Non‐pharmacological care for opioid withdrawal in newborns

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To evaluate the efficacy and safety of non‐pharmacological treatment of infants at risk for or having symptoms of opioid withdrawal on the need for pharmacological treatment and hospitalization.

Comparison 1: In infants at risk for or having early symptoms of opioid withdrawal, does non‐pharmacological treatment reduce the need for pharmacological treatment and reduce the length of hospitalization?

Comparison 2: In infants on pharmacological treatment for symptoms of opioid withdrawal, does concurrent non‐pharmacological treatment reduce duration of pharmacological treatment, maximum and cumulative doses of opioid medication, and length of hospitalization?

Background

Illicit drug use is an international public health concern. Prevalence is increasing in many areas of the world. Drug use by women of childbearing age contributes to increasing neonatal abstinence syndrome. Regional incidence of neonatal abstinence syndrome varies, and rising rates are not universal. Incidence in Australia and England is 2.7 per 1000 hospital births and stable (Davies 2016). Incidence in the United States and Canada is rising. Incidence increased four‐fold in the United States between 2003 and 2012 to 5.8 per 1000 hospital births (Corr 2017; Patrick 2015a). Incidence in Canada rose 16‐fold between 1992 to 2011 to 4.3 per 1000 (Brogly 2017).

There is regional variability within countries. In New South Wales, Australia, incidence is 3.18 per 1000 hospital births (Uebel 2016). Within the United States, there is a wide range in incidence, ranging from 0.7 to 33.4 per 1000 hospital births (Ko 2016). Socioeconomic, racial, and local factors including legislation, culture, and medical practices contribute to the variability. Incidence is 14.4 per 1000 hospital births in the subgroup of low‐income United States infants with public insurance (Winkelman 2018). Substance use affects all socioeconomic and racial groups, but is disproportionately reported in women of color and low socioeconomic status (Paltrow 2013). Under‐recognition may also lower the measured incidence (Burns 2007).

Increasing illicit drug use places demands on the medical system. Infants with neonatal abstinence syndrome now occupy 4% of neonatal intensive care unit (NICU) beds in the United States, an increase from 0.6% in only nine years (Tolia 2015). Over 95% of these patients are withdrawing from prenatal exposure (Patrick 2012).

Drug exposure or drug withdrawal may be associated with serious long‐term neurological complications (Enevoldson 2004).

Description of the condition

The contemporary definition of neonatal abstinence syndrome is broad, and includes symptoms due to prenatal exposure to many substances that cause withdrawal. These may include methadone, buprenorphine, selective serotonin reuptake inhibitors (SSRIs), and tobacco, among other substances (Levinson‐Castiel 2006). Exposure may occur in isolation or in combination with other drugs. Polysubstance use is common among opioid users (Goel 2011).

It is important to identify neonates withdrawing from opioids. Opioid withdrawal is more likely to respond to postnatal treatment with opioids. Neonatal opioid withdrawal syndrome (NOWS) is new terminology that focuses on the unique nature of withdrawal due at least in part to opioids.

Infants express varied signs of withdrawal from opioids and other drugs following birth. Symptoms are those of dysregulated autonomic, gastrointestinal, and central nervous systems. The most severe manifestations of withdrawal may include seizure and severe weight loss. Symptoms of opioid withdrawal peak in the first week of life due to cessation of opioid transfer through the placenta. Infants need medical monitoring and treatment during this period. Symptoms are more severe with maternal methadone maintenance, smoking, and polysubstance exposure (Brogly 2014; Goel 2011; Patrick 2015b). Symptoms are reduced in preterm infants (Lemon 2018).

The American Academy of Pediatrics recommends standardized assessment of symptom severity (Hudak 2012). Published standardized withdrawal assessment tools include the Finnegan Neonatal Abstinence Scoring Tool (score range 0 to 62) (Finnegan 1975), Lipsitz Neonatal Drug Withdrawal Scoring System (score range 0 to 20) (Lipsitz 1975), Neonatal Narcotic Withdrawal Index (score range 0 to 14) (Green 1981), Neonatal Withdrawal Inventory (score range 0 to 19) (Zahorodny 1998), MOTHER NAS scale (score range 0 to 42) (Jones 2010), and Finnegan Neonatal Abstinence Syndrome Scale ‐ Short Form (score range 0 to 16) (Maguire 2013). Each tool assesses a combination of symptoms of opioid or non‐opioid withdrawal. The majority of hospitals use a version of the Finnegan Neonatal Abstinence Scoring Tool (Mehta 2013; Sarkar 2006), yet the tool is not validated and has poor psychometric properties and poor internal consistency (Jones 2016). Newer approaches in the United States shift from a score‐based treatment approach to an approach based on a care pathway including evaluation of basic functional symptoms including the infants ability to eat, sleep, and console (Grossman 2018; Wachman 2018).

The first‐line treatment for neonatal abstinence syndrome is non‐pharmacological care (Hudak 2012). Severe symptoms despite maximal non‐pharmacological treatment mark a threshold for pharmacological treatment. Though norms exist, scores are often subjective, and treatment thresholds are not validated. Pharmacological treatments that reduce withdrawal symptoms include opioid or sedative medications or both. Morphine is the most common opioid treatment; methadone and buprenorphine are also used. Adjunctive therapies may include phenobarbital and clonidine to address polydrug exposure. Long‐term developmental impact of pharmacological treatment is unclear. Immediate side effects of pharmacological treatment include respiratory depression and sedation. Most hospitals care for infants on sedating medications on a cardiac monitor in the intensive care unit (ICU) (Milliren 2018). Unfortunately, ICU care separates infants from caregivers. This interferes with bonding, caregiver self efficacy, and full non‐pharmacological treatment.

Current care for infants with neonatal abstinence syndrome is not standardized (Bogen 2017; Mehta 2013; O'Grady 2009; Sarkar 2006). Surveys show differences in prenatal counseling, written policies, staff training, threshold for pharmacological treatment, weaning protocols, breastfeeding support, and location of care, among other aspects of care (Bogen 2017; Mehta 2013). Most hospitals use a standardized withdrawal assessment tool, however hospitals have differing treatment protocols. Almost half lack a written policy for management of opioid‐exposed newborns (Sarkar 2006). There is no clear standard for non‐pharmacological care or pharmacological treatment thresholds (Mehta 2013). Non‐pharmacological treatment and pharmacological treatment thresholds are not well studied and likely vary between centers.

Outcomes such as treatment rate and length of stay also vary widely. The per cent of infants requiring pharmacological treatment ranges from 13% to 90% (Milliren 2018). The average length of stay is as low as 5.9 days at some centers, while the United States national average is 16.9 days (Grossman 2017; Patrick 2015a).

Variations in diagnosis and management of neonatal abstinence syndrome represent an important opportunity to improve care. Multicenter quality improvement collaboratives in the United States show that increased standardization of care can reduce length of stay (Hall 2015; Patrick 2016). Emerging evidence suggests that standardization of non‐pharmacological care also reduces length of stay and need for treatment (Grossman 2017; Holmes 2016; Wachman 2018).

Description of the intervention

Non‐pharmacological treatments focus on minimizing dysregulation and maximizing infant functioning. Treatments are heterogeneous interventions within three main categories of care:

1. environmental stimulation;

2. feeding strategies; and

3. functioning of the mother‐infant dyad.

Interventions may occur alone or in combination with other non‐pharmacological and pharmacological treatments.

Environmental stimulation: Treatments addressing environmental stimulation reduce negative stimuli and promote positive experiences. Gentle handling and maintaining a low‐light, quiet environment reduce negative stimulation. Infant containment or swaddling, bedding choice including vibrating beds, and infant positioning may also soothe infants. Positive experiences may include non‐nutritive sucking and bathing. Aromatherapy, music therapy, massage, and acupuncture/acupressure are therapies that may also calm infants through stimulation.

Feeding strategies: Disorganized feeding and weight loss are common in infants withdrawing from opioids. In general, breast milk and breastfeeding reduce withdrawal symptoms. Small, frequent feeds and infant‐led feeding are often helpful to improve transfer of feeds. Higher calorie feeds or tube feeds may reduce weight loss in these infants. Breast milk or low‐lactose formula may reduce gas and feeding discomfort.

Functioning of the mother‐infant dyad: Treatments also address the health and support of the mother‐infant dyad as a unit (Velez 2009). Parental presence alone is an important aspect of non‐pharmacological care (Howard 2017). Rooming in and skin‐to‐skin care promote mother‐infant bonding and infant regulation. Direct parental support promotes parental well‐being. Well caregivers are better able to recognize and respond to infant cues. Parental supports enhance comfort and plan for respite. Examples include 'cuddler' programs and designated parental hospital spaces. Staff contribute to parental well‐being by using trauma‐informed care principles. A thorough needs assessment may also improve parental well‐being. Needs may include addiction, social, mental health, legal, and custody supports.

How the intervention might work

Many non‐pharmacological practices improve autonomic regulation for infants. Tactile contact and mother’s presence improve visual attention in term infants (Arditi 2006). Skin‐to‐skin contact between caregiver and infant (also termed 'kangaroo care'), breastfeeding, non‐nutritive sucking, and acupressure reduce infant pain response (Carbajal 2003; Chen 2017; Gray 2000; Gray 2002; Pinelli 2002). Facilitated tucking by holding the infant in a gently flexed position lowers stress‐related behaviors and vital sign changes in infants. (Liaw 2011). Massage improves weight gain, growth, and sleep in infants (Juneau 2015). Sensitive maternal caregiving as measured by the Emotional Availability scales lowers cortisol and improves infant regulation (Kaplan 2008). Interparental relationships, specifically the levels of avoidance and dyadic adjustment, affect infant vagal tone (Graham 2010). These non‐pharmacological measures and others affect autonomic functioning and are likely to attenuate withdrawal symptoms due to dysregulation and treat neonatal withdrawal.

Why it is important to do this review

Other Cochrane Reviews address the evidence for pharmacological treatments including opiates, sedatives, and naloxone treatments for opioid‐exposed newborns (Moe‐Byrne 2013; Osborn 2010a; Osborn 2010b). The reviews conclude that initial pharmacological treatment of neonatal opioid withdrawal should be an opiate. Opiates reduce time to regain birth weight but increase length of hospital stay. Adding a sedative may further reduce symptoms. Given methodologic limitations of the included studies, further firm recommendations are not made.

Non‐pharmacological interventions are not assessed or controlled in the majority of studies. Standardized non‐pharmacological care may improve care outcomes (Grossman 2017; Holmes 2016; Wachman 2018). Evidence for non‐pharmacological interventions will guide future efforts to improve care. This review will evaluate the current literature and gaps in research regarding non‐pharmacological care. Acupuncture and acupressure will be addressed by another Cochrane Review, and will not be included in this review.

Objectives

To evaluate the efficacy and safety of non‐pharmacological treatment of infants at risk for or having symptoms of opioid withdrawal on the need for pharmacological treatment and hospitalization.

Comparison 1: In infants at risk for or having early symptoms of opioid withdrawal, does non‐pharmacological treatment reduce the need for pharmacological treatment and reduce the length of hospitalization?

Comparison 2: In infants on pharmacological treatment for symptoms of opioid withdrawal, does concurrent non‐pharmacological treatment reduce duration of pharmacological treatment, maximum and cumulative doses of opioid medication, and length of hospitalization?

Methods

Criteria for considering studies for this review

Types of studies

We plan to include randomized controlled trials, quasi‐randomized controlled trials, and cluster trials in our formal analysis (see Selection of studies). We will exclude cross‐over trials. Non‐randomized studies identified in the search process will be formally evaluated using the ROBINS‐I tool and presented in narrative fashion.

Types of participants

Inclusion criteria

Comparison 1: Term (≥ 37 weeks' gestation) and late preterm infants (34 to 37 weeks' gestation) with known or suspected prenatal opioid exposure or having opioid withdrawal in the first 7 days of life.

Comparison 2: Term (≥ 37 weeks' gestation) and late preterm infants (34 to 37 weeks' gestation) on opioid treatment for opioid withdrawal in the first 28 days of life.

Opioid withdrawal may be defined by the presence of symptoms consistent with opioid withdrawal or an elevated score on a standardized withdrawal assessment tool.

Symptoms consistent with opioid withdrawal are those of dysregulated autonomic, gastrointestinal, and central nervous systems. Symptoms include but are not limited to increased crying, irritability, inability to sleep, tremors, increased tone, myoclonic jerks, fever, sweating, rapid breathing, labored breathing, sneezing, yawning, unco‐ordinated feeding, excessive sucking, vomiting, loose stools, and excessive weight loss.

Scores are often used to quantitate the symptoms and provide for potential treatment. Elevated scores on standardized withdrawal assessment tools include Finnegan Neonatal Abstinence Scoring Tool score above 8 (Finnegan 1975), Lipsitz Neonatal Drug Withdrawal Scoring System score above 4 (Lipsitz 1975), Neonatal Narcotic Withdrawal Index score above 5 (Green 1981), Neonatal Withdrawal Inventory score above 8 (Zahorodny 1998), MOTHER NAS score above 9 (Jones 2010), Finnegan Neonatal Abstinence Syndrome Scale ‐ Short Form score above 8 (Maguire 2013), or a score exceeding the stated threshold on any novel validated assessment tool.

Exclusion criteria

1. Preterm infants less than 34 weeks' gestation.

2. Critically ill term and late preterm infants (> 34 weeks' gestation) with medical comorbidities unrelated to opioid withdrawal. Medical comorbidities include but are not limited to the need for mechanical ventilation (positive pressure ventilation), culture‐proven infection, necrotizing enterocolitis, major congenital anomaly, and status post‐major surgical intervention.

Types of interventions

Comparison 1: Trials comparing single or multiple non‐pharmacological interventions to no non‐pharmacological treatment or other non‐pharmacological interventions in infants at risk for or having early symptoms of opioid withdrawal as defined above.

Comparison 2: Trials comparing single or multiple non‐pharmacological interventions to no non‐pharmacological treatment or other non‐pharmacological interventions in infants on opioid treatment for symptoms of opioid withdrawal as defined above.

Non‐pharmacological care is a heterogeneous group of interventions addressing three aspects of care, as follows.

1. Environmental stimulation: Adjustments of environmental stimulation include low light, low noise, clustered care, containment or swaddling, bedding type, positioning, non‐nutritive sucking, bathing, aromatherapy, music therapy, and massage.

2. Feeding practices: Feeding modifications include infant‐led feeding, high caloric feeds, tube feeds, maternal breast milk feeds, non‐maternal breast milk feeds, low‐lactose formula, and breastfeeding.

3. Functioning of the maternal‐infant dyad: Treatments focused on the maternal‐infant dyad include parental presence, rooming in, skin‐to‐skin or 'kangaroo care,' parental respite or 'cuddler' programs, trauma‐informed care, social work support, mental health support, treatment program support, and legal support.

We will assess non‐pharmacological interventions independently and in combination based on sufficient similarity in population, intervention, and comparison groups studied.

Types of outcome measures

Primary outcomes

Comparison 1:

1. Need for pharmacological treatment with one or more doses of opioid or sedative medication.

2. Length of hospitalization (days).

Comparison 2:

1. Length of pharmacological treatment with opioid or sedative medication (days).

2. Length of hospitalization (days).

3. Maximum and cumulative dose of opioid medication (milligrams/kilogram and morphine milligram equivalents).

Secondary outcomes

1. Peak neonatal abstinence syndrome (NAS) score in first 72 hours of life as measured by a standardized withdrawal assessment tool. Tools include the Finnegan Neonatal Abstinence Scoring Tool (score range 0 to 62) (Finnegan 1975), Lipsitz Neonatal Drug Withdrawal Scoring System (score range 0 to 20) (Lipsitz 1975), Neonatal Narcotic Withdrawal Index (score range 0 to 14) (Green 1981), Neonatal Withdrawal Inventory (score range 0 to 19) (Zahorodny 1998), MOTHER NAS scale (score range 0 to 42) (Jones 2010), or Finnegan Neonatal Abstinence Syndrome Scale ‐ Short Form (score range 0 to 16) (Maguire 2013). Separate assessments will be made for each score. (Comparison 1 only)

2. NICU admission (Comparison 1 only)

3. Length of NICU stay (days)

4. Physical growth: weight:

   1. days to regain birth weight;

   2. growth rate (grams/day) during study period and hospital stay; growth velocity;

   3. weight nadir (per cent weight loss) (Fenton 2007).

5. Neonatal seizures (any seizures, clinical seizures, electroencephalogram (EEG)‐proven seizures; seizure treated with anticonvulsant therapy).

6. Neonatal and infant all‐cause mortality.

7. Cerebral palsy (clinical cerebral palsy diagnosed if the child had a non‐progressive motor impairment characterized by abnormal muscle tone and decreased range or control of movements). If data are available, we will determine the level of gross motor function using the Gross Motor Function Classification System (Palisano 1997).

8. Neurodevelopmental outcome at approximately two years' corrected age (acceptable range 18 months to 28 months) including: cerebral palsy, significant mental developmental delay (Bayley Scales of Infant Development Mental Developmental Index < 70 or Griffith 2 standard deviations (SD) below mean) (Bayley 1993; Chaudhary 2013), legal blindness (< 20/200 visual acuity), and hearing deficit (aided or < 60 dB on audiometric testing). The composite outcome “neurodevelopmental impairment” was defined as having any one of the aforementioned deficits (modified from definitions of moderate‐to‐severe developmental delay) (Schmidt 2007).

9. Complications of therapy: apnea, need for positive pressure ventilation, need for oxygen, somnolence.

10. Measures of maternal mood and bonding including Edinburgh Postpartum Depression Scale (Cox 1987), Patient Health Questionnaire (2 or 9) (Kroenke 2001; Whooley 1997), Maternal Attachment Inventory (Muller 1994), Maternal Postpartum Attachment Scale (Condon 1998), Mother‐Infant Bonding Scale (Taylor 2005), or Postpartum Bonding Questionnaire (Brockington 2006). Seperate comparisons will be made for each score.

11. Custody status at discharge.

Search methods for identification of studies

We will use the criteria and standard methods of Cochrane and Cochrane Neonatal (see the Cochrane Neonatal search strategy for specialized register). We will search for errata or retractions from included studies published in full text on PubMed (www.ncbi.nlm.nih.gov/pubmed) and report the date this was done in the review.

Electronic searches

We will conduct a comprehensive search including: Cochrane Central Register of Controlled Trials (CENTRAL, current issue) in the Cochrane Library; MEDLINE via Ovid (1946 to current); Embase (1980 to current); Maternity and Infant Care Database (MIDIRS) (1971 to current); and CINAHL (Cumulative Index to Nursing and Allied Health Literature) (1982 to current) using search terms specific to this review, plus database‐specific limiters for randomized controlled trials and neonates. (See Appendix 1 for the full search strategies for each database). We will not apply language restrictions. We will search the following clinical trials registries for ongoing or recently completed trials: US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov), the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (www.who.int/ictrp/en/), and the ISRCTN registry (www.isrctn.com/).

Searching other resources

We will also review the reference lists of all identified articles for relevant articles not located in the primary search.

Data collection and analysis

We will collect information regarding the method of randomization, blinding, intervention, stratification, and whether the trial was single or multicenter for each included study. We will note information regarding trial participants including gestational age criteria, birth weight criteria, and other inclusion or exclusion criteria. We will analyze the clinical outcomes listed above in Types of outcome measures.

Selection of studies

We will include all randomized, quasi‐randomized controlled trials, and cluster trials fulfilling our inclusion criteria. Both superiority trials and non‐inferiority trials will be eligible for inclusion. All review authors will review the results of the search and separately select studies for inclusion. Any disagreements will be resolved by discussion.

We will record the selection process in sufficient detail to complete a PRISMA flow diagram and 'Characteristics of excluded studies' table (Moher 2009).

We will consider non‐randomized studies when no randomized trials are available. We will assess the risk of bias of these non‐randomized trials using the ROBINS‐I tool (sites.google.com/site/riskofbiastool//welcome/home) (Sterne 2016).

Data extraction and management

Two review authors (AP and RS) will extract, assess, and code all data for each study, using a form designed specifically for this review. Any standard error of the mean will be replaced by the corresponding standard deviation. Any disagreements will be resolved by discussion. For each study, one review author (AP) will enter final data into Review Manager 5 (Review Manager 2014), which the other review author (RS) will check. All review authors will review the protocol, analysis, and draft manuscript.

Assessment of risk of bias in included studies

For randomized controlled trials, two review authors will independently assess the risk of bias (low, high, or unclear) of all included trials using the Cochrane ‘Risk of bias’ tool for the following domains (Higgins 2017).

1. Sequence generation (selection bias)

2. Allocation concealment (selection bias)

3. Blinding of participants and personnel (performance bias)

4. Blinding of outcome assessment (detection bias)

5. Incomplete outcome data (attrition bias)

6. Selective reporting (reporting bias)

7. Any other bias

Any disagreements will be resolved by discussion or by consulting a third review author. See Appendix 2 for a more detailed description of risk of bias for each domain.

We will assess the risk of bias of non‐randomized trials using the ROBINS‐I tool (Sterne 2016; Appendix 3).

Measures of treatment effect

We will perform the statistical analyses using Review Manager 5 software (Review Manager 2014). We will analyze categorical data using risk ratio (RR) and risk difference (RD). We will report 95% confidence intervals (CIs) for all outcomes. For statistically significant outcomes, we will calculate the number needed to treat for an additional beneficial outcome (NNTB) or number needed to treat for an additional harmful outcome (NNTH). We will calculate mean differences (MDs) as weighted mean difference (WMD) or standardized mean difference (SMD) between treatment groups where outcomes are measured in the same way for continuous data.

Unit of analysis issues

The unit of analysis will be the participating infant in individually randomized trials, and an infant will be considered only once in the analysis. The participating neonatal unit or section of a neonatal unit or hospital will be the unit of analysis in cluster‐randomized trials. We will analyze them using an estimate of the intracluster correlation coefficient (ICC) derived from the trial (if possible), or from a similar trial or from a study with a similar population as described in Section 16.3.6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). If we use ICCs from a similar trial or from a study with a similar population, we will report this and conduct a sensitivity analysis to investigate the effect of variation in the ICC.

If we identify both cluster‐randomized trials and individually randomized trials, we will only combine the results from both if there is little heterogeneity between the study designs, and the interaction between the effect of the intervention and the choice of randomization unit is considered to be unlikely.

We will acknowledge any possible heterogeneity in the randomization unit and perform a sensitivity analysis to investigate possible effects of the randomization unit.

Dealing with missing data

Where feasible, we intend to carry out analysis on an intention‐to‐treat basis for all outcomes. Whenever possible, we will analyze all participants in the treatment group to which they were randomized, regardless of the actual treatment received. If we identify important missing data (in the outcomes) or unclear data, we will request the missing data by contacting the original investigators. We will make explicit the assumptions of any methods used to deal with missing data. We may perform sensitivity analyses to assess how sensitive results are to reasonable changes in the undertaken assumptions. We will address the potential impact of missing data on the findings of the review in the Discussion section of the review.

Assessment of heterogeneity

We will estimate the treatment effects of individual trials and examine heterogeneity among trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I² statistic. We will grade the degree of heterogeneity as: less than 25% no heterogeneity; 25% to 49% low heterogeneity; 50% to 75% moderate heterogeneity; more than 75% substantial heterogeneity. If we note statistical heterogeneity (I² > 50%), we will explore the possible causes (e.g. differences in study quality, participants, intervention regimens, or outcome assessments).

Assessment of reporting biases

We intend to conduct a comprehensive search for eligible studies and will be alert for duplication of data. If we identify 10 or more trials for meta‐analysis, we will assess possible publication bias by inspection of a funnel plot. If we uncover reporting bias that could, in the opinion of the review authors, introduce serious bias, we will conduct a sensitivity analysis to determine the effect of including and excluding these studies in the analysis.

Data synthesis

If we identify multiple studies that we consider to be sufficiently similar, we will perform meta‐analysis using Review Manager 5 (Review Manager 2014). We will determine study similarity based on concordance of population, intervention or combination of interventions, and comparison group. For categorical outcomes, the typical estimates of RR and RD, each with its 95% CI, will be calculated; for continuous outcomes, the WMD or a summary estimate for the SMD, each with its 95% CI, will be calculated. We will use a fixed‐effect model to combine data where it is reasonable to assume that studies were estimating the same underlying treatment effect. If we judge meta‐analysis to be inappropriate, we will analyze and interpret individual trials separately. If there is evidence of clinical heterogeneity, we will try to explain this based on the different study characteristics and subgroup analyses.

Quality of evidence

We will use the GRADE approach, as outlined in the GRADE Handbook (Schünemann 2013), to assess the quality of evidence for the following (clinically relevant) outcomes.

Comparison 1:

1. Need for pharmacological treatment with opioid or sedative medication.

2. Length of hospitalization (days).

3. Peak NAS score in first 72 hours of life.

4. NICU admission.

5. Neonatal seizure requiring anticonvulsant therapy.

6. Neurodevelopmental outcome at approximately two years' corrected age (cerebral palsy, developmental delay (Bayley or Griffith assessment more than two SD below mean) or intellectual impairment (IQ more than two SD below mean), blindness (vision < 6/60 in both eyes), sensorineural deafness requiring amplification.

7. Measures of maternal mood and bonding including Edinburgh Postpartum Depression Scale, Patient Health Questionnaire (2 or 9), Maternal Attachment Inventory, Maternal Postpartum Attachment Scale, Mother‐Infant Bonding Scale, or Postpartum Bonding Questionnaire (Brockington 2006; Condon 1998; Cox 1987; Kroenke 2001; Muller 1994; Taylor 2005; Whooley 1997)

Comparison 2:

1. Length of pharmacological treatment with opioid or sedative medication (days).

2. Maximum dose of opioid medication (morphine milligram equivalents).

3. Length of hospitalization (days).

4. Length of NICU stay.

5. Neonatal seizure requiring anticonvulsant therapy.

6. Neurodevelopmental outcome at approximately two years' corrected age (cerebral palsy, developmental delay (Bayley or Griffith assessment more than two SD below mean) or intellectual impairment (IQ more than two SD below mean), blindness (vision < 6/60 in both eyes), sensorineural deafness requiring amplification.

7. Measures of maternal mood and bonding including Edinburgh Postpartum Depression Scale, Patient Health Questionnaire (2 or 9), Maternal Attachment Inventory, Maternal Postpartum Attachment Scale, Mother‐Infant Bonding Scale, or Postpartum Bonding Questionnaire (Brockington 2006; Condon 1998; Cox 1987; Kroenke 2001; Muller 1994; Taylor 2005; Whooley 1997).

Two review authors will independently assess the quality of the evidence for each of the outcomes listed above. We will consider evidence from randomized controlled trials as high quality, downgrading the evidence one level for serious (or two levels for very serious) limitations based upon the following: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates, and presence of publication bias. We will use GRADEpro GDT to create a ‘Summary of findings’ table to report the quality of the evidence (GRADEpro GDT).

The GRADE approach results in an assessment of the quality of a body of evidence in one of the following four grades.

1. High: We are very confident that the true effect lies close to that of the estimate of the effect.

2. Moderate: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

3. Low: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.

4. Very low: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Subgroup analysis and investigation of heterogeneity

Planned subgroup analyses:

1. Gestational age (late preterm (34 to 37 weeks' gestation), term (≥ 37 weeks' gestation)).

2. Birth weight (< 2500 grams, birth weight ≥ 2500 grams).

3. Type of non‐pharmacological intervention:

   1. environmental stimulation: adjustments of environmental stimulation include low light, low noise, clustered care, containment or swaddling, bedding type, positioning, non‐nutritive sucking, bathing, aromatherapy, music therapy, and massage;

   2. feeding practices: feeding modifications include infant‐led feeding, high‐caloric feeds, tube feeds, maternal breast milk feeds, non‐maternal breast milk feeds, low‐lactose formula, and breastfeeding;

   3. functioning of the maternal‐infant dyad: treatments focused on the maternal‐infant dyad include parental presence, rooming in, skin‐to‐skin or 'kangaroo care,' parental respite or 'cuddler' programs, trauma‐informed care, social work support, mental health support, treatment program support, and legal support.

4. Prenatal opioid exposure: polysubstance use, single substance (opioid) use, prescribed opioid, illicit opioid, not known.

5. Other prenatal drug exposures:

   1. nicotine exposure: nicotine use, no nicotine use;

   2. alcohol exposure (based on maternal history or evidence of fetal alcohol spectrum disorder);

   3. SSRI exposure.

6. Maternal social situation (custody status, homelessness, employment status, public insurance, ethnicity, involvement of birth father, marital status, family support).

Sensitivity analysis

Where we identify substantial heterogeneity, we will conduct sensitivity analysis to determine if the findings are affected by inclusion of only those trials considered to have used adequate methodology with a low risk of bias (selection and performance bias). We will report results of sensitivity analyses for primary outcomes only.

Appendices

Appendix 1. Cochrane Neonatal search strategy

The Cochrane Central Register of Controlled Trials (CENTRAL) via John Wiley’s Cochrane Library:

ID	Search
#1	MeSH descriptor: [Neonatal Abstinence Syndrome] explode all trees
#2	neonatal abstinence:ti,ab,kw (Word variations have been searched)
#3	neonatal drug abstinence:ti,ab,kw (Word variations have been searched)
#4	neonatal drug withdrawal:ti,ab,kw (Word variations have been searched)
#5	neonatal substance withdrawal:ti,ab,kw (Word variations have been searched)
#6	neonatal withdrawal syndrome:ti,ab,kw (Word variations have been searched)
#7	newborn abstinence syndrome:ti,ab,kw (Word variations have been searched)
#8	newborn drug withdrawal syndrome:ti,ab,kw (Word variations have been searched)
#9	newborn withdrawal syndrome:ti,ab,kw (Word variations have been searched)
#10	neonatal withdrawal symptom*:ti,ab,kw (Word variations have been searched)
#11	#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10
#12	MeSH descriptor: [Opioid‐Related Disorders] explode all trees
#13	MeSH descriptor: [Opiate Substitution Treatment] explode all trees
#14	opiate substitution treatment:ti,ab,kw (Word variations have been searched)
#15	opiate substitution therapy:ti,ab,kw (Word variations have been searched)
#16	opiate replacement therapy:ti,ab,kw (Word variations have been searched)
#17	opiate replacement treatment:ti,ab,kw (Word variations have been searched)
#18	opioid replacement therapy:ti,ab,kw (Word variations have been searched)
#19	opioid replacement treatment:ti,ab,kw (Word variations have been searched)
#20	NAS:ti,ab,kw (Word variations have been searched)
#21	#12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20
#22	MeSH descriptor: [Infant] explode all trees
#23	MeSH descriptor: [Infant, Newborn] explode all trees
#24	neonat* or "neo nat*":ti,ab,kw (Word variations have been searched)
#25	newborn* or "new born*" or "newly born*":ti,ab,kw (Word variations have been searched)
#26	infant* or infancy:ti,ab,kw (Word variations have been searched)
#27	baby or babies:ti,ab,kw (Word variations have been searched)
#28	#22 or #23 or #24 or #25 or #26 or #27
#29	#21 and #28
#30	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "opioid dependen*":ti,ab,kw (Word variations have been searched)
#31	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "opiate dependen*":ti,ab,kw (Word variations have been searched)
#32	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "narcotic dependen*":ti,ab,kw (Word variations have been searched)
#33	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "heroin dependen*":ti,ab,kw (Word variations have been searched)
#34	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "cocaine dependen*":ti,ab,kw (Word variations have been searched)
#35	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "opioid toleran*":ti,ab,kw (Word variations have been searched)
#36	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "opiate toleran*":ti,ab,kw (Word variations have been searched)
#37	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "narcotic toleran*":ti,ab,kw (Word variations have been searched)
#38	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "heroin toleran*":ti,ab,kw (Word variations have been searched)
#39	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "cocaine toleran*":ti,ab,kw (Word variations have been searched)
#40	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "opioid withdraw*":ti,ab,kw (Word variations have been searched)
#41	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "opiate withdraw*":ti,ab,kw (Word variations have been searched)
#42	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "narcotic withdraw*":ti,ab,kw (Word variations have been searched)
#43	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "heroin withdraw*":ti,ab,kw (Word variations have been searched)
#44	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "cocaine withdraw*":ti,ab,kw (Word variations have been searched)
#45	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "opioid expos*":ti,ab,kw (Word variations have been searched)
#46	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "opiate expos*":ti,ab,kw (Word variations have been searched)
#47	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "narcotic expos*":ti,ab,kw (Word variations have been searched)
#48	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "heroin expos*":ti,ab,kw (Word variations have been searched)
#49	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "cocaine expos*":ti,ab,kw (Word variations have been searched)
#50	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "opioid addiction":ti,ab,kw (Word variations have been searched)
#51	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "opiate addiction":ti,ab,kw (Word variations have been searched)
#52	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "narcotic addiction":ti,ab,kw (Word variations have been searched)
#53	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "heroin addiction":ti,ab,kw (Word variations have been searched)
#54	(neonatal* or newborn* or baby* or babies* or infant* or child*) near/5 "cocaine addiction":ti,ab,kw (Word variations have been searched)
#55	#30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 or #46 or #47 or #48 or #49 or #50 or #51 or #52 or #53 or #54
#56	#29 or #55
#57	MeSH descriptor: [Prenatal Exposure Delayed Effects] explode all trees
#58	MeSH descriptor: [Amphetamine‐Related Disorders] explode all trees
#59	MeSH descriptor: [Cocaine‐Related Disorders] explode all trees
#60	MeSH descriptor: [Heroin Dependence] explode all trees
#61	MeSH descriptor: [Inhalant Abuse] explode all trees
#62	MeSH descriptor: [Marijuana Abuse] explode all trees
#63	MeSH descriptor: [Opioid‐Related Disorders] explode all trees
#64	MeSH descriptor: [Phencyclidine Abuse] explode all trees
#65	MeSH descriptor: [Substance Abuse, Intravenous] explode all trees
#66	MeSH descriptor: [Substance Abuse, Oral] explode all trees
#67	MeSH descriptor: [Substance Withdrawal Syndrome] explode all trees
#68	(opioid* or opiate* or narcotic* or heroin or cocaine) near/5 (addiction or depend* or toleran* or withdraw* or expos*):ti,ab,kw (Word variations have been searched)
#69	#58 or #59 or #60 or #61 or #62 or #63 or #64 or #65 or #66 or #67 or #68
#70	#57 and #69
#71	#11 or #56 or #70

Embase Via OVID SP Database: Embase <1974 to current>

1	Neonatal Abstinence Syndrome/
2	Congenital Drug Dependence/
3	neonatal abstinence.ti,ab,kw.
4	neonatal drug abstinence.ti,ab,kw.
5	neonatal drug withdrawal.ti,ab,kw.
6	neonatal substance withdrawal.ti,ab,kw.
7	neonatal withdrawal symptom$.ti,ab,kw.
8	neonatal withdrawal syndrome.ti,ab,kw.
9	newborn abstinence syndrome.ti,ab,kw.
10	newborn drug withdrawal syndrome.ti,ab,kw.
11	newborn withdrawal syndrome.ti,ab,kw.
12	1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11
13	(random* or factorial* or placebo* or assign* or allocat* or crossover*).tw.
14	(cross adj over*).tw.
15	(trial* and (control* or comparative)).tw.
16	((blind* or mask*) and (single or double or triple or treble)).tw.
17	(treatment adj arm*).tw.
18	(control* adj group*).tw.
19	(phase adj (III or three)).tw.
20	(versus or vs).tw.
21	rct.tw.
22	Crossover Procedure/
23	Double Blind Procedure/
24	Single Blind Procedure/
25	Randomization/
26	Placebo/
27	exp Clinical Trial/
28	Parallel Design/
29	Latin Square Design/
30	13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29
31	exp animal/ or exp nonhuman/ or exp animal experiment/ or exp animal model/
32	exp human/
33	31 not 32
34	30 not 33
35	12 and 34
36	Opioid Addiction/
37	exp Opioid‐Related Disorders/
38	Opiate Substitution Treatment/
39	(opiate substitution treatment or opioid substitution treatment).ti,ab,kw.
40	(opiate substitution therapy or opioid substitution therapy).ti,ab,kw.
41	(opiate replacement therapy or opioid replacement therapy).ti,ab,kw.
42	(opiate replacement treatment or opioid replacement treatment).ti,ab,kw.
43	NAS.ti,ab.
44	36 or 37 or 38 or 39 or 40 or 41 or 42 or 43
45	Infant/ or Newborn/
46	(neonat$ or neo nat$).ti,ab.
47	(newborn$ or new born$ or newly born$).ti,ab.
48	infan$.ti,ab.
49	(baby or babies).ti,ab.
50	45 or 46 or 47 or 48 or 49
51	44 and 50
52	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opioid dependen$).ti,ab,kw.
53	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opiate dependen$).ti,ab,kw.
54	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 narcotic dependen$).ti,ab,kw.
55	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 heroin dependen$).ti,ab,kw.
56	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 cocaine dependen$).ti,ab,kw.
57	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opioid toleran$).ti,ab,kw.
58	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opiate toleran$).ti,ab,kw.
59	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 narcotic toleran$).ti,ab,kw.
60	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 heroin toleran$).ti,ab,kw.
61	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 cocaine toleran$).ti,ab,kw.
62	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opioid withdraw$).ti,ab,kw.
63	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opiate withdraw$).ti,ab,kw.
64	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 narcotic withdraw$).ti,ab,kw.
65	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 heroin withdraw$).ti,ab,kw.
66	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 cocaine withdraw$).ti,ab,kw.
67	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opioid expos$).ti,ab,kw. (80)
68	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opiate expos$).ti,ab,kw.
69	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 narcotic expos$).ti,ab,kw.
70	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 heroin expos$).ti,ab,kw.
71	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 cocaine expos$).ti,ab,kw.
72	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opioid addiction).ti,ab,kw.
73	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opiate addiction).ti,ab,kw.
74	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 narcotic addiction).ti,ab,kw.
75	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 heroin addiction).ti,ab,kw.
76	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 cocaine addiction).ti,ab,kw.
77	51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59 or 60 or 61 or 62 or 63 or 64 or 65 or 66 or 67 or 68 or 69 or 70 or 71 or 72 or 73 or 74 or 75 or 76
78	(random* or factorial* or placebo* or assign* or allocat* or crossover*).tw.
79	(cross adj over*).tw.
80	(trial* and (control* or comparative)).tw.
81	((blind* or mask*) and (single or double or triple or treble)).tw.
82	(treatment adj arm*).tw.
83	(control* adj group*).tw.
84	(phase adj (III or three)).tw.
85	(versus or vs).tw.
86	rct.tw.
87	Crossover Procedure/
88	Double Blind Procedure/
89	Single Blind Procedure/
90	Randomization/
91	Placebo/
92	exp Clinical Trial/
93	Parallel Design/
94	Latin Square Design/
95	78 or 79 or 80 or 81 or 82 or 83 or 84 or 85 or 86 or 87 or 88 or 89 or 90 or 91 or 92 or 93 or 94
96	exp animal/ or exp nonhuman/ or exp animal experiment/ or exp animal model/
97	exp human/
98	96 not 97
99	95 not 98
100	77 and 99
101	prenatal exposure/
102	drug dependence/ or amphetamine dependence/ or benzodiazepine dependence/ or cannabis addiction/ or cocaine dependence/ or drug misuse/ or glue sniffing/ or methamphetamine dependence/ or multiple drug abuse/ or exp narcotic dependence/ or phencyclidine dependence/
103	((opioid$ or opiate$ or narcotic$ or heroin or cocaine) adj5 (addiction or depend$ or toleran$ or withdraw$ or expos$)).ti,ab,kw.
104	102 or 103
105	101 and 104
106	(random* or factorial* or placebo* or assign* or allocat* or crossover*).tw.
107	(cross adj over*).tw.
108	(trial* and (control* or comparative)).tw.
109	((blind* or mask*) and (single or double or triple or treble)).tw.
110	(treatment adj arm*).tw.
111	(control* adj group*).tw.
112	(phase adj (III or three)).tw.
113	(versus or vs).tw.
114	rct.tw.
115	Crossover Procedure/
116	Double Blind Procedure/
117	Single Blind Procedure/
118	Randomization/
119	Placebo/
120	exp Clinical Trial/
121	Parallel Design/
122	Latin Square Design/
123	106 or 107 or 108 or 109 or 110 or 111 or 112 or 113 or 114 or 115 or 116 or 117 or 118 or 119 or 120 or 121 or 122
124	exp animal/ or exp nonhuman/ or exp animal experiment/ or exp animal model/
125	exp human/
126	124 not 125
127	123 not 126
128	105 and 127
129	35 or 100 or 128

Maternity and Infant Care via OVID SP Database: Maternity and Infant Care Database (MIDIRS) <1971 to current>

1	Neonatal abstinence syndrome.de.
2	neonatal abstinence.ti,ab,kw.
3	neonatal drug abstinence.ti,ab,kw.
4	neonatal drug withdrawal.ti,ab,kw.
5	neonatal substance withdrawal.ti,ab,kw.
6	neonatal withdrawal symptom$.ti,ab,kw.
7	neonatal withdrawal syndrome.ti,ab,kw.
8	newborn abstinence syndrome.ti,ab,kw.
9	newborn drug withdrawal syndrome.ti,ab,kw.
10	newborn withdrawal syndrome.ti,ab,kw.
11	1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10
12	Opioid‐related disorders.de.
13	(opiate substitution treatment or opioid substitution treatment).ti,ab,kw.
14	(opiate substitution therapy or opioid substitution therapy).ti,ab,kw.
15	(opiate replacement therapy or opioid replacement therapy).ti,ab,kw.
16	(opiate replacement treatment or opioid replacement treatment).ti,ab,kw.
17	NAS.ti,ab.
18	12 or 13 or 14 or 15 or 16 or 17
19	(Infant or Infant ‐ newborn).de.
20	(neonat$ or neo nat$).ti,ab.
21	(newborn$ or new born$ or newly born$).ti,ab.
22	infan$.ti,ab.
23	(baby or babies).ti,ab.
24	19 or 20 or 21 or 22 or 23
25	18 and 24
26	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opioid dependen$).ti,ab,kw.
27	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opiate dependen$).ti,ab,kw.
28	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 narcotic dependen$).ti,ab,kw.
29	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 heroin dependen$).ti,ab,kw.
30	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 cocaine dependen$).ti,ab,kw.
31	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opioid toleran$).ti,ab,kw.
32	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opiate toleran$).ti,ab,kw.
33	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 narcotic toleran$).ti,ab,kw.
34	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 heroin toleran$).ti,ab,kw.
35	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 cocaine toleran$).ti,ab,kw.
36	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opioid withdraw$).ti,ab,kw.
37	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opiate withdraw$).ti,ab,kw.
38	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 narcotic withdraw$).ti,ab,kw.
39	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 heroin withdraw$).ti,ab,kw.
40	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 cocaine withdraw$).ti,ab,kw.
41	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opioid expos$).ti,ab,kw.
42	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opiate expos$).ti,ab,kw.
43	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 narcotic expos$).ti,ab,kw.
44	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 heroin expos$).ti,ab,kw.
45	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 cocaine expos$).ti,ab,kw.
46	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opioid addiction).ti,ab,kw.
47	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opiate addiction).ti,ab,kw.
48	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 narcotic addiction).ti,ab,kw.
49	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 heroin addiction).ti,ab,kw.
50	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 cocaine addiction).ti,ab,kw.
51	26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50
52	11 or 25 or 51
53	limit 52 to randomised controlled trial

MEDLINE and MEDLINE In Process via OVID SP Database: Ovid MEDLINE(R) Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to Present>

1	Neonatal Abstinence Syndrome/
2	neonatal abstinence.ti,ab,kw.
3	neonatal drug abstinence.ti,ab,kw.
4	neonatal drug withdrawal.ti,ab,kw.
5	neonatal substance withdrawal.ti,ab,kw.
6	neonatal withdrawal symptom$.ti,ab,kw.
7	neonatal withdrawal syndrome.ti,ab,kw.
8	newborn abstinence syndrome.ti,ab,kw.
9	newborn drug withdrawal syndrome.ti,ab,kw.
10	newborn withdrawal syndrome.ti,ab,kw.
11	1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10
12	randomized controlled trial.pt.
13	controlled clinical trial.pt.
14	randomized.ab.
15	placebo.ab.
16	drug therapy.fs.
17	randomly.ab.
18	trial.ab.
19	groups.ab.
20	12 or 13 or 14 or 15 or 16 or 17 or 18 or 19
21	exp animals/ not humans.sh.
22	20 not 21
23	11 and 22
24	exp Opioid‐Related Disorders/
25	Opiate Substitution Treatment/
26	(opiate substitution treatment or opioid substitution treatment).ti,ab,kw.
27	(opiate substitution therapy or opioid substitution therapy).ti,ab,kw.
28	(opiate replacement therapy or opioid replacement therapy).ti,ab,kw.
29	(opiate replacement treatment or opioid replacement treatment).ti,ab,kw.
30	NAS.ti,ab.
31	24 or 25 or 26 or 27 or 28 or 29 or 30
32	exp Infant/ or Infant, Newborn/
33	(neonat$ or neo nat$).ti,ab.
34	(newborn$ or new born$ or newly born$).ti,ab.
35	infan$.ti,ab.
36	(baby or babies).ti,ab.
37	32 or 33 or 34 or 35 or 36
38	31 and 37
39	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opioid dependen$).ti,ab,kw.
40	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opiate dependen$).ti,ab,kw.
41	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 narcotic dependen$).ti,ab,kw.
42	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 heroin dependen$).ti,ab,kw.
43	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 cocaine dependen$).ti,ab,kw.
44	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opioid toleran$).ti,ab,kw.
45	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opiate toleran$).ti,ab,kw.
46	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 narcotic toleran$).ti,ab,kw.
47	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 heroin toleran$).ti,ab,kw.
48	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 cocaine toleran$).ti,ab,kw. (0)
49	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opioid withdraw$).ti,ab,kw.
50	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opiate withdraw$).ti,ab,kw.
51	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 narcotic withdraw$).ti,ab,kw.
52	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 heroin withdraw$).ti,ab,kw.
53	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 cocaine withdraw$).ti,ab,kw.
54	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opioid expos$).ti,ab,kw.
55	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opiate expos$).ti,ab,kw.
56	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 narcotic expos$).ti,ab,kw.
57	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 heroin expos$).ti,ab,kw.
58	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 cocaine expos$).ti,ab,kw.
59	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opioid addiction).ti,ab,kw.
60	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 opiate addiction).ti,ab,kw.
61	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 narcotic addiction).ti,ab,kw.
62	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 heroin addiction).ti,ab,kw.
63	((neonatal$ or newborn$ or baby$ or babies$ or infant$ or child$) adj5 cocaine addiction).ti,ab,kw.
64	38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59 or 60 or 61 or 62 or 63
65	randomized controlled trial.pt.
66	controlled clinical trial.pt.
67	randomized.ab.
68	placebo.ab.
69	drug therapy.fs.
70	randomly.ab.
71	trial.ab.
72	groups.ab.
73	65 or 66 or 67 or 68 or 69 or 70 or 71 or 72
74	exp animals/ not humans.sh.
75	73 not 74
76	64 and 75
77	Prenatal Exposure Delayed Effects/
78	amphetamine‐related disorders/ or cocaine‐related disorders/ or heroin dependence/ or inhalant abuse/ or marijuana abuse/ or opioid‐related disorders/ or phencyclidine abuse/ or substance abuse, intravenous/ or substance abuse, oral/ or substance withdrawal syndrome/
79	((opioid$ or opiate$ or narcotic$ or heroin or cocaine) adj5 (addiction or depend$ or toleran$ or withdraw$ or expos$)).ti,ab,kw.
80	78 or 79
81	77 and 80
82	randomized controlled trial.pt.
83	controlled clinical trial.pt.
84	randomized.ab.
85	placebo.ab.
86	drug therapy.fs.
87	randomly.ab.
88	trial.ab.
89	groups.ab.
90	82 or 83 or 84 or 85 or 86 or 87 or 88 or 89
91	exp animals/ not humans.sh.
92	90 not 91
93	81 and 92
94	23 or 76 or 93

Appendix 2. 'Risk of bias' tool

We will use the standard methods of Cochrane and Cochrane Neonatal to assess the methodological quality of the trials. For each trial, we will seek information regarding the method of randomization, blinding, and reporting of all outcomes of all the infants enrolled in the trial. We will assess each criterion as being at a low, high, or unclear risk of bias. Two review authors will separately assess each study. Any disagreements will be resolved by discussion. We will add this information to the 'Characteristics of included studies' table. We will evaluate the following issues and enter the findings into the 'Risk of bias' table.

1. Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?

For each included study, we will categorize the method used to generate the allocation sequence as:

• low risk (any truly random process, e.g. random number table; computer random number generator);

• high risk (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number); or

• unclear risk.

2. Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?

For each included study, we will categorize the method used to conceal the allocation sequence as:

• low risk (e.g. telephone or central randomization; consecutively numbered, sealed, opaque envelopes);

• high risk (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth); or

• unclear risk

3. Blinding of participants and personnel (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study?

For each included study, we will categorize the methods used to blind study participants and personnel from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or class of outcomes. We will categorize the methods as:

• low risk, high risk, or unclear risk for participants; and

• low risk, high risk, or unclear risk for personnel.

4. Blinding of outcome assessment (checking for possible detection bias). Was knowledge of the allocated intervention adequately prevented at the time of outcome assessment?

For each included study, we will categorize the methods used to blind outcome assessment. We will assess blinding separately for different outcomes or class of outcomes. We will categorize the methods as:

• low risk for outcome assessors;

• high risk for outcome assessors; or

• unclear risk for outcome assessors.

5. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were incomplete outcome data adequately addressed?

For each included study and for each outcome, we will describe the completeness of data including attrition and exclusions from the analysis. We will note whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported or supplied by the trial authors, we will re‐include missing data in the analyses. We will categorize the methods as:

• low risk (< 20% missing data);

• high risk (≥ 20% missing data); or

• unclear risk.

6. Selective reporting bias. Are reports of the study free of the suggestion of selective outcome reporting?

For each included study, we will describe how we investigated the possibility of selective outcome reporting bias and what we found. For studies in which study protocols were published in advance, we will compare prespecified outcomes versus outcomes eventually reported in the published results. If the study protocol was not published in advance, we will contact the study authors to gain access to the study protocol. We will assess the methods as:

• low risk (where it is clear that all of the study's prespecified outcomes and all expected outcomes of interest to the review have been reported);

• high risk (where not all the study's prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified outcomes of interest and are reported incompletely and so cannot be used; the study fails to include results of a key outcome that would have been expected to have been reported); or

• unclear risk.

7. Other sources of bias. Was the study apparently free of other problems that could put it at high risk of bias?

For each included study, we will describe any important concerns we had about other possible sources of bias (e.g. whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data‐dependent process). We will assess whether each study was free of other problems that could put it at risk of bias as:

• low risk;

• high risk; or

• unclear risk.

If needed, we plan to explore the impact of the level of bias by undertaking sensitivity analyses.

Appendix 3. Assessment of risk of bias of non‐randomized studies (ROBINS‐I)

Bias assessment

For each type of bias we will assign a risk of bias judgement category of low risk, moderate risk, serious risk, critical risk, or no information. A domain with 'low risk' of bias is comparable to a well‐performed randomized trial. A domain with 'moderate risk' of bias is sound for a non‐randomized study, but cannot be considered comparable to a well‐performed randomized trial. A domain with 'serious risk' of bias has some important problems. A domain with 'critical risk' of bias is too problematic to provide any useful evidence on the effects of the intervention.

Pre‐intervention

Bias due to confounding

Baseline confounding occurs when one or more prognostic variables (factors that predict the outcome of interest) also predicts the intervention received at baseline. ROBINS‐I can also address time‐varying confounding, which occurs when individuals switch between the interventions being compared and when postbaseline prognostic factors affect the intervention received after baseline.

Bias in the selection of participants into the study

When exclusion of some eligible participants, or the initial follow‐up time of some participants, or some outcome events is related to both intervention and outcome, there will be an association between interventions and outcome even if the effects of the interventions are identical. This form of selection bias is distinct from confounding; a specific example is bias due to the inclusion of prevalent users, rather than new users, of an intervention.

For the included studies, we will assess baseline confounding factors and bias in selection of participants including the following.

1. Infant characteristics (gestational age, birth weight, small for gestational age, sex, postnatal opioid exposure, non‐opioid‐related medical comorbidities).

2. Maternal characteristics (maternal age, primiparous status, type of delivery, prenatal care), maternal substance use history (prenatal opioid exposure, prenatal benzodiazepine exposure, prenatal SSRI exposure, prenatal polysubstance exposure, prenatal nicotine exposure, prescribed maternal opioid), maternal medical history (hepatitis C status, psychiatric diagnosis, and non‐opioid medications), and social situation (custody status, homelessness, employment status, public insurance, ethnicity, involvement of birth father, marital status, family support).

3. Co‐interventions (at study entry):

   1. environmental stimulation: adjustments of environmental stimulation include low light, low noise, clustered care, containment or swaddling, bedding type, positioning, non‐nutritive sucking, bathing, aromatherapy, music therapy, and massage;

   2. feeding practices: feeding modifications include infant‐led feeding, high‐caloric feeds, tube feeds, maternal breast milk feeds, non‐maternal breast milk feeds, low‐lactose formula, and breastfeeding;

   3. functioning of the maternal‐infant dyad: treatments focused on the maternal‐infant dyad include parental presence, rooming in, skin‐to‐skin or 'kangaroo care,' parental respite or 'cuddler' programs, trauma‐informed care, social work support, mental health support, treatment program support, and legal support;

   4. pharmacological treatments: opioid and non‐opioid medications including morphine, methadone, buprenorphine, phenobarbital, and clonidine.

At intervention

Bias in classification of intervention

Bias introduced by either differential or non‐differential misclassification of intervention status. Non‐differential misclassification is unrelated to the outcome and will usually bias the estimated effect of intervention towards the null. Differential misclassification occurs when misclassification of intervention status is related to the outcome or the risk of the outcome, and is likely to lead to bias.

This may include issues such as type of intervention, setting, dose, frequency, intensity, or timing of intervention.

Postintervention

Bias due to deviations from intended interventions

Bias that arises when there are systematic differences between experimental intervention and comparator groups in the care provided, which represent a deviation from the intended intervention(s).

Assessment of bias in this domain will depend on the type of effect of interest (either the effect of assignment to intervention or the effect of starting and adhering to intervention).

Bias due to missing data

Bias that arises when later follow‐up is missing for individuals initially included and followed (such as differential loss to follow‐up that is affected by prognostic factors).

This includes bias due to exclusion of individuals with missing information about intervention status or other variables such as confounders.

Bias in measurements of outcomes

Bias introduced by either differential or non‐differential errors in measurement of outcome data. Such bias can arise when outcome assessors are aware of intervention status; if different methods are used to assess outcomes in different intervention groups; or if measurement errors are related to intervention status or effects.

Bias in selection of the reported results

Selective reporting of results in a way that depends on the findings and prevents the estimate from being included in a meta‐analysis (or other synthesis).

Contributions of authors

Adrienne Pahl and Roger Soll drafted the protocol. Leslie Young, Lenora Marcellus, and Madge E Buus‐Frank provided expert review and comment.

Sources of support

Internal sources

• No sources of support supplied

External sources

• Vermont Oxford Network, Other.

  Cochrane Neonatal Reviews are produced with support from Vermont Oxford Network, a worldwide collaboration of health professionals dedicated to providing evidence‐based care of the highest quality for newborn infants and their families.

• National Institute for Health Research, UK.

  Editorial support for Cochrane Neonatal has been funded by a UK National Institute of Health Research (NIHR) Cochrane Programme Grant (16/114/03). The views expressed in this publication are those of the authors and not necessarily those of the National Health Service (NHS), the NIHR, or the UK Department of Health.

Declarations of interest

Adrienne Pahl has no conflicts of interest relevant to this review. Leslie Young Madge E Buus‐Frank Lenora Marcellus Roger Soll is Co‐ordinating Editor of Cochrane Neonatal and has no conflicts of interest relevant to this review.

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