overall risk of bias rated as serious.
Indirectness: Retention in the trial was deemed a suitable proxy measure for retention in substance use treatment. The evidence was not downgraded for indirectness.
Imprecision: The confidence interval is wide and the sample size is less than 400 (GRADE guideline for assessing continuous data) 8Imprecision: Event rate was very low and the confidence interval was wide.
Imprecision: Event rate is very low and the confidence interval is very wide.

# Quality assessment
No. of patients

# General treatment settings
No trials were identified from these settings. No women were lost from the trial.

# Specialist treatment settings

# Infant birthweight in grams
The mean infant birthweight in the intervention groups was 123.54 higher (187.58 lower to 434.66 higher)
  LOW 1,5

# Infant prematurity

# Estimated gestational age at delivery in weeks
The mean infant prematurity in the intervention groups was 1.13 higher (0.11 lower to 2.37 higher)
(1 study) No women experienced a spontaneous abortion in the trial  The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval. RR: Risk ratio.

# GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Risk of Bias: Rated as Serious. Lack of reporting results in the randomization process being marked as unclear. The lack of blinding is a high risk due to the possible presence of performance and detection bias. 2 Indirectness: Rated as Serious. Illicit opioid use could not be determined by urinalysis so identification of injection sites served as a proxy measure. 3 Imprecision: Rated as Serious. The event rate is low and the confidence interval is wide. 4 Indirectness: The proxy measure of retention in the trial is used to indicate treatment retention. The report states that women participated actively in the treatment programme but no comparison between groups is provided. 5 Indirectness: The number of premature births was not reported. The range of EGA indicates that there were some premature < 37 week births. 6 Imprecision: Rated as Serious: There is a likelihood of imprecision due to the small overall sample size. 7 Imprecision: Rated as Serious: The confidence interval is wide.
Guidelines for the identification and management of substance use and substance use disorders in pregnancy Risk of Bias: Rated as Serious. Lack of reporting results in the randomization process being marked as unclear. The lack of blinding is a high risk due to the possible presence of performance and detection bias.
Indirectness: Rated as Serious. Illicit opioid use could not be determined by urinalysis so identification of injection sites served as a proxy measure.
3 Imprecision: Rated as Serious. The event rate is low and the confidence interval is wide.
Indirectness: The proxy measure of retention in the trial is used to indicate treatment retention. The report states that women participated actively in the treatment programme but no comparison between groups is provided.
5 Imprecision: Rated as Serious. The sample size is very small N = 48 and the confidence interval is wide.
Indirectness: The number of premature births was not reported. The range of EGA indicates that there were some premature < 37 week births.
Imprecision: Rated as Serious: There is a likelihood of imprecision due to the small overall sample size.
Imprecision: Rated as Serious: The confidence interval is wide.
Evidence profile 5: Breastfeeding Evidence question:
In the management of postpartum women using alcohol or drugs or with substance use disorders, does encouraging breastfeeding result in better maternal or infant outcomes than not encouraging breastfeeding, discouraging breastfeeding (recommending breast milk substitutes), or recommending intermittent use of breast milk substitutes following periods of substance use?
Study selection criteria for the systematic review:
Study design: RCTs Population: Postpartum women using alcohol or drugs or with substance use disorders.
Interventions: Encouraging breastfeeding.
Control: Not encouraging breastfeeding (treatment-as-usual), discouraging breastfeeding (recommending breast milk substitutes), or recommending short-term use of breast milk substitutes for periodic substance use.
The following outcomes were of interest:
Outcome Importance (0-9)

# EVIDENCE TO RECOMMENDATIONS TABLE
Breastfeeding with maternal alcohol and/or other substance dependence There were no randomized controlled trials identified for this evidence profile. The evidence summary is based on a narrative review of the evidence.

# Summary of evidence (see the longer narrative review of evidence following this table)
- Enhanced maternal-infant attachment through breastfeeding (Luijk et al., 2012) is especially important, particularly for women feeling guilty about their prenatal drug use and those with lack of self-confidence in parenting skills. - Breastfeeding and/or breast milk may reduce the incidence and/or severity of neonatal abstinence syndrome in opioid exposed infants (McQueen et al., 2012). - Evidence of decreased stress response (Mezzacappa et al., 2005) and increased vagal tone, indicating better autonomic regulation, in lactating versus non-lactating women is salient for drug dependent women. Stress can be a major factor in the development of psychiatric symptoms, and has been linked to relapse to substance abuse (Sinha, et al. 2007) Further maternal dysregulation of the stress and reward systems is associated with drug seeking and neglectful parenting behaviors (Rutherford et al., 2011). - For alcohol, binge alcohol, tobacco and cannabis use, breastfeeding rates rebound substantially in the postpartum period compared with use during pregnancy (National Survey on Drug Use and Health, combined data from 2002-2007). - Depression correlates with substance use, and new mothers with postpartum depression may be at high risk for substance use or return to substance use (Chapman & Wu, 2013). - Maternal psychopathology is more common in substance dependent women than in the general population (Fitzsimons et al., 2007) and is not infrequently related to poor judgment, enhancing the physical risk to the breastfed infant. Maternal somnolence, lack of adequate sleep-wake cycling, or decreased reaction times due to psychoactive medication or drug use may additionally result in infant injury. Women with substance use disorders are more likely to minimize risks, have less self-control, and less regard for their own and other people's safety in situations that can be risky for the breastfed infant, further enhancing the possibility of harm. - Breastfed infants necessarily accompany their mothers and require attention more frequently than the nonbreastfed infant. For women who are medically or psychiatrically unstable, have continued drug use, or live in environments that are unsafe or chaotic, this translates to increased infant exposures to violence, maternal drug seeking/drug trade, or maternal prostitution. Due to brain changes that are associated with drug use, drug dependent women often view normal infant cues as stressful instead of rewarding (Rutherford et al., 2011). - Women who are regular cocaine or amphetamines/methamphetamines users and unstable should be advised against breastfeeding. Mothers who use these stimulants infrequently may be candidates for breastfeeding, provided that they express and throw away the milk after using, have a supplementary feeding plan in place, and do not breastfeed for 24 hours after use. Mothers need to be advised that these substances have been found in the breast milk, and has been shown to cause toxicity in the infant. - There is insufficient information regard breastfeeding during cannabis use, although it has been found in breast milk.
Its effects on the infant are unknown. - Two small sample size reports have noted that women prescribed methadone may want to consider weaning their children off breast milk gradually to reduce the risk of developing withdrawal symptoms (Malpas & Darlow, 1999;Isemann et al., 2010).

# Benefits and harms
- Pregnancy and the immediate postpartum period represents an ideal time for mother-child bonding and breastfeeding may increase this bonding - Breastfeeding represents the single best way for a mother to feed her child - Breastfeeding is likely to lead to better short-and long-term child development outcomes - Breastfeeding may serve as a protective factor from many illnesses - Breastfeeding may help protect babies from developing allergies - Breastfeeding may boost a child's intelligence - Breastfeeding may protect a child from obesity - Breastfeeding may lower a baby's risk of SIDS - Breastfeeding can reduce maternal stress level and risk of postpartum depression - Breastfeeding is less costly, more hygienic and easier to deliver than other feeding methods

# EVIDENCE TO RECOMMENDATIONS TABLE
- Potential higher risk of difficulties bonding due to neonatal withdrawal symptoms - Short and long term risks of the child being exposed via breast milk to varying amounts of substances consumed by the mother. These risks depend on the substance consumed by the mother, with little data available for several substances (e.g., hallucinogens, volatile agents). The most harmful exposures are alcohol (>50gms in one occasion) - Risk that a mother who is using sedative substances may inadvertently suffocate the child - Greater risk exposure of breastfed child to chaotic lifestyle harms such as violence, maternal drug seeking/ prostitution. - Maternal psychopathology may enhance risk to breast fed child

# Values and preferences

# In favour: Mother
Health-care worker Community

# Against: Mother

# Health-care worker
- Fatigue, irritability, poor bonding may make breastfeeding undesirable - Lifestyle-need to seek drugs/engage in prostitution may make breastfeeding undesirable - Physical effects -painful enlarged breasts, poor lactation -may make breast feeding undesirable to mother - May believe breastfeeding will harm infant - May believe mother is incapable of breastfeeding - May believe mother is likely to smother infant - May find time and commitment needed to support mother burdensome - May believe infant is at risk from mother's substance use - Partners/family/employers may believe breast feeding is inappropriate and actively oppose it

# Costs and feasibility

# Feasibility (including economic consequences)
- Managing breastfeeding in women who use alcohol requires support, trust and clear advice: e.g. women who use alcohol should be discouraged from breastfeeding for 2 hours after consuming one drink, and 4 to 8 hours after consuming more than one drink in a single sitting. - The availability of safe and affordable breast milk substitutes, including access to clean water, sterilizing equipment, the affordability of breast milk substitutes and the age of the infant/child needs to be considered and balanced against risks of breastfeeding. - Breastfeeding itself imposes little additional cost beyond providing basic services to the mother and child. However, trained staff and a sustainable programme is needed to support breastfeeding and bonding and teach and support mother with care of the infant. - A comprehensive care model in which there is a focus on the mother-infant dyad and is part of a women-centred, trauma-informed programme would be the best model of care -and also the costliest.

# Draft recommendations:
- The decision to breastfeed should take into account the specifics risks and benefits of breastfeeding compared to alternatives in each case. In most instances, the benefits will outweigh the risks of breastfeeding and in this situation women with a substance use disorders should be encouraged to breastfeed with appropriate support and precautions.
- Skin-to-skin contact is important regardless of feeding choice and needs to be actively encouraged for the mother who is fully conscious and aware and able to respond to her baby's needs.
- Mothers who are stably maintained on opioid agonist medication, either methadone or buprenorphine, should be encouraged to breastfeed.
- Mothers who are stably maintained on opioid antagonist medication, such as naltrexone, should be discouraged from breastfeeding because naltrexone does pass into breastmilk, and naltrexone has been shown to cause tumors in animal studies.
RECOMMENDATION  A.
Mothers with substance use disorders should be encouraged to breastfeed unless the risks clearly outweigh the benefits. B. Breastfeeding women using alcohol or drugs should be advised and supported to cease alcohol or drug use; however, substance use is not necessarily a contraindication to breastfeeding.

# Strength of recommendation: Conditional

# Quality of evidence: Low
- A risk assessment should take into account the risks of exposure to alcohol and drugs in breast milk, HIV status, the specific pattern of substance use in each case, the availability of safe and affordable breast milk substitutes, as well as access to clean water, sterilizing equipment, and the age of the infant/child. Heavy daily alcohol consumption, such as in alcohol dependence, would constitute high risk to the infant, for example, and in the presence of safe breast milk alternatives, it would be preferable not to breastfeed. - The message to breastfeeding women who have used alcohol and drugs, to cease using alcohol and drugs while breastfeeding should be given in such a way that it does not undermine the potential benefits of breastfeeding. - It is possible to reduce the risk of exposure through breastfeeding by altering the timing of breastfeeding, or by the use of temporary alternatives, such as stored (frozen) breast milk or breast milk substitutes where they are available and can be safely used. Women who use alcohol intermittently should be discouraged from breastfeeding for 2 hours after consuming one standard drink (10 g of pure alcohol), and 4 to 8 hours after consuming more than one drink in a single occasion. Breastfeeding advice for women with HIV should also take into consideration the risk of HIV transmission (refer to WHO guidelines on breastfeeding and HIV). - Mothers of infants with a neonatal withdrawal syndrome should be offered appropriate breastfeeding information and support. - This recommendation was considered conditional because the different values and preferences of women and the lack of strong evidence of harms of low levels of substance use in pregnancy.

# RECOMMENDATION 
Skin-to-skin contact is important regardless of feeding choice and needs to be actively encouraged for the mother with a substance use disorder who is able to respond to her baby's needs.

# Strength of recommendation: Strong

# Quality of evidence: Low
- It was decided that the recommendation should be strong despite the very low quality evidence as the risk of harm is minimal, it consumes no resources, the values and preferences were in favour of the recommendation, and there was considered to be certainty about the balance between benefits and harms.

# RECOMMENDATION 
Mothers who are stable on opioid maintenance treatment with either methadone or buprenorphine, should be encouraged to breastfeed unless the risks clearly outweigh the benefits.

# Strength of recommendation: Strong

# Quality of evidence: Low
- Women prescribed opioids such as methadone and buprenorphine and wishing to stop breastfeeding may wean their children off breast milk gradually to reduce the risk of developing withdrawal symptoms. - It was decided that the recommendation should be strong, as, despite the low quality of evidence of effect, it was considered highly likely that the benefit of avoiding withdrawal symptoms in the infant strongly outweighed any potential harms. The values and preferences expressed by end-users surveyed were strongly in favour of the recommendation and there was certainty about the balance between benefits and resources being consumed.

# Factors in considering the strength of the recommendations (recommendations 12-14):
Factor Decision Is there high or moderate quality evidence?
The higher the quality of evidence, the more likely is a strong recommendation.
Is there certainty about the balance of benefits versus harms and burdens?
In case of positive recommendations (a recommendation to do something), do the benefits outweigh harms? In case of negative recommendations (a recommendation not to do something), do the harms outweigh benefits?

# Are the expected values and preferences clearly in favour of the recommendation? Yes
Is there certainty about the balance between benefits and resources being consumed?
In case of positive recommendations (recommending to do something) is there certainty that the benefits are worth the costs of the resources being consumed? In case of negative recommendations (recommending not to do something) is there certainty that the costs of the resources being consumed outweigh any benefit gained?
Breastfeeding and substance use/misuse: A review of the evidence and estimates of risks associated with individual substances

# Lauren M. Jansson
Both licit and illicit substance use remain a significant problem among women of childbearing age. The 2007 National Survey on Drug Use and Health (NSDUH) revealed that among pregnant women aged 15 to 44 years, 5.2 percent used illicit drugs in the past month in the US. Although the prevalence of prescribed opioid pain relievers/narcotic analgesics, such a hydrocodone and oxycodone, among pregnant women is not well known, there is growing evidence that misuse of opioid pain relievers/narcotic analgesics is increasing internationally (RADARs system report 2012; Maxwell & McCance-Katz, 2009). In the US, the incidence of NAS and maternal opioid use has tripled between 2000 and 2009. Adolescents are a particular concern; in 2010-11, among young pregnant women between 15 and 17 years the rate of illicit drug use was 20.9% and smoking rates are higher in pregnant vs non-pregnant teens in this group (NIDA). Other substance use during pregnancy is also of significant concern throughout the world: In Barcelona, 11% of meconium tested was positive for drugs of abuse in a random survey of 175 newborns (Concheiro et al., 2012); 14% of Canadian women report alcohol use during their last pregnancy in 2005 (Health Canada, 2005), and worldwide, the incidence on fetal alcohol syndrome is 1:2000 live births (Sachdeva et.al., 2009). Breast milk is well-known as optimal nutrition for the newborn. There are myriad other recognized benefits from breast milk and lactation that are likely to provide a particular benefit to the drug dependent dyad who are, in general, at higher risk for many acute and chronic physical and psychological conditions. These include reduced infections in the neonate, a diminution of certain chronic health conditions in later life, such as Types I and II diabetes and obesity, and improved cognition and brain development (Isaacs et al., 2010). Breastfeeding is an analgesic for newborns (Gray, et al., 2002) and there is some evidence that breast milk and/or breastfeeding can ameliorate the incidence or severity of neonatal abstinence syndrome (NAS, or withdrawal, typically found in opioid exposed infants after delivery) (Welle-Strand et al., 2013, McQueen, 2011. Mothers also have significant health benefits, such as reduced incidence of breast and ovarian cancer, decreased stress response (Mezzacappa et al., 2005) and increased vagal tone, indicating better autonomic regulation, in lactating vs nonlactating women. This may be a particularly salient benefit for drug dependent women, as stress can be a major factor in the development of psychiatric symptoms, and has been linked to relapse to substance abuse (Sinha, et al. 2007) and maternal dysregulation of the stress and reward systems is associated with drug seeking and neglectful parenting behaviors (Rutherford et al., 2011). Enhanced maternal-infant attachment (Luijk et al., 2012) may be another especially important benefit, particularly for women who may harbor guilt in regards to their prenatal drug use and lack of self-confidence in parenting skills.
Despite the significant and specific benefits of breast milk and breastfeeding for the substance exposed dyad, when considering lactation among this high risk population, there must necessarily be a discussion regarding the risk: benefit ratio of this practice, and several risk factors must be considered. These factors stem from: 1) maternal functioning, 2) infant functioning, and 3) toxicities associated with the substance(s) used.

# The substance dependent mother
Substance dependent women may have health or other conditions that can increase the risk to the breast fed infant. These include HIV or other infections, poor nutrition, and psychiatric disorders that require psychotropic medications with known toxicity. Research has indicated that the mother's decision to breastfeed does not necessarily reflect a lifestyle including drug abstinence that would preclude toxic exposures in her offspring (Frank et al., 1992). Drug dependent women frequently use more than one substance (illicit and/or licit), and the incidence of concurrent alcohol use and cigarette smoking is high. Exposure to alcohol or drugs can significantly impair the mother's judgment and ability to care for the baby, and for chronic drug users, repetitive exposures increase this risk and lead to brain changes that enhance this risk. For women who are able to achieve abstinence during pregnancy, relapse to substance use after delivery is a significant concern. For alcohol, binge alcohol, tobacco and cannabis use, rates rebound substantially in the postpartum period compared with use during pregnancy (National Survey on Drug Use and Health, combined data from. Some women relapse on substances that are not usually detected in the urine toxicology tests that are part of the regular screening for drug use in treatment programs or hospitals (e.g. clonidine, some benzodiazepines). In most societies, pregnant and parenting drug dependent women are usually under considerable social pressure to deny substance use, making detection of perinatal substance dependence both important and problematic. Depression correlates with substance use, and new mothers with postpartum depression may be at high risk for substance use or return to substance use (Chapman & Wu, 2013). Additionally, substance using and/ or dependent women frequently display some behaviors or conditions that can be harmful for the breastfed infant independently or in addition to the drug exposure per se. Maternal psychopathology is more common in substance dependent women than in the general population (Fitzsimons et al., 2007) and is not infrequently related to poor judgment, enhancing the physical risk to the breastfed infant. Maternal somnolence, lack of adequate sleep-wake cycling, or decreased reaction times due to psychiatric medication may additionally result in infant injury. Women with substance use disorders are more likely to minimize risks, have less self-control, and less regard for their own and other people's safety in situations that can be risky for the breastfed infant, further enhancing the possibility of harm.

# The substance exposed infant
The risks associated with substances in breast milk to the infant are also influenced by factors beyond what is known about the pharmacokinetics of the drug. Certain drugs may accumulate in the infant due to reduced clearance or immature metabolic pathways (AAP, 2013). Specific genotypes may provide increased vulnerability, such as those associated with ultra-rapid metabolism of codeine (Berlin, et al., 2009). The substance exposed infant, particularly the opioid exposed infant, may undergo NAS after birth, which can entail significant morbidity and prolonged pharmacotherapeutic treatment. Infants with NAS may be particularly difficult to breastfeed due to symptoms of the disorder, such as hypertonicity, suck-swallow incoordination, or other feeding difficulties (Jansson et.al., 2004), which can lead to failure to thrive for infants relying solely on breast milk for nutrition in addition to maternal frustration or feelings of guilt or inadequacy which can lead to depression or relapse. An important consideration is that the breastfed infant, as opposed to the infant receiving formula, necessarily accompanies his mother and requires attention more frequently. For women who are medically or psychiatrically unstable, have continued drug use, or live in environments that are unsafe and/or chaotic, this translates to increased infant exposures to harmful situations. Infants in these situations can be at risk for exposure to violence, maternal drug seeking/drug trade, or maternal prostitution. Due to brain changes that are associated with drug use, drug dependent women often view normal infant cues as stressful instead of rewarding (Rutherford et al., 2011), and this can additionally lead to situations of infant neglect and/or abuse.

# Substances and breast milk/breastfeeding
Risks of breastfeeding in substance dependent women include direct toxicities of the substances transmitted into breast milk and ingested by the infant, as well as secondary exposures resulting in additional toxicities to the infant due to maternal substance use or the environment in which the substance dependent woman lives. Drugs with long half lives are more likely to accumulate in human milk, and drugs with high bioavailability are more easily absorbed by the infant (Hale, 2004). Illicit substances can be cut with dangerous and unknown adulterants. Vaporized substances can provide a secondary exposure to the infant; for example, there are over 450 compounds in THC smoke, many of which are toxic; 6 to 53% of  9 -THC is released into the air during smoking by side stream. For women living in poor environments, as many drug dependent women are, additional environmental exposures such as heavy metals, insecticides, inhaled aromatic hydrocarbons, etc. should be considered (Erlin & van den Anker, 2012).
There exists sparse literature on the subject of substances of abuse and transmission into breast milk in total, as this research is, in general, fraught with ethical and practical dilemmas, and is additionally difficult to perform.
There is a near absence of literature on long term effects of exposures via breast milk. Most clinical trials in this arena explore the issues of lactation and medications used to treat opioid dependence. The large majority of literature in the area of illicit substance use and lactation consists primarily of case reports. All suffer from small numbers. While any discussion of individual substances of abuse is somewhat artificial in this population of women due to the high prevalence of poly-substance use, individual substances and toxicities related to infant exposures via breast milk are considered below. Estimates of risk for each substance are included, but it is important to note that most are largely author opinion based on a review and synthesis of available literature.
Both the parent drug and the metabolite are present in milk, and high concentrations are expected due to the chemical nature of cocaine (Bailey, 1998), which can result in significant exposures (Winecker et al., 2001).
There is considerable variability in the concentrations of cocaine reported in breast milk, and cocaine is not consistently detected in the breast milk of known users, so analysis of breast milk is not a sensitive method of exposure. For a 4 kg infant feeding every 3 hours, the blood concentration of cocaine can reach 200ng/mL comparable to an adult blood cocaine concentration measured after administration of 1.5 mg/kg intranasal or 16 mg IV dose of cocaine (Winecker et al., 2001). Newborns are particularly sensitive to cocaine because metabolism of cocaine to benzoylecgonine, its principal metabolite, is delayed due to immaturity of the cholinesterase system. Intoxication in the breastfed infant of the intranasal cocaine using mother has been reported (Chasnoff et al., 1987) as has intoxication in an infant whose mother used cocaine for nipple soreness (Chaney et al., 1988). Guidelines have been developed for the lactating cocaine occasionally using woman (Sarkar et al., 2005). A 24-hour period of breastfeeding abstinence has been recommended for women who occasionally use cocaine (Cressman, 2012).
Estimate of risk: Due to the immaturity of the newborn's ability to metabolize cocaine ingested via breast milk, high concentrations are possible, and reported intoxications, risks of lactation in chronically cocaine using, or cocaine dependent, women are significant. It is likely that the risks associated with lactation in heavy or chronic cocaine users outweigh benefit when safe alternatives to breastfeeding are available. In non dependent or intermittent users the risk is lower, and can be further reduced by a 24-hours cessation in breastfeeding (when safe and affordable alternatives to breastfeeding are available).
Methamphetamine undergoes demethylation to amphetamine which is the active metabolite. Amphetamines often contain other substances with unpredictable effects. Amphetamines are concentrated in breast milk and 2.8 to 7.5 times maternal plasma (ACOG, 2011) and infant symptoms, including irritability and agitation (AAP, 2001) and infant death (Ariagno et al., 1995) have been reported. In one study, two women taking street methamphetamine (doses unknown) intravenously had drug levels measures in plasma and breast milk. Calculated infant doses were 16.7 and 42.2 mcg/kg/day of methamphetamine and 0.8 and 2.5 mcg/kg/day of amphetamine (Bartu, et al., 2009), which are less that therapeutic doses of equipotent dextroamphetamine for older children with ADHD.
Estimate of risk: Accurate information regarding the safety of methamphetamine abuse/misuse is unavailable.
 9 -THC is the main compound in cannabis, and it is very fat soluble, and it persists in the body fat of users and can be released over long periods of time depending on extent of use. There are many compounds, most toxic, in  9 -THC smoke. It appears that active components of cannabis are excreted into breast milk in small quantities. There is some concern about cannabis' effect of neurotransmitters, CNS development and endocannabinoid functions in the infant exposed via breast milk (Fernandez-Ruiz, et.al., 2004;Schuel, et.al.,2002).  9 -THC is concentrated to a milk/plasma ratio of 8 in breast milk in heavy users, secreted into breast milk and absorbed and metabolized by the infant (THC metabolites are found in infant feces) (Perez-Reyes & Wall, 1982). In one feeding the infant could ingest 0.8% of the weight adjusted maternal intake of one joint (Bennett, 1997). Cannabis exposure via breast milk in the first month of infant life was associated with decreased motor development, but not growth or intellectual development, at one year (Astley & Little, 1990), and infant effects, such as sedation, growth delay (Hale & Hartman, 2006) low tone and poor sucking (Liston, 1998) have been described. Two studies (Astley & Little, 1990;Tennes, et.al., 1985) found that occasional cannabis use during breastfeeding did not have any discernable effects on breastfed infants. However, because an important phase of brain growth occurs in the period just after birth, THC could theoretically alter brain cell metabolism (Garry et al., 2009) and hence development. Among chronic THC users, 50% report "impaired control over their use", and THC use itself is associated with a wide range of psychiatric conditions (Hall & Degenhardt, 2004), which implies an additional risk to the breastfed infant of the THC using mother.
Estimate of risk: Due to the potentially high concentrations of THC in breast milk of chronic/heavy users and toxicities present in smoke, the potential for altered development in exposed infants, and frequently altered sensorium of heavily using mothers, there is a significant risk. It is likely that the risks associated with lactation in heavy or chronic THC users outweigh benefit when safe alternatives to breastfeeding are available. However, small amounts of available literature regarding light or occasional use point to little effect on the infant. It may be, in the case of light or infrequent maternal THC use, that the benefits of breast milk/breastfeeding, with appropriate supports for infant care during period of maternal use, may outweigh risk in certain circumstances.
In cases of heavy cannabis use the risk is greater and it may be safer not to breastfeed when safe and affordable alternatives are available.
Benzodiazepines are frequently prescribed to drug dependent women, and also frequently abused/misused. Based on relatively small numbers, adverse event rates of 0-50% have been reported for various agents (17% alprazolam, 22% diazepam, and 50% clonazepam). These events include lethargy, irritability, poor weight gain and apnea. No adverse events have been reported for other agents (oxazepam, lorazepam, or temazepam) (Rubin et al., 2004). When used as an adjunctive medication, there exists the potential for drug-drug interactions and increased risk for CNS depression (for example, the opioid analgesic morphine and anxiolytic diazepam when taken together potentiate CNS depression) but use alone may present minimal risk. In one study among 124 benzodiazepine prescribed women, adverse outcomes, specifically sedation, was reported in 1.6% of infants.
Benzodiazepine use in the postpartum period that is prescribed is usually compatible with breastfeeding (Kelly et al., 2012).
Estimate of risk: While it has been found that prescribed benzodiazepine use is usually compatible with lactation, there is no available literature on benzodiazepine abuse/misuse and breastfeeding. Particularly in women who are polydrug dependent, where the potential exists for drug synergy to produce untoward effects in the infant, the risks are significant and it would appear that the risk of lactation in this population would outweigh benefit, when safe alternatives to breastfeeding are available.
There are many international beliefs that alcohol (particularly beer) intake improves breastfeeding success (Koletzka & Lehner, 2000) and that alcohol will increase milk yield and relax both the mother and the infant (Menella, 2002). Despite these beliefs, the opposite is true. Alcohol blocks the release of oxytocin, resulting in decreased milk yield and milk ejection reflex (Bowen & Tumbach, 2011). Alcohol exposure via breast milk can alter the infant's milk intake by decreased milk production and increased infant sucking, which may be compensatory (Giglia et al., 2006). Animal research has found that alcohol changes the structure of the mammary gland in rats, leading to impaired mammary gland function during the first few days of lactation (Steven et al., 1989). Early cessation of breastfeeding has been associated with a high frequency of alcohol consumption during lactation, even after controlling for confounders (Howard & Lawrence, 1998). Animal models have demonstrated diminished infant growth (Detering et al., 1979;Hekmatpanah et al., 1994;Vilaro et al., 1985). Alcohol enters breast milk by passive diffusion and reflects maternal blood levels within 30-60 minutes after ingestion (Lawton, 1985, Kesaniemi, 1974, Mennella & Beauchamp, 1993; for heavy drinkers, alcohol levels are higher in breast milk than in blood (Lawton et al., 1985). The infant brain is extremely sensitive to alcohol even in small quantities, and the small quantities ingested during lactation are accumulated in the infant because it is metabolized and excreted more slowly than in adults (Little et al., 1989). Alterations in infant sleep-wake cycles (Menella & Gerrish, 1998), development (Little et al., 1990), and infant growth (Backstrand et al., 2004) have been reported. There has been reported a strong inverse linear relationship between chronic exposure of ethanol in breast milk and the psychomotor developmental index on the Bayley Scales of infant development at one year (Little et al., 1989). Alcohol intake by lactating mothers recommended as "safe" for non-lactating women may have a negative effect on infant development and behavior (Giglia et al., 2006). The Institute of Medicine National Academy of Sciences (1991) concluded that alcohol consumption by lactating women in excess of 0.5 g/kg of maternal weight may be harmful to the infant. The American Academy of Pediatrics advises breastfeeding mothers to avoid alcohol consumption in general (AAP, 2005).
Estimate of risk: Lower levels of alcohol use (i.e. 1 standard drink per day) are unlikely to cause significant short or long term problems in the nursing infant, especially if the mother waits 2 to 2.5 hours per drink before nursing, and the risks are likely to be less than not breastfeeding. Daily heavy use of alcohol (i.e. more than 2 drinks per day) may affect infants negatively; alcohol appears to be eliminated from breast milk more slowly and there is a decrease in the length of time that mothers breastfeed their infants, resulting in significant risk. Chronically alcohol dependent women, or women who binge drink heavily represent a high risk to the infant, and breastfeeding is high risk and not recommended.
The first reports of problems with maternal opioid use and nursing were in 1985, when 4 infants became apneic after breastfeeding from mothers prescribed codeine every 4-6 hours (Davis & Bhutan, 1985). For codeine, 39 adverse events and 1 infant death (Koren et al., 2006) have been reported (Hendrickson et al., 2012). Infant toxicities may be related to a duplication of the CYP2D6 gene, causing mothers to be ultra-rapid metabolizers of codeine to morphine, leading to high plasma and milk levels (Madadi et al., 2009). Since there is no tangible method of assessing cytochrome phenotypes, codeine is not advised in nursing mothers. Other opioids may be equally unsafe. Twenty percent of oxycodone using mothers report neonatal CNS depression after breast feedings (Lam, 2012). One toddler death in a methadone misusing opioid naive breastfeeding mother has been described (West et al., 2009). Heroin transfers into breast milk and is converted to morphine. Morphine, in acceptable doses and used in the short term for pain control, is safe for breastfeeding women (Wittels et al., 1990;Hendrickson et al., 2012), however, heroin using women frequently consume larger (or unknown) doses making this practice dangerous (D'Appolito, 2013).
In general, agents used for the treatment of opioid dependence are likely to be compatible with breastfeeding. Maternal methadone and buprenorphine maintenance in opioid dependent pregnant woman are associated with improved maternal and neonatal outcomes in the context of comprehensive drug treatment and prenatal care. Methadone is distributed into breast milk in low concentrations, there are low ratios of milk to plasma concentrations (~0.4) and calculated theoretic infant doses are low (0.038-0.0152 mg/day) (Jansson et al., 2008;Bogen et al., 2011). Additionally, concentrations in infant plasma at two weeks of age are low (2.2 -8.1 ng/mL), making breastfeeding among stable and otherwise abstinent methadone maintained women recommended (Jansson et al., 2004) regardless of maternal methadone dose, as dose is unrelated to milk concentrations (Jansson et al., 2008). Reports on buprenorphine exposure via breast milk are somewhat limited.
Buprenorphine is excreted into human milk and achieves a level similar to that in maternal plasma. Extant literature finds low concentrations and low calculated theoretic infant doses (Ilett et al., 2012, Lindemalm et al., 2009; in addition this agent is poorly bioavailable, making it likely that breastfeeding should be encouraged in otherwise abstinence, stable buprenorphine maintained women. It is unlikely that either agent, when delivered to the breastfeeding infant from a medically maintained mother, would be present in substantial amounts necessary to prevent or ameliorate neonatal abstinence syndrome. There is a single report of a naltrexone maintained woman with low concentrations of naltrexone in breast milk and low calculated infant dose. Naltrexone is concentrated in breast milk at a milk:plasma ratio of 1.9 (Chan et al., 2004).
Estimate of risk: Opioid dependent women using heroin or misusing prescription opioid containing medications in a way that results in cycles of intoxication and withdrawal are likely to present a significant risk to their breastfed infant, and therefore this practice is discouraged. Prescribed oxycodone for lactating women has also been found to be unsafe. Prescribed morphine for pain control in the postpartum period is low risk and compatible with lactation. Breastfeeding in methadone and buprenorphine maintained and otherwise abstinent women women is low risk should be encouraged if they meet other criteria.
Advising the substance using woman on breastfeeding can present a dilemma to the treating practitioner. A complete and thorough evaluation of the dyad in the perinatal period would consider several factors, including:
- maternal medical and psychiatric status; o maternal drug use and substance abuse treatment histories and medication requirements; o maternal family and community support systems; o maternal plans for postpartum health and psychiatric care, substance abuse treatment and pediatric care; o access to and capacity to afford breastmilk substitutes, access to clean water and capacity to sterilize feeding equipment.
Evidence profile 6: Management of infants exposed to alcohol and other psychoactive substances

# Evidence question
Does the identification and treatment of neonates with disorders due to alcohol or drug exposure in utero result in better maternal, neonatal or infant outcomes, compared to treatment-as-usual or other forms of treatment of neonatal disorders due to alcohol or drug exposure in utero?
Study selection criteria for the systematic review:
Study design: RCTs Population: Neonates with disorders due to alcohol or drug exposure in utero such as neonatal substance withdrawal and fetal alcohol syndrome.
Interventions: Systematic methods of identification and treatment of disorders due to alcohol and drug exposure in utero, including medication for neonatal withdrawal.
Control: Treatment-as-usual, non systematic identification, other treatments of disorders due to alcohol or drug exposure in utero.
The following outcomes were of interest:
Outcome Importance (0-9)  4) buprenorphine compared to an opium solution; ( 5) oral morphine compared to tincture of opium in the treatment of neonatal withdrawal/neonatal abstinence syndrome (NWS/NAS). See accompanying GRADE tables for evaluation of treatment effect against critical outcomes. The small size and risk of bias in the studies evaluated means the evidence of treatment effect is very uncertain. - Protocols for the management of NAS have seen significant development over the past 40+ years. Initial NAS treatment guidelines were weight-based, and tables for treatment with phenobarbital and paregoric were published. Current treatment follows similar practices. Either an opioid such as morphine sulfate or tincture of opium, or a sedative, typically phenobarbital, predominate, with infrequent use of a benzodiazepine.
A measure of NAS such as the Finnegan scale is typically used to guide treatment initiation, maintenance, and weaning. Because there is neither a uniform assessment method to measure NAS nor an established treatment protocol, and health-care practices and costs worldwide are not uniform, it is difficult to state with any precision how NAS is treated across the globe. Moreover, the availability of opioids as a treatment for NAS varies worldwide, further complicating the ability to make general statements regarding NAS treatment. Patrick and colleagues  found that, between 2000 and 2009, per 1,000 hospital live births, prenatal exposure to opioids increased from 1.2 to 5.6 and the incidence of NAS increased from 1.2 to 3.4. Hospital charges for discharges with NAS increased more than 46% during this same 10-year period. - An opioid probably confers greater benefit than either phenobarbitone or diazepam as first-line pharmacotherapy for NAS (Osborne et al., 2013). Buprenorphine may prove to be an effective alternative front-line pharmacotherapy for NAS (Kraft et al., 2008).Buprenorphine may be superior to methadone in the reduction in NAS severity and time in treatment for NAS. - Jones et al. (2012a,b) reviewed the comparative efficacy studies of buprenorphine versus methadone. Regardless of whether the study was a randomized controlled trial, prospective study, or case report, there is clear evidence that prenatal buprenorphine exposure is related to NAS, and that such NAS may be less frequent, less severe, and/ or of shorter duration. However, conclusions are limited in regard to NAS due to the fact that most studies fail to adequately define and/or measure NAS and/or specify a treatment protocol. - There is limited experience with opioid antagonists in pregnancy outside of its investigation in Australia (Hulse et al., 2000(Hulse et al., 2001(Hulse et al., 2003(Hulse et al., 2004Hulse & O'Neil, 2002). Rapid opioid detoxification using sedation followed by naltrexone, as well as oral and implantable formulations of naltrexone, has been investigated. In all cases, there have been no reports of adverse fetal effects, and neonatal birth parameters were within normal limits. However, maternal outcomes were not reported and relapse to maternal opioid use was evident. Neonatal outcomes following prenatal exposure to implanted naltrexone were within normal limits, with some suggestion of a lower risk of prematurity and a higher 1-minute Apgar scores in naltrexone than methadone-exposed neonates. The small samples sizes and limited focus on outcomes suggest caution in the interpretation of the results of these studies; however, findings do not indicate that prenatal naltrexone exposure results in an increased risk for poor neonatal outcomes. - A rooming-in approach may help reduce the need for NAS pharmacotherapy, NICU admissions, and length of stay for term infants (Abrahams et al., 2007;Abrahams et al., 2010;Hodgson and Abrahams, 2012). Feeding on demand and swaddling may be sufficient to treat mild withdrawal symptoms (Kieviet et al. (2012)). - Early identification of Fetal Alcohol Syndrome (FAS) is feasible and can increase the uptake of early intervention programmes for children with FAS and their families, enabling children with FAS to reach their full potential (Bertrand, Floyd & Weber, 2005).

# EVIDENCE TO RECOMMENDATIONS TABLE

# Benefits and harms
- Pregnancy and the immediate postpartum period represents an ideal time for mother-child bonding, an opportunity to develop basic parenting skills. - Considerable research (e.g., Hudak & Tan, 2012) has found pharmacotherapy for NAS yields these benefits: -Less risk of seizures -Less risk of neonatal morbidity and mortality -Improved outcomes (e.g. weight gain, maternal bonding -provided mother and child are allowed to be together) -Possible reduction in congenital anomalies - In non-opioid-agonist maintained postpartum women, immediate and uninterrupted skin-toskin contact at birth, and rooming-in during the postpartum period is beneficial for establishing maternal-child bonding (Dumas 2013). - Early identification of Fetal Alcohol Syndrome (FAS) can improve the chances that children with FAS will reach their full potential.
- Risk of adverse neonatal response to pharmacological agent. Buprenorphine may have less adverse impact than methadone on fetal neurobehaviour (Jansson et al., 2012;Salisbury et al., 2012). - Jones et al (2010) found there may be a higher incidence of non-serious maternal adverse events, particularly non-serious maternal cardiovascular events, associated with methadone than buprenorphine. They found no differences in between the two medications for neonatal adverse events. - Early identification of Fetal Alcohol Syndrome (FAS) may stigmatize children and their mothers.

# Values and preferences

# In favour: Mother
Health-care worker Community - Resent extra time and resources devoted to managing mother and infant with NAS - Negative view of mother's ability to care for child - Community may have punitive view-may demand incarceration of mother or removal of child - Community may consider extra resources needed to manage mother and child wasteful

# Draft recommendations:
- Infants of all opioid-dependent mothers should be monitored for NAS. o Hospitals providing obstetrical care should have a protocol in place for identifying, assessing, monitoring and intervening using non-pharmacological and pharmacological methods for neonates prenatally exposed to opioids. o Pharmacological treatment of infants with NAS due to opioids should be initiated according to a validated NAS treatment protocol. o Non-pharmacological treatments including low lights, quiet environment, swaddling and skin to skin contact should be used with all prenatally opioid exposed neonates. o An opioid should be used as initial treatment for infants with NAS symptoms severe enough to need intervention due to opioid withdrawal. o If there has been concurrent use of other drugs in pregnancy, particularly benzodiazepines, and symptoms of NAS are not adequately suppressed by an opioid alone, phenobarbitone may be indicated as an additional therapy. If opioids are unavailable, phenobarbitone may be used as an alternative therapy. o If an infant has signs of NAS and reaches the treatment threshold and the drugs used by the mother are unknown, or are sedatives, or the infant was born to a mother intoxicated with alcohol, then phenobarbitone may be a preferable initial treatment. o Mothers of infants at risk of NAS should receive appropriate breastfeeding information and support, parenting support and assessment, and should be taught settling techniques. Women and their partners/ support persons should also receive information about safe sleeping practices, especially if using sedative substances.

# Final recommendations:
RECOMMENDATION  Health-care facilities providing obstetric care should have a protocol in place for identifying, assessing, monitoring and intervening, using non pharmacological and pharmacological methods, for neonates prenatally exposed to opioids.

# Strength of recommendation: Strong

# Quality of evidence: Low
- Evidence of a dose-response relationship between opioid maintenance treatment and neonatal withdrawal syndrome has been inconsistent, which implies that all infants should be assessed. - Infants exposed to opioids during pregnancy should remain in the hospital at least 4-7 days following birth and be monitored for neonatal withdrawal symptoms using a validated assessment instrument which should be first administered 2 hours after birth and then every 4 hours thereafter. - Non-pharmacological interventions including low lights, quiet environments swaddling and skin to skin contact should be used with all neonates prenatally exposed to alcohol and drugs. - It was decided that the recommendation should be strong despite the low quality of evidence of effect, as the GDG agreed that the benefits of such an approach strongly outweighed any potential harms. The values and preferences of end-users were in favour of the recommendation and there was certainty that while resources would be consumed, the benefits strongly outweighed costs. There was a high value placed on identifying preventable suffering in affected neonates. (1 study)

# Days to regain birthweight
The mean days to regain birthweight in the intervention groups was 2.8 lower (5.33 to 0.27 lower)
  VERY LOW 1,2,5

# Duration of treatment for NAS Days
The mean duration of treatment for nas in the intervention groups was 12.5 higher (7.52  LOW 5,6,7 As this was a RCT, the GRADE assessment was done within the RCT study design category.

# Total length of hospital stay Days in hospital
The mean total length of hospital stay in the intervention groups was 2.54 lower (7.06 lower to 1.98 higher)

# (2 studies)
  VERY LOW 8,9 As this was a meta-analysis of two quasitrials, the GRADE assessment was done within the observational study design category.

# Infant weight gain
See comment See comment Not estimable -See comment Not reported

# Days to regain birthweight
The mean days to regain birthweight in the intervention groups was 1.4 lower (3.47 lower to 0.67 higher)
VERY LOW 10,11 As this was a quasi-trial, the GRADE assessment was done within the observational study design category.

# Duration of treatment for NAS Days
The mean duration of treatment for nas in the intervention groups was 3.73 lower (7.75 lower to 0.29 higher)

# (2 studies)
  VERY LOW 8,9 As this was a meta-analysis of two quasitrials, the GRADE assessment was done within the observational study design category.

# OPIATES COMPARED TO PHENOBARBITONE FOR OPIOID WITHDRAWAL IN NEWBORN INFANTS
Patient or population: Opioid withdrawal in newborn infants Settings: Hospital Intervention: Opioid Comparison: Phenobarbitone  The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval. RR: Risk ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. This RCT (Langefeld 2005) was well-conducted with adequate random generation and allocation concealment, blinding (solutions identical in appearance and flasks were only identified with a number and name of the newborn) and no attrition nor selection reporting. 2 Not applicable as only one study included. 3 The report did not provide details of treatment failure, but reported mean maximum Finnegan score values for each group: Morphine: 15.4g and Tincture: 15.5g. No SD reported. 4 The mean and ranges were reported, not standard deviations or a confidence interval of the difference. Based on the sample size being very small and the wide ranges, the results are judged to be very imprecise. 5 The sample size is very small. As no variance estimates are reported for means, it is not possible to calculate the mean difference nor the variance. The mean weight gain per day is reported for each group, but not for the mean difference between the groups. However, a 95% confidence interval for the mean difference in weight gain per day between the groups (15.9; -4.1g) is reported.

# Quality assessment
No. of patients This is reported as a quasi-randomized trial which allocated participants to groups using the last number of the participant's hospital number. Both random generation and allocation concealment were judged to be inadequate and there is thus a high risk of selection bias. There was no blinding of providers or parents so performance bias may be present. Blinding was unreported for short-term outcomes and the risk of detection bias is unclear. Long-term outcomes were not measured.
Not applicable as results are from one study only.
The sample size is small and the event rate is extremely low so imprecision is highly likely in the results.
The sample size is small and the confidence interval is very wide.
The sample size is small and the confidence interval is wide.

# Quality assessment
No. of patients Treatment failure defined by review as failure to reduce a standardised score of NAS from a clinically significant level to a clinically 'safe' level defined by author of the trial, or the use of additional pharmacological treatments for control of NAS.
The meta-analysis combines results from two randomized controlled trials (Jackson 2004 andMadden 1977) and two quasi-randomized trials (Finnegan 1984 andKhoo 1995). Random generation and allocation concealment were lacking in three of the four studies and there is thus a risk of selection bias. Blinding of participants and providers was only performed in one study so performance and measurement bias may be present in the other studies. In Jackson 2004, infants randomly allocated to phenobarbitone tended to have been exposed to benzodiazepines and other classes of drugs compared with those randomized to morphine.
3 Statistical heterogeneity was not present (I squared = 0%). Some clinical heterogeneity may be present as drug types and doses differed but it was not downgraded for unexplained inconsistency. The opiates and dosages used in the four studies were: Finnegan 1984 -Paregoric, dose not reported; Jackson 2004 -Morphine 50 microg/kg/dose four times a day with no titration; Khoo 1995 -Morphine 0.5mg/kg/day in 4 -6 divided doses, titrated up to maximum 0.9mg/kg/day; Madden 1977 -Methadone 0.25mg 6 hourly increased every 6 hours to maximum 0.5mg 6 hourly 4The combined sample size is 302. The event rate is very low. Although the confidence interval is narrow, according to GRADE criteria for dichotomous data, event rates less than 300 are downgraded for imprecision.
This RCT (Kandall 1983) was judged to be at unclear risk of selection bias as no method of random generation was reported. The randomized groups were very imbalanced (49 vs 62), increasing the likelihood of selection bias. Detection and performance bias may be present as no blinding was reported. Attrition was not reported and the risk of selective reporting was unclear.
Not applicable as results are from one trial only.
The sample size is small, the event rate very low (zero events in the opioid group) and the confidence interval is wide.
The two studies (Khoo 1995 andMadden 1977) included in this meta-analysis are quasi-randomized trials. There is a high risk of selection bias as random generation and allocation concealment were inadequate. Blinding was not reported and there is thus an unclear risk of detection and performance bias. Both studies accounted for incomplete outcome data and attrition bias is thus a low risk. Selective reporting bias was unclear.
The sample size is small and the confidence interval is very wide.
This quasi-RCT (Khoo 1995) is at high risk of selection bias as random generation (use of last number of the participant's hospital number) and allocation concealment were judged to be inadequate. Blinding was not reported and performance and detection bias may be present.
The sample size is small and the confidence interval is wide.

# Quality assessment
No. of patients   Treatment failure defined by review as failure to reduce a standardised score of NAS from a clinically significant level to a clinically 'safe' level defined by author of the trial, or the use of additional pharmacological treatments for control of NAS.
The risk of selection bias is high for the quasi-trial (Finnegan 1988) as random generation and allocation concealment were judged as inadequate. No method was reported in the Madden 1977 RCT. Blinding was lacking or unclear and performance and detection bias may be present. Both studies accounted for incomplete outcomes so attrition bias is a low risk.
The meta-analysis reported here was conducted using a fixed effects model and a RR = 0.43 (95%CI: 0.23, 0.80) with Finnegan 1984 showing a statistically significant benefit of opiates over diazepam and Madden 1977 showing a benefit of diazepam over opiates. Clinical heterogeneity may explain this result as Finnegan compared Paregoric with diazepam and Madden compared methadone with diazepam. In this situation when heterogeneity is present, a random effects model is more appropriate. This would change the RR = 0.55 (95% CI: 0.10, 2.89) and is no longer statistically significant. The relatively large difference in results following sensitivity analyses reduces the robustness of the results. The assessment is downgraded for unexplained inconsistency.
The sample size is very small with very few events.
This RCT (Madden 1977) was judged to be at unclear risk of selection bias as no random generation or allocation concealment was reported. Blinding was not reported for the trial so performance and detection bias may be present. Incomplete outcome data was addressed so attrition bias was minimal.
Not applicable as only one study included.
The sample size is very small and the confidence interval is wide.
Guidelines for the identification and management of substance use and substance use disorders in pregnancy   This RCT (Kraft 2009) was judged to be at low risk of selection bias. Random generation and allocation concealment were adequate as the sequence was generated centrally by the Hospital Investigational Drug Service. The study was not blinded and detection and performance bias may be present. All outcomes were accounted for and attrition bias was judged to be low. Selective outcome reporting was not present.
Not applicable as only one study.
The sample size is very small with very few events and the confidence interval is very wide.

# Quality assessment
No. of patients   Not applicable as only one study included.
The report did not provide details of treatment failure, but reported mean maximum Finnegan score values for each group: Morphine: 15.4g and Tincture: 15.5g. No SD reported.
The mean and ranges were reported, not standard deviations or a confidence interval of the difference. Based on the sample size being very small and the wide ranges, the results are judged to be very imprecise.
The sample size is very small. As no variance estimates are reported for means, it is not possible to calculate the mean difference nor the variance. The mean weight gain per day is reported for each group, but not for the mean difference between the groups. However, a 95% confidence interval for the mean difference in weight gain per day between the groups (15.9; -4.1g) is reported.

# Quality assessment
No. of patients This meta-analysis combined two quasi-trials (Finnegan 1984 andKaltenbach 1986). It was unclear whether some of the infants reported in the study were also included in Finnegan 1984, and there is a risk of double-counting the participants. The studies allocated groups from envelopes designated according to the first letter of the last name. Allocation concealment was judged to be inadequate and selection bias may is a high risk. Blinding was not clearly reported for short-term outcomes but it is unlikely as the treatment regimens were different so there is a high risk of performance and detection bias. Selective reporting of outcomes was unclear and could not be judged.
Statistical heterogeneity is present (I squared = 85%). The studies were similar but doses are not reported except for Phenobarbitone in Finnegan 1984), so the heterogeneity is unexplained. This was downgraded for unexplained inconsistency.
The sample size is small and the event rate is low and the confidence interval is wide.
No method of random generation was reported in the Madden 1977 RCT and allocation concealment was unlikely. There is a high risk of selection bias. Blinding was not reported performance and detection bias may be present. The study accounted for incomplete outcomes so attrition bias is a low risk.
Not applicable as only one trial.
The sample size is very small, the event rate is very low and the confidence interval is very wide.
This meta-analysis combines a quasi-RCT (Khoo 1995) and a RCT (Jackson 2004). In Khoo 1995 there is a high risk of selection bias as random generation (use of last number of the participant's hospital number) and allocation concealment were judged to be inadequate. Blinding was not performed for treatment and not reported for assessment so performance and detection bias may be present. Jackson 2004 was well-conducted and at low risk of selection, performance and detection bias. However, the GRADE assessment is done according to the lower quality of evidence so the analysis is downgraded for bias.
Statistical heterogeneity is not present and there did not appear to be unexplained clinical heterogeneity.
There is statistical heterogeneity (I squared = 67%). The studies were similar but doses are not reported so the heterogeneity is unexplained. This was downgraded for unexplained inconsistency.
Although the confidence interval is narrow, it was downgraded for imprecision due to the small sample size and low event rate.

# GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 This placebo-controlled RCT (Agthe 2009) was well-conducted and judged to be at low risk of selection, performance and detection bias. The infants in the Clonidine and Tincture of Opium group had statistically significantly lower mean birthweights. 61% of infants were also exposed to cocaine in utero and 6 of 80 infants had positive benzodiazepine urine screens. 2 The event rates are very low and the confidence interval is very wide. 3 The event rate is very low and the confidence interval is wide. 4 The sample size is small and according to GRADE criteria for rating continuous data, a sample size of less than 400 indicates imprecision and should be downgraded. 5 Inverse measure for infant weight gain (proxy outcome)
Guidelines for the identification and management of substance use and substance use disorders in pregnancy  This quasi-randomized trial (Khoo 1995) allocated participants to groups using the last number of the participant's hospital number. Both random generation and allocation concealment were judged to be inadequate and there is thus a high risk of selection bias. The group numbers are also not balanced (29 vs 36). There was no blinding of providers or parents so performance bias may be present. Blinding was unreported for short-term outcomes and the risk of detection bias is unclear.
Not applicable as only one study is included.
The sample size is very small and the event rate is very low so imprecision is likely in these results.
The sample size is small and the confidence interval is wide. Notwithstanding the very large difference in means and the highly statistically significant finding, the lack of information about the primary outcome and power of the trial reduces our confidence in this estimate.
The sample size is small. The primary outcome is not clearly defined and it is therefore not possible to determine the power of the study for this outcome: time to regain birthweight. In the light of this uncertainty, the GRADE criteria recommend that a sample size of less than 400 for continuous outcomes be downgraded for imprecision.  The risk of selection bias is high for the quasi-trial (Finnegan 1984) as random generation and allocation concealment were judged as inadequate. No method was reported in the Madden 1977 RCT so risk is unclear. Blinding of clinical and research staff was not reported in Madden 1977 and was unlikely as the treatment regimens were different so performance bias may be present. In Finnegan 1984 the nurses were not blinded but the research staff were blinded for short-term outcome assessment. Detection bias may be present. Both studies accounted for incomplete outcomes so attrition bias is a low risk. The groups are unbalanced in Finnegan 1984 (87 vs 20) as the Diazepam group was found to have excessive complications at interim analysis and enrolment was stopped.

# Quality assessment

# No. of patients
The meta-analysis reported here was conducted using a fixed effects model and a RR = 0.39 (95%CI: 0.24, 0.62) with Finnegan 1984 showing a statistically significant benefit of phenobarbitone over diazepam and Madden 1977 showing a nonsignificant benefit of diazepam over phenobarbitone. In this situation when heterogeneity is present, a random effects model is more appropriate. This would change the RR = 0.60 (95% CI: 0.08, 4.56) and is no longer statistically significant. The relatively large difference in results following sensitivity analyses reduces the robustness of these results. The assessment is downgraded for unexplained inconsistency.
The overall sample size is small and there are very few events.
This RCT (Madden 1977) was judged to be at unclear risk of selection bias as no random generation or allocation concealment was reported. Blinding was not reported for the trial so performance and detection bias may be present. Incomplete outcome data was addressed so attrition bias was minimal.
Not applicable as only one trial included.
The sample size is very small and the confidence interval is very wide.   In this RCT (Kahn 1969) the method of random generation was not reported and the risk of selection bias is unclear. The study was blinded for personnel and assessors so the risk of performance and detection bias is low. The risk of selective outcome reporting was unclear as the primary outcome was not explicitly stated and the trial pre-dates trial registration.

# Quality assessment

# No. of patients
Not applicable as only one trial included.
The sample size is very small and the event rate low with a wide confidence interval.
The sample size is very small and zero events.  The quasi-trial (Kaltenbach 1986) allocated groups from envelopes designated according to the first letter of the last name. Allocation concealment was judged to be inadequate and selection bias may be present. There was no blinding for short-term outcomes and there is a risk of performance and detection bias. Selective reporting of outcomes was unclear and could not be judged.

# Quality assessment

# No. of patients
Not applicable as only one trial included.
3 The sample size is small, the event rate low and the confidence interval is wide.  In this RCT (Kahn 1969) the method of random generation was not reported and the risk of selection bias is unclear. The study was blinded for personnel and assessors so the risk of performance and detection bias is low. The risk of selective outcome reporting was unclear as the primary outcome was not explicitly stated and the trial pre-dates trial registration.

# Quality assessment

# No. of patients
Not applicable as only one trial is included.  In this RCT (Kahn 1969) the method of random generation was not reported and the risk of selection bias is unclear. The study was blinded for personnel and assessors so the risk of performance and detection bias is low. The risk of selective outcome reporting was unclear as the primary outcome was not explicitly stated and the trial pre-dates trial registration 2Not applicable as only one trial is included.

# Quality assessment

# No. of patients
The sample size is very small, the number of events is low and the confidence interval is very wide. This study (Coyle 2002) is probably a quasi-randomized trial. Infants were matched on Finnegan scores but the method is incompletely described. If no match was possible, then infants were randomly assigned. Allocation concealment was judged to be inadequate. Selection bias is a high risk. Performance bias is a low risk as the trial was placebo-controlled and nurses were blinded to the treatment assignments. However, weekly phenobarbitone levels were reported to the physician so there is an unclear risk of detection bias as it is not certain if the physicians were also assessing the outcomes. Of note is that an earlier abstract reported 35 infants but the principal article only reports on 21 infants.

# Quality assessment

# No. of patients
Not applicable as only one study included.
The sample size is small. Although a sample size calculation was done a priori the outcome used in the formula is reduction in hospital days. This calculation found that 48 patients were required. However, the trial was stopped early on the basis of significance but no details are provided if formal stopping rules were applied to determine the significance level. A systematic review of RCTs stopped early for benefit found that such RCTs were found to overestimate treatment effects. When trials with events fewer than the median number (n=66) were compared with those with event numbers above the median, the odds ratio for a magnitude of effect greater than the median was 28 (95% CI 11-73) (Montori VM, Devereaux PJ and Adhikari NK et al.. Randomized trials stopped early for benefit: a systematic review. JAMA 2005;294:2203-09.)
4 The sample size is small and the confidence interval is wide. Although a sample size calculation was done a priori for this outcome: reduction in hospital days. This calculation found that 48 patients were required. However, the trial was stopped early on the basis of significance but no details are provided if formal stopping rules were applied to determine the significance level. A systematic review of RCTs stopped early for benefit found that such RCTs were found to overestimate treatment effects. When trials with events fewer than the median number (n=66) were compared with those with event numbers above the median, the odds ratio for a magnitude of effect greater than the median was 28 (95% CI 11-  Where there were uncertainties or disagreements, or where disputes could not be resolved, these studies remained in awaiting assessment or ongoing studies and the authors were contacted for clarification. NS and NC made final decisions regarding inclusion.

# Data extraction and management
- Extraction NS extracted data from included studies. NC checked each data entry. We resolved disputes by discussion. If it was not possible to extract data or if further information was needed, we attempted to contact the authors. We extracted data presented only in tables and figures whenever possible, and when further information was necessary, we contacted authors of studies in order to obtain missing data or for clarification of methods.
We extracted data onto standardized, simple forms, including: o Administrative details: Trial or study identification number; author(s); published or unpublished; year of publication; number of studies included in paper; year in which study was conducted; details of other relevant papers cited; o Details of the study: Study design; type, duration and completeness of follow-up; country and location of study (e.g. higher-income vs. lower-income country); informed consent and ethics approval; o Details of participants: Setting, numbers, relevant baseline characteristics including age; o Details of intervention: Type of intervention, timing and duration of intervention, additional co-interventions; o Details of comparison: Type and comparison, timing and duration of comparative intervention; o Details of outcomes: Maternal and infant outcomes; o Details of the analysis: For RCTs, details of the type of analysis (intention-to-treat or per protocol).

# Scale-derived data
We included continuous data from rating scales only if: o the psychometric properties of the measuring instrument have been described in a peer-reviewed journal; and o the measuring instrument has not been written or modified by one of the trialists for that particular trial.
Ideally the measuring instrument should either be i) a self-report or ii) completed by an independent rater or relative (not the therapist). We realize that this is not often reported clearly and noted this to assist in the Risk of Bias assessment.

# Endpoint versus change data
There are advantages of both endpoint and change data. Change data can remove a component of betweenperson variability from the analysis. On the other hand, calculation of change needs two assessments (baseline and endpoint), which can be difficult in unstable and difficult to measure conditions such as substance dependence. We decided to primarily use endpoint data, and only use change data if the former were not available. We combined endpoint and change data in the analysis as we used mean differences (MD) rather than standardized mean differences throughout (Higgins 2011, Chapter 9.4.5.2).

# Skewed data
Continuous data on clinical and social outcomes are often not normally distributed. To avoid the pitfall of applying parametric tests to non-parametric data, we aimed to apply the following standards to all data before inclusion: o standard deviations and means are reported in the paper or obtainable from the authors; o when a scale starts from the finite number zero, the standard deviation, when multiplied by two, is less than the mean (as otherwise the mean is unlikely to be an appropriate measure of the centre of the distribution (Altman 1996).
Endpoint scores on scales often have a finite start and end point and these rules can be applied. We entered skewed endpoint data from studies of fewer than 200 participants as other data within Data and analyses rather than into a statistical analysis. Skewed data pose less of a problem when looking at means if the sample size is large; we entered such endpoint data into syntheses.
When continuous data are presented on a scale that includes a possibility of negative values (such as change data), it is difficult to tell whether data are skewed or not. For these cases, we entered skewed change data into analyses regardless of size of study.

# Common measure
To facilitate comparison between trials, we intended to convert variables that can be reported in different metrics, such as days in hospital (mean days per year, per week or per month) to a common metric (e.g. mean days per month).

# Direction of graphs
Where possible, we entered data in such a way that the area to the left of the line of no effect indicated a favourable outcome for the treatment intervention. Where keeping to this made it impossible to avoid outcome titles with clumsy double-negatives (e.g. 'Not improved') we reported data where the left of the line indicates an unfavourable outcome. This was noted in the relevant graphs.

# Assessment of risk of bias in included studies
NS worked independently by using criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to assess trial quality. This set of criteria is based on evidence of associations between overestimate of effect and high risk of bias of the article such as sequence generation, allocation concealment, blinding, incomplete outcome data and selective reporting. outcomes are to change when data only from people who complete the study to that point were compared to the intention to treat analysis using the above assumptions.

# Continuous Data
In the case where attrition for a continuous outcome is between 0 and 50%, and data only from people who complete the study to that point are reported, we reproduced these.

# Standard deviations
If standard deviations are not reported, we first tried to obtain the missing values from the authors. If not available, where there are missing measures of variance for continuous data, but an exact standard error and confidence intervals available for group means, and either 'p' value or 't' value available for differences in mean, we can calculate them according to the rules described in the Cochrane Handbook for Systemic reviews of Interventions (Higgins 2011): when only the standard error (SE) is reported, standard deviations (SDs) are calculated by the formula SD = SE  square root (n). Chapters 7.7.3 and 16.1.3 of the Cochrane Handbook for Systemic reviews of Interventions (Higgins 2011) present detailed formula for estimating SDs from p-values, t or F values, confidence intervals, ranges or other statistics.

# Last observation carried forward
We anticipated that in some studies the method of last observation carried forward (LOCF) would be employed within the study report. As with all methods of imputation to deal with missing data, LOCF introduces uncertainty about the reliability of the results (Leucht 2007). Therefore, where LOCF data have been used in the trial, if less than 50% of the data have been assumed, we would present and use these data and indicate that they are the product of LOCF assumptions.

# Assessment of heterogeneity

# Clinical heterogeneity
We considered all included studies initially, without seeing comparison data, to judge clinical heterogeneity. We inspected all studies for clearly outlying people or situations which we had not predicted would arise. When such situations or participant groups arose, we fully discussed these.

# Methodological heterogeneity
We considered all included studies initially, without seeing comparison data, to judge methodological heterogeneity. We inspected all studies for clearly outlying methods which we had not predicted would arise. When such methodological outliers arose, we fully discussed these.

# Statistical heterogeneity

# Visual inspection
We visually inspected graphs to investigate the possibility of statistical heterogeneity.

# Employing the I 2 statistic
We investigated heterogeneity between studies by considering the I 2 method alongside the Chi 2 P value. The I 2 provides an estimate of the percentage of inconsistency thought to be due to chance (Higgins 2003). The importance of the observed value of I 2 depends on i) magnitude and direction of effects and ii) strength of evidence for heterogeneity (e.g. P value from Chi 2 test, or a confidence interval for I 2. I 2 estimate greater than or equal to around 50% accompanied by a statistically significant Chi 2 statistic was interpreted as evidence of substantial levels of heterogeneity (Higgins 2011). When substantial levels of heterogeneity were found in the primary outcome, we explored reasons for heterogeneity (Subgroup analysis and investigation of heterogeneity).

# Assessment of reporting biases
Reporting biases arise when the dissemination of research findings is influenced by the nature and direction of results (Egger 1997). These are described in Section 10 of the Handbook (Higgins 2011). We are aware that funnel plots may be useful in investigating reporting biases but are of limited power to detect small-study effects. We did not plan to use funnel plots for outcomes where there were 10 or fewer studies, or where all studies were of similar sizes. As no meta-analyses of more than five studies were undertaken, we did not conduct funnel plot analysis.

# Data synthesis
Where RCTs are found to be methodologically or clinically comparable, we pooled trial results in a meta-analysis.
Where we found the presence of statistical heterogeneity we combined the data using the random effects model.
For meta-analysis of RCTs, we combined the results and the relative risk and the 95% confidence intervals for dichotomous data. For continuous data, we combined the mean differences to calculate a weighted mean difference and standard deviation.

# Subgroup analysis and investigation of heterogeneity
We will explore heterogeneity by conducting sub-group analyses between:
- Type of substance dependence 2. Setting of treatment (e.g. inpatient versus outpatient)

# Main results

# Results of the search
The number of records retrieved from each database can be seen in the
After electronic and manual deduplication using ENDNOTE software, we screened 5632 records of which 172 were identified as potentially eligible RCTs and 73 systematic reviews and the full texts for these were obtained -see Figure 1.