Maintenance agonist treatments for opiate‐dependent pregnant women
Abstract
Background
The prevalence of opiate use among pregnant women can range from 1% to 2% to as high as 21%. Just in the United States alone, among pregnant women with hospital delivery, a fourfold increase in opioid use is reported from 1999 to 2014 (Haight 2018). Heroin crosses the placenta, and pregnant, opiate‐dependent women experience a six‐fold increase in maternal obstetric complications such as low birth weight, toxaemia, third trimester bleeding, malpresentation, puerperal morbidity, fetal distress and meconium aspiration. Neonatal complications include narcotic withdrawal, postnatal growth deficiency, microcephaly, neuro‐behavioural problems, increased neonatal mortality and a 74‐fold increase in sudden infant death syndrome. This is an updated version of the original Cochrane Review first published in 2008 and last updated in 2013.
Objectives
To assess the effectiveness of any maintenance treatment alone or in combination with a psychosocial intervention compared to no intervention, other pharmacological intervention or psychosocial interventions alone for child health status, neonatal mortality, retaining pregnant women in treatment, and reducing the use of substances.
Search methods
We updated our searches of the following databases to February 2020: the Cochrane Drugs and Alcohol Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and Web of Science. We also searched two trials registers and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs).
Selection criteria
Randomised controlled trials which assessed the efficacy of any pharmacological maintenance treatment for opiate‐dependent pregnant women.
Data collection and analysis
We used the standard methodological procedures expected by Cochrane.
Main results
We found four trials with 271 pregnant women. Three compared methadone with buprenorphine and one methadone with oral slow‐release morphine. Three out of four studies had adequate allocation concealment and were double‐blind. The major flaw in the included studies was attrition bias: three out of four had a high dropout rate (30% to 40%), and this was unbalanced between groups.
Methadone versus buprenorphine:
There was probably no evidence of a difference in the dropout rate from treatment (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.37 to 1.20, three studies, 223 participants, moderate‐quality evidence). There may be no evidence of a difference in the use of primary substances between methadone and buprenorphine (RR 1.81, 95% CI 0.70 to 4.68, two studies, 151 participants, low‐quality evidence). Birth weight may be higher in the buprenorphine group in the two trials that reported data MD;‐530.00 g, 95%CI ‐662.78 to ‐397.22 (one study, 19 particpants) and MD: ‐215.00 g, 95%CI ‐238.93 to ‐191.07 (one study, 131 participants) although the results could not be pooled due to very high heterogeneity (very low‐quality of evidence). The third study reported that there was no evidence of a difference. We found there may be no evidence of a difference in the APGAR score (MD: 0.00, 95% CI ‐0.03 to 0.03, two studies,163 participants, low‐quality evidence). Many measures were used in the studies to assess neonatal abstinence syndrome. The number of newborns treated for neonatal abstinence syndrome, which is the most critical outcome, may not differ between groups (RR 1.19, 95% CI 0.87 to1.63, three studies, 166 participants, low‐quality evidence).
Only one study which compared methadone with buprenorphine reported side effects. We found there may be no evidence of a difference in the number of mothers with serious adverse events (AEs) (RR 1.69, 95% CI 0.75 to 3.83, 175 participants, low‐quality evidence) and we found there may be no difference in the numbers of newborns with serious AEs (RR 4.77, 95% CI 0.59, 38.49,131 participants, low‐quality evidence).
Methadone versus slow‐release morphine:
There were no dropouts in either treatment group. Oral slow‐release morphine may be superior to methadone for abstinence from heroin use during pregnancy (RR 2.40, 95% CI 1.00 to 5.77, one study, 48 participants, low‐quality evidence).
In the comparison between methadone and slow‐release morphine, no side effects were reported for the mother. In contrast, one child in the methadone group had central apnoea, and one child in the morphine group had obstructive apnoea (low‐quality evidence).
Authors' conclusions
Methadone and buprenorphine may be similar in efficacy and safety for the treatment of opioid‐dependent pregnant women and their babies. There is not enough evidence to make conclusions for the comparison between methadone and slow‐release morphine. Overall, the body of evidence is too small to make firm conclusions about the equivalence of the treatments compared. There is still a need for randomised controlled trials of adequate sample size comparing different maintenance treatments.
PICOs
Plain language summary
Maintenance treatments for opiate‐dependent pregnant women
Review question
This review summarised research studies comparing different types of pharmacologic maintenance treatments for pregnant women with opioid dependence
Key messages:
Methadone and buprenorphine may be substantially similar in efficacy and safety for the treatment of opioid‐dependent pregnant women and their babies. There is not enough evidence to make conclusions for the comparison between methadone and slow‐release morphine. Overall, the body of evidence is too small to make firm conclusions.
Background
Some women continue to use opiates when they are pregnant, yet heroin readily crosses the placenta. Opiate‐dependent women experience a sixfold increase in maternal obstetric complications and may give birth to low‐weight babies. The newborn may experience narcotic withdrawal (neonatal abstinence syndrome) and have development problems. There is also increased neonatal mortality and a 74‐fold increase in the risk of sudden infant death syndrome. Maintenance treatment with methadone provides a steady concentration of opiate in the pregnant woman's blood, and so prevents the adverse effects on the fetus of repeated withdrawals. Buprenorphine is also used.
Search date
The evidence is current to 18 February 2020.
Study characteristics
Only four randomised controlled trials with 271 participants satisfied the inclusion criteria for the review: two from Austria (outpatients), one from the USA (inpatients) and the fourth a multicentre, international study conducted in Austria, Canada and the USA. The trials continued for 15 to 18 weeks. Three compared methadone with buprenorphine (223 participants) and one compared methadone with oral slow‐release morphine (48 participants).
Study funding sources
The National Institute on Drug Abuse funded two studies, one received a grant from the Mayor of Vienna, and in the fourth study Schering Plough provided an educational grant to the first author to employ personnel required to conduct this study.
Key results
This review found few differences in newborn or maternal outcomes for pregnant, opiate‐addicted women who were maintained on methadone, buprenorphine or oral slow‐release morphine from a mean gestational age of 23 weeks to delivery.
Comparing methadone with buprenorphine, there is probably little or no difference in the number of women who dropped out of treatment. There may be little or no difference in the use of a primary substance and the number of newborns treated for neonatal abstinence syndrome between the methadone and buprenorphine groups. We are very uncertain whether newborns with mothers receiving buprenorphine could have a heavier birth weight.
Comparing methadone with oral slow‐release morphine, there were no dropouts in the only study included. The use of heroin in the third trimester may be lower with slow‐release morphine. However, there may be little or no difference in infant birth weight or duration of neonatal abstinence syndrome.
The number of participants in the trials was small and may not be sufficient to draw firm conclusions. All the included studies ended immediately after the baby was born. No severe complications were noted.
Quality of evidence
In the comparison of methadone with buprenorphine, the quality of the evidence ranged from moderate to very low because of inconsistency in the results of the studies for some outcomes, high rates of participants who dropped out from the studies, and small sample sizes of the included studies. In the comparison of methadone with slow‐release morphine, the quality of the evidence was low because of the small sample size of the study.
Authors' conclusions
Summary of findings
| Methadone compared to buprenorphine for opiate‐dependent pregnant women | ||||||
| Patient or population: opiate‐dependent pregnant women | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with buprenorphine | Risk with methadone | |||||
| Dropout rate | Study population | RR 0.66 | 223 | ⊕⊕⊕⊝ | ||
| 318 per 1000 | 210 per 1000 | |||||
| Use of primary substance | Study population | RR 1.81 | 151 | ⊕⊕⊝⊝ | ||
| 75 per 1000 | 135 per 1000 | |||||
| Birth weight | The mean birth weight ranged from 3.093 g to 3530 gr | MD ranged from ‐530.00 gr (662.78,lower to 397.22 lower) to ‐215.00 gr (238.93, lower to 191.07 lower) | ‐ | 19 and 131 participants | ⊕⊝⊝⊝ | |
| APGAR score | The mean APGAR score was 8.95 | MD 0 | ‐ | 163 | ⊕⊕⊝⊝ | |
| Number treated for NAS | Study population | RR 1.19 | 166 | ⊕⊕⊝⊝ | ||
| 447 per 1000 | 532 per 1000 | |||||
| Serious adverse events for the mother | Study population | RR 1.69 | 175 | ⊕⊕⊝⊝ | ||
| 93 per 1000 | 157 per 1000 | |||||
| Serious adverse events for the child | Study population | RR 4.77 | 131 | ⊕⊕⊝⊝ | ||
| 17 per 1000 | 82 per 1000 | |||||
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 downgraded one level due to imprecision: optimal information size not met 2 downgraded one level due to study limitations: high risk of attrition bias 3 downgraded one level due to inconsistency: high heterogeneity: I2 95% 4 downgraded one level due to imprecision: fewer than 400 participants | ||||||
| Methadone compared to oral slow‐release morphine for opiate‐dependent pregnant women | ||||||
| Patient or population: opiate‐dependent pregnant women | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with oral slow‐release morphine | Risk with methadone | |||||
| Dropout rate from treatment | No dropouts from either group | 48 | ⊕⊕⊝⊝ | |||
| Use of substance | Study population | RR 2.40 | 48 | ⊕⊕⊝⊝ | ||
| 208 per 1000 | 500 per 1000 | |||||
| Birth weight | The mean birth weight was 2912 g | MD 124 higher | ‐ | 48 | ⊕⊕⊝⊝ | |
| APGAR score (APGAR score ) | The study did not assess this outcome | ‐ | ||||
| Adverse events for the mother follow‐up: mean 15 weeks | No side effects for the mother were reported | 48 | ⊕⊕⊝⊝ | |||
| Serious adverse events for the child follow‐up: mean 15 weeks | No severe complications were noted in any of the neonates as monitored by polysomnography, although one child in the methadone group had central apnoea and one child in the morphine group had obstructive apnoea. | 48 | ⊕⊕⊝⊝ | |||
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 not applicable 2 downgraded two levels: fewer than 100 participants 3 downgraded two level: optimal information size not met | ||||||
Background
Description of the condition
Prenatal opioid use has increased dramatically since 2000. In the United States, the trend of current illegal drug use among pregnant women remained relatively stable from 2007 to 2008 (5.1%) up to 2009 to 2010 (4.4%) (Behnke 2013). However, the nationwide use of opioids during pregnancy has increased and more than quadrupled between 1999 and 2014 (Haight 2018).
The prevalence of opioid abuse is also increasing in other countries. In Australia, the National Drug Strategy Household Survey in 2013 found that among pregnant women, a small minority had used illicit substances; 2.4% before knowledge of their pregnancy and 1.6% after they knew they were pregnant (AIHW 2014). In the older version of the same survey conducted in 2010, it was reported that less than one in 20 women (4.2%) who were pregnant and breastfeeding in the past 12 months used any illicit drug while they were pregnant. This included those who used illicit drugs in the time before they knew they were pregnant (AIHW 2011).
The Canadian Maternity Experiences Survey found that 7% of women reported street drug use in the three months before pregnancy, which was then reduced to 1% once aware of pregnancy (Ordean 2018). The European Monitoring Centre for Drug & Drug Addiction (EMCDDA 2014) report indicates that the actual prevalence of drug use among pregnant women in Europe is difficult to ascertain. In many European countries, the data are simply not available due to a lack of scheduled antenatal visits among drug users. An isolated study conducted in a maternity hospital in Dublin, Ireland, found that 4% of prenatal and 6% of postnatal women tested positive for drug metabolites. Prevalence data of opioid use among pregnant women in other important data resources are limited (sources searched: World Health Organization (WHO 2014), United Nations Office on Drug and Crime ‐ World Drug Report (UNODC 2018), Office of National Drug Control Policy, USA (ONDCP 2020), Monitoring the Future 2019 Survey (Monitoring the future 2017).
Heroin readily crosses the placenta, and untreated opiate dependence in pregnant women is associated with many environmental and medical factors that contribute to poor maternal and child outcomes. It causes a six‐fold increase in obstetric complications, such as low birth weight, toxaemia, third trimester bleeding, malpresentation, puerperal morbidity, fetal distress and meconium aspiration. Neonatal complications include neonatal abstinence syndrome (NAS), postnatal growth deficiency, microcephaly, neurobehavioural problems, increased neonatal mortality and a 74‐fold increase in sudden infant death syndrome (Dattel 1990; Fajemirokun 2006; Ludlow 2004; Reddy 2017).
All of the commonly used opioids, including heroin and methadone, can produce neonatal abstinence syndrome in infants born to opiate‐dependent mothers. Neonatal abstinence syndrome combines all the symptoms of an adult withdrawal syndrome with irritability, poorly co‐ordinated sucking and, in the most severe cases, seizures and death (Kaltenbach 1998).
Description of the intervention
Since the early 1970s, treatment with methadone has been the standard of care for pregnant women addicted to opiates. Despite its ability to induce fetal dependence and withdrawal, maintenance treatment provides a steady concentration in the maternal blood plasma. It thus prevents the adverse effects of repeated withdrawal on the fetus (Jarvis 1994).
Buprenorphine has also been administered to opioid‐dependent pregnant women as a maintenance treatment. Placental transfer of buprenorphine may be less than with methadone, reducing fetal exposure and development of neonatal abstinence syndrome (Rayburn 2004).
How the intervention might work
Methadone maintenance treatment given during pregnancy reduces maternal illicit opiate use and fetal exposure, enhances compliance with obstetric care, and is associated with improved neonatal outcomes such as heavier birth weight (Fajemirokun 2006; Kaltenbach 1998). Additional benefits include a potential reduction in drug‐seeking behaviours, including commercial sex, to gain money for drugs. This reduction may decrease a woman's chance of acquiring sexually transmitted diseases such as human immunodeficiency virus (HIV) and hepatitis. For all these reasons, methadone treatment has become the 'gold standard' for the management of pregnant heroin users (NIH 1998) and many guidelines, in the UK (UK Guidelines 2007), USA (CSAT 2005) and Australia (Dunlop 2003), support the use of methadone during pregnancy.
Previous studies have been performed in centres that offered methadone and comprehensive services, including obstetric, health, psychiatric care, individual, group and family therapy. Consequently, it is difficult to evaluate the results of these studies and to distinguish the benefits of methadone itself from other measures of psychosocial and obstetric care (Wang 1999).
The available clinical literature suggests that buprenorphine maintenance is also associated with reduced maternal illicit opiate use and fetal exposure, enhanced compliance with obstetric care, and improved neonatal outcomes such as heavier birth weight (Johnson 2003; Lejuene 2006).
Why it is important to do this review
The Cochrane Drugs and Alcohol Group has conducted several systematic reviews on maintenance treatment: methadone (Faggiano 2003; Mattick 2009), heroin (Ferri 2011), levomethadyl acetate hydrochloride (LAAM) (Clark 2002), buprenorphine (Mattick 2008), naltrexone (Minozzi 2011), psychosocial treatment alone (Mayet 2004) and psychosocial treatment combined with maintenance treatment (Amato 2011). However, none of these reviews include studies on pregnant, opiate‐dependent women.
Two narrative reviews have discussed the risks and benefits of maintenance treatment in opiate‐dependent women (Rayburn 2004; Wang 1999); however, neither specified the inclusion criteria for the studies. They also described the studies and the results in a very generic way and did not draw firm conclusions about the superiority of one drug treatment over another. Two other out‐of‐date reviews also included observational studies and assessed the relationship between maternal opiate use and infant birth weight (Hulse 1997) and neonatal mortality (Hulse 1998). They found better results in patients taking methadone in terms of birth weight but no reduction in mortality. A more recent observational systematic review was conducted on the efficacy and safety of detoxification from opioids compared to maintenance with methadone or buprenorphine to treat opioid‐dependent pregnant women (Wang 2018). They included 235 pregnant women from three cohort studies in the meta‐analysis. Maternal maintenance therapy was associated with increased risk of relapse (RR 1.91, 95% confidence interval (CI) 1.14 to 3.21) but no treatment differences were observed for rates of NAS (RR 0.99, 95% CI 0.38 to 2.53) or preterm birth (RR 0.39, 95% CI 0.10 to 1.60). Another narrative review was conducted (including 75 articles from 1975 to 2015) and concluded that women with opioid use addiction during pregnancy could be treated with methadone or buprenorphine (Klaman 2017).
Objectives
To assess the effectiveness of any opioid agonist maintenance treatment alone or in combination with a psychosocial intervention compared to no intervention, other pharmacological intervention or psychosocial interventions for child health status, neonatal mortality, retaining pregnant women in treatment, and reducing the use of substances.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials which enrolled pregnant women were eligible. Studies starting after the delivery were excluded.
Types of participants
Opiate‐addicted according to the "Diagnostic and Statistical Manual of mental disorders" (DSM‐IV or DSM‐V) criteria pregnant women of any age irrespective of the duration of pregnancy. There was no restriction concerning the physical or psychological illness.
Types of interventions
Experimental intervention
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Any pharmacological intervention (methadone, buprenorphine, LAAM, heroin, morphine, codeine) alone or combined with psychosocial intervention(s) for maintenance treatment
Control intervention
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No intervention
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Other pharmacological interventions
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Psychosocial intervention alone
Types of outcome measures
For the woman
1. Dropout from treatment, as measured by the number of women who had dropped out at the end of the intervention
2. Use of primary substance of abuse
2.1 Use of primary substance as measured by the number of women using heroin during or at the end of treatment (self‐report or urine analysis results)
2.2. Use of primary substance at follow‐up as measured by the number of women using heroin at the end of follow‐up (after childbirth)
3. Obstetric outcomes
3.1 Third trimester bleeding
3.2 Fetal distress and meconium aspiration
3.3 Caesarean section
3.4 Abnormal presentation
3.5 Medical complications at delivery
3.6 Breastfeeding following delivery
3.7 Puerperal morbidity
For the child
4. Health status measured as:
4.1 Birth weight
4.2 APGAR score (Activity, Pulse, Grimace, Appearance and Respiration score)
4.3 Neonatal abstinence syndrome
4.4 Prenatal and neonatal mortality
Secondary outcomes
5. Nicotine consumption
6. Use of other substances
7. Side effects for the mother
8. Side effects for the child
Search methods for identification of studies
Electronic searches
For this update, we revised all our search strategies in line with current Cochrane Drugs and Alcohol Group practices. We searched the following databases up to 18 February 2020:
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Cochrane Drugs and Alcohol Group (CDAG) Specialised Register (searched 18 February 2020) Appendix 1;
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Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies (CRS‐Web); (searched 18 February 2020) Appendix 2;
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MEDLINE (OVID) (2013 to 18 February 2020) Appendix 3;
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Embase (OVID) (2013 to 18 February 2020) Appendix 4;
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PsycINFO (Ovid) (2013 to 18 February 2020) Appendix 5;
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CINAHL (EBSCO Host) (2013 to 18 February 2020) Appendix 6;
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Web of Science (2013 to 18 February 2020) Appendix 7.
We searched the following trials registries on 18 February 2020:
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ClinicalTrials.gov (clinicaltrials.gov);
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World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/).
Details of the previous search strategies are available in Minozzi 2013.
Searching other resources
We checked the bibliographies of included studies and relevant reviews for further references to relevant trials.
We contacted the authors of included studies and experts in the field in various countries to find out if they knew any other published or unpublished controlled trials.
We did not apply any language restrictions.
Data collection and analysis
Selection of studies
Two authors (Minozzi, Bellisario) independently inspected the search hits by reading titles and abstracts. We obtained each potentially relevant study located by the search in full text and the two authors assessed each for inclusion independently. Doubts were resolved by discussion between the authors.
Data extraction and management
Two authors (Minozzi, Bellisario) independently extracted data from studies using a standardised checklist. Any disagreement was resolved by discussion.
Assessment of risk of bias in included studies
Two authors (Minozzi, Bellisario) independently performed the 'Risk of bias' assessment for RCTs and "Controlled Clinical Trials"(CCTs) using the criteria recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The recommended approach for assessing the risk of bias in studies included in Cochrane Reviews is a two‐part tool, addressing six specific domains, namely: sequence generation and allocation concealment (selection bias), blinding of participants and providers (performance bias), blinding of outcome assessor (detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias). The first part of the tool involves describing what was reported to have happened in the study. The second part of the tool consists of assigning a judgement relating to the risk of bias for that entry in terms of low, high or unclear risk. To make these judgements, we used the criteria indicated in the Cochrane Handbook for Systematic Reviews of Interventions adapted to the addiction field. See Appendix 8 for details.
We considered blinding of participants, personnel and outcome assessors (avoidance of performance bias and detection bias) separately for objective outcomes (e.g. dropouts, use of the substance of abuse measured by urine analysis, participants relapsed at the end of follow‐up, participants engaged in further treatment) and subjective outcomes (e.g. duration and severity of signs and symptoms of withdrawal, patient self‐reported use of the substance, side effects).
We considered incomplete outcome data (avoidance of attrition bias) for all outcomes except for dropout from the treatment, which is very often the primary outcome measure in trials on addiction.
Grading of evidence
We assessed the overall quality of the evidence for the primary outcomes and the secondary outcome "side effects" using the GRADE system. The Grading of Recommendation, Assessment, Development and Evaluation Working Group (GRADE) developed a method for grading the quality of evidence (Schunemann 2013), which takes into account issues not only related to internal validity but also external validity, such as directness of results. The 'Summary of findings' tables presents the main findings of a review in a transparent and straightforward tabular format. In particular, they provide crucial information concerning the quality of evidence, the magnitude of the effect of the interventions examined and the sum of available data on the primary outcomes.
The GRADE system uses the following criteria for assigning grades of evidence:
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High: further research is very unlikely to change our confidence in the estimate of effect.
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Moderate: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
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Low: 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.
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Very low: any estimate of effect is very uncertain.
Grading is decreased for the following reasons:
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Serious (‐1) or very serious (‐2) limitation to study quality.
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Important inconsistency (‐1).
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Some (‐1) or major (‐2) uncertainty about directness.
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Imprecise or sparse data (‐1).
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High probability of reporting bias (‐1).
Measures of treatment effect
We analysed dichotomous outcomes by calculating the risk ratio (RR) for each trial with the uncertainty in each result being expressed by its confidence interval. We analysed continuous outcomes by calculating the mean difference (MD) or the standardised mean difference (SMD) with 95% CI. For nicotine use, we compared the contrast of the mean number of cigarettes smoked from baseline to end of treatment in the experimental and control groups. In the case of missing standard deviations (SDs) for the difference from baseline to the end of treatment, we imputed the SD using the SD of the mean at the end of treatment for each group.
We did not use data presented as the number of positive urine tests over the total number of tests in the experimental and control group as a measure of substance abuse. This is because using tests instead of participants as the unit of analysis violates the hypothesis of independence among observations. In fact, the results of tests done in each participant are not independent.
Unit of analysis issues
If multi‐arm studies were included in the meta‐analyses and one arm was considered more than once in the same comparisons (e.g. two different dosages of drugs compared with the same control group), we combined all the relevant experimental groups into a single group and we compared it with the control to avoid double counting of participants in the control groups. No cross‐over or cluster‐randomised trials were expected to be found because these study desings are not adequate with these types of participants and of interventions .
Dealing with missing data
For the analysis of binary outcome data (number of women using heroin), all randomised patients were included in the statistical analysis, with those who dropped out or were lost to follow‐up assigned to the 'using drug' category. For continuous outcomes, only the available data were considered.
Assessment of heterogeneity
We analysed heterogeneity by means of the I2 statistic and the Chi2 test for heterogeneity. The cut points were an I2 value > 50% and a P‐value of the Chi2 test of < 0.1.
Assessment of reporting biases
We intended to use funnel plots (plots of the effect estimate from each study against the standard error) to assess the potential for bias related to the size of the trials, which could indicate possible publication bias, if a sufficient number of studies (i.e. at least ten studies) were included. If asymmetry had been found, we would have conducted the Egger test (Egger 1997).
Data synthesis
We combined the outcome measures from the individual trials through meta‐analysis where possible (good comparability of intervention and outcomes between trials). We used the random‐effect model because we expected a certain degree of heterogeneity among trials
Subgroup analysis and investigation of heterogeneity
No subgroup analyses were planned. In case of substantial heterogeneity (i.e. I2 value > 90%) and inconsistency in the direction of effect, meta‐analysis was not done.
Sensitivity analysis
To incorporate the assessment of risk of bias into the review process, we first plotted the intervention effect estimates against the evaluation of risk of bias. We inspected the results stratified for risk of bias. If we found significant associations between the measure of effect and risk of bias, we excluded studies with a high risk of bias from the analysis. The items considered in the sensitivity analysis were: random sequence generation, allocation concealment and blinding of personnel and outcome assessors.
Results
Description of studies
Results of the search
In the previous version of our review (Minozzi 2013), we retrieved a total of 1385 records. Once duplicates had been removed, we had a total of 968 records. We excluded 933 records based on titles and abstracts. We obtained the full text of the remaining 35 records. We excluded 20 studies. We included four studies reported in 15 references (see Characteristics of included studies). For a further description of our screening process, see the study flow diagram (Figure 1).
Study flow diagram September 2013.
As shown in Figure 2, our update searches identified 633 records. Once duplicates had been removed, we had a total of 467 records. We screened out 462 references based on titles and abstracts. We examined the remaining five records in full text and excluded one (see Characteristics of excluded studies). We did not include new studies; the remaining four records are new reposts of a previously included study (MOTHER Study). We identified one ongoing study (NCT 03098407).
Study flow diagram February 2020.
Included studies
Four studies with 271 participants met the inclusion criteria for this review.
Duration of trials
The mean duration of the trials was 16.3 weeks (range 15 to 18 weeks).
Treatment regimens and settings
Two trials were conducted in Austria (Fischer 1999; Fischer 2006) and one in the USA (Jones 2005). The MOTHER study is a multicentre, international study conducted in Austria, Canada and the USA.
Three trials compared a methadone dose of between 20 and 140 mg/day with a buprenorphine dose of between 2 and 32 mg/day (Fischer 2006; Jones 2005; MOTHER Study). One trial compared methadone (mean dose at delivery 53.48 mg) with oral slow‐release morphine (mean dose at delivery 300.43 mg) (Fischer 1999).
Three studies were conducted in an outpatient setting (Fischer 1999; Fischer 2006; MOTHER Study) and one in an inpatient setting (Jones 2005).
Participants
Two hundred seventy‐one opiate‐dependent pregnant women meeting the DSM‐IV criteria were included in the studies. The mean age of participants was 27.3 years. The mean gestational age was 22 weeks. Nicotine use during pregnancy was reported only in one trial (Fischer 1999) as a mean number of cigarettes per day: it was 27.56 (SD 26.28) for the methadone group and 31.30 (SD 22.56) for the morphine group.
Rating instruments utilised in the studies
All the included studies measured neonatal abstinence syndrome using the Finnegan scale (Finnegan 1992), but the MOTHER Study used a modified Finnegan scale (called the MOTHER neonatal abstinence syndrome scale), which includes 28 items with 19 items used for scoring and medication decisions. Scores on the modified scale range from 0 to 42, with higher scores indicating more severe withdrawal. Original neonatal abstinence syndrome item definitions, as well as the morphine medication protocol, were refined before data collection.
Comparisons
Comparison 1
Methadone versus buprenorphine was compared in three trials with 223 participants (Fischer 2006; Jones 2005; MOTHER Study).
Comparison 2
Methadone versus slow‐release morphine was compared in one trial with 48 participants (Fischer 1999).
Excluded studies
Twenty‐one studies did not meet the criteria for inclusion in this review. The grounds for exclusion were: study design (13 studies) (Bandstra 2012; Binder 2008; Ebner 2007; Fisher 1998; Gordon 2004; Hulse 2004; Keyser‐Marcus 2002; Jones 2008; Lacroix 2011; Laken 1997; Martin 2011; Newman 2009; Stine 2009), type of participants (four studies) (Bell 2007; Dawe 2007; Jackson 2004; Suchman 2007), type of experimental intervention (two studies) (Carroll 1995; Cochran 2019) and type of control intervention (two studies) (Jones 2011; Tuten 2012).
Risk of bias in included studies
See Figure 3 and Figure 4. All of the studies were randomised controlled trials.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Random sequence generation
Only one study (Jones 2005) used a random sequence generation method and was at low risk of selection bias. We judged all the other studies to be at unclear risk of bias.
Allocation concealment
There was a low risk of bias for allocation concealment in three studies (Fischer 2006; Jones 2005; MOTHER Study) and an unclear risk in the fourth study (Fischer 1999).
Blinding
Subjective outcomes
We judged one study (Fischer 1999) to be at a high risk of performance and detection bias because it was an open‐label study. All the other studies were double‐blind, and we judged them to be at a low risk of bias.
Objective outcomes
We judged all four studies to be at a low risk of performance and detection bias.
Incomplete outcome data
Only one study had no attrition (Fischer 1999). We judged the other three to be at high risk of attrition bias because the attrition rate was high and unbalanced between groups.
Selective reporting
Only one study (MOTHER Study) had a protocol published before the completion of the study; it was judged at low risk of selective reporting because the results of all the predefined outcomes were reported. The other studies were judged to be at unclear risk because no protocol was available
Effects of interventions
See: Summary of findings 1 Methadone compared to buprenorphine for opiate‐dependent pregnant women; Summary of findings 2 Methadone compared to oral slow‐release morphine for opiate‐dependent pregnant women
Comparison 1: Methadone versus buprenorphine
See summary of findings Table 1.
Primary outcomes: for the woman
1. Dropouts from treatment
We analysed the number of participants who did not complete the treatment (Fischer 2006; Jones 2005; MOTHER Study): There was no evidence of a difference between treatments (RR 0.66, 95% confidence interval (CI) 0.37 to 1.20, 223 participants, three studies, moderate quality evidence). (Analysis 1.1).
2. Use of primary substance of abuse
2.1 During or at the end of treatment
We pooled two trials (Jones 2005, MOTHER Study) with 151 participants. There was no evidence of a difference between treatments (RR 1.81, 95% CI 0.70 to 4.68, low quality evidence) (Analysis 1.2).
2.2 At follow‐up
None of the studies considered this outcome.
3. Obstetric outcomes
3.1 Third trimester bleeding
Data for this outcome were not reported in any of the included studies.
3.2 Preterm delivery
In Fischer 2006, three children were delivered prematurely in the methadone group and two in the buprenorphine group (one at week 34, one at week 35 and three at week 36). In Jones 2005, there was one preterm birth in the methadone group (week not reported). In the MOTHER Study, there were 19% preterm deliveries in the methadone group and 7% in the buprenorphine group. There was no evidence of a difference between treatments.
3.3 Fetal distress and meconium aspiration
Data for this outcome were not reported in Jones 2005 and Fischer 2006. In the MOTHER Study, there was one case of meconium aspiration in the buprenorphine group.
3.4 Caesarean section
In Jones 2005, all but one birth in each group were vaginal. In Fischer 2006, two women maintained on buprenorphine were delivered by planned caesarean section at week 40. In the MOTHER Study, there were 37% of caesarean sections in the methadone group and 29% in the buprenorphine group. There was no evidence of a difference between treatments.
3.5 Abnormal presentation
In Jones 2005, all births were normal presentation. Data were not reported in Fischer 2006. In the MOTHER Study, there were 14% abnormal fetal presentations in the methadone group and 5% in the buprenorphine group. There was no evidence of a difference between treatments.
3.6 Medical complications at delivery
In Fischer 2006, one woman in the methadone group required vacuum extraction due to a prolonged delivery. No medical complications occurred in Jones 2005. In the MOTHER Study, there were 51% medical complications at delivery in the methadone group and 31% in the buprenorphine group (P = 0.03).
3.7 Breastfeeding following delivery
Data were not reported in any of the included studies.
3.8 Puerperal morbidity
No cases of puerperal morbidity were observed in Jones 2005 or in the MOTHER Study. Data were not reported in Fischer 2006.
Primary outcomes: for the child
4. Health status
4.1 Birth weight
Two studies (Jones 2005; MOTHER Study) with 150 participants reported data for this outcome (one mother in the buprenorphine group delivered twins; twin data were not considered for this outcome because it could be altered by twin status). The results were in favour of buprenorhine in both studies: MD; ‐530.00 g (95%CI ‐662.78 to ‐397.22) in Jones 2005 and MD: ‐215.00 g (95%CI ‐238.93 to ‐191.07) in the MOTHER Study; data were not pooled due to high heterogeneity ( P < 0.00001, I2 = 95%). Quality of evidence was judged as very low.The third study (Fischer 2006) did not report data but stated that there was no evidence of a difference between treatments in birth weight (mean 2820 g).
4.2 APGAR score (Activity, Pulse, Grimace, Appearance and Respiration score) at five minutes
We pooled two studies (Jones 2005; MOTHER Study) with 163 participants. There was no evidence of a difference between treatments (MD 0.00, 95% CI ‐0.03 to 0.03, low quality evidence) (Analysis 1.4;). The third study (Fischer 2006) did not report data but stated that there was no evidence of a difference between treatments in the APGAR score between groups.
4.3 Neonatal abstinence syndrome
We pooled the number of newborns treated for neonatal abstinence syndrome from three studies with 166 participants (Fischer 2006; Jones 2005; MOTHER Study). There was no evidence of a difference between treatments (RR 1.19; 95% CI 0.87 to 1.66, low quality evidence) (Analysis 1.5).
Neonatal abstinence syndrome peak score during the overall observation days were measured in two studies (Jones 2005; MOTHER Study). In Jones 2005 (21 participants), the results were methadone: 4.9, buprenorphine: 6.8 (SDs not provided); There was no evidence of a difference between treatments. In the MOTHER Study (131 participants), the results were methadone: 12.8 ± 0.6, buprenorphine: 11.0 ± 0.6 (P = 0.04), which is in favour of buprenorphine.
We pooled the mean duration of treatment for neonatal abstinence syndrome results from two studies (Fischer 2006; MOTHER Study) (145 participants). There was no evidence of a difference between treatments (MD 0.00; 95% CI ‐0.03 to 0.03) (Analysis 1.6).
The total number of morphine drops administered was measured in one study with 21 participants (Jones 2005). The results were methadone: 93.1, buprenorphine: 23.6; There was no evidence of a difference between treatments.
Length of hospital stay was reported by two studies (Jones 2005; MOTHER Study) (152 participants). One study (Jones 2005) did not found signficant difference (MD 1.30,days, 95%CI 0.60, to 2.00), while the MOTHER Study repoted shorter hospital stay in the buprenorphin group: MD 6.70 days, 95%CI 6.24 to 7.16). Data were not pooled to very high heterogeneity (P < 0.00001, I2 = 99%) (Analysis 1.7).
Total amount of morphine required to manage neonatal abstinence syndrome was reported in two studies (Fischer 2006; MOTHER Study) (145 participants). One study (Fischer 2006) did not found signficant diference (MD: 0.71mg, 95%CI ‐1.22,to 2.64), while the MOTHER Study reported significant less morphine required in the buprenorphine group (MD:9.30 mg, 95%CI 8.68 to 9.92) Data were not pooled to very high heterogeneity (P < 0.00001, I2 = 99%) (Analysis 1.8).
4.4 Prenatal and neonatal mortality
In one study (Fischer 2006), there was one sudden intrauterine death at 38 weeks of pregnancy and one late abortion at 28 weeks of pregnancy, both in the methadone group. In the first woman, urine toxicology revealed 66% opioid‐positive results, 48% cocaine‐positive results and 16% benzodiazepine‐positive results over the study period. Cigarette consumption was a mean of 35 per day. In the second woman, all urine toxicology results were negative.
Secondary outcomes
5. Nicotine consumption
Smoking data were available from 124 (methadone n = 67 and buprenorphine n = 57) of the patients enrolled in the MOTHER Study. Among the sample, 95% reported cigarette smoking at treatment entry. Participants in the two medication conditions were similar for pretreatment characteristics, including smoking rates and daily cigarette amounts. Throughout the pregnancy, no meaningful changes in cigarette smoking were observed for either medication condition. The fitted difference in change in adjusted cigarettes per day between the two conditions was small and non‐significant (â = 0.08, standard error (SE) = 0.05, P = 0.132).
6. Use of other substances
Jones 2005 reported the percentage of results that were urine positive for each substance during the study period for the methadone and buprenorphine group, respectively. The results were cocaine: 15.6% and 16.7%; benzodiazepines: 0.4% and 2.5%; amphetamine: 0% and 0%; and marijuana 7.5% and 0%. The Fischer 2006 study reported the median number of urine samples positive for methadone and buprenorphine, respectively: cocaine: 0.00 and 0.00; benzodiazepines: 7.82 and 5.36. No data were reported in the MOTHER Study.
7. Side effects for the mother
No side effects for the mothers were reported in the Jones 2005 and Fischer 2006 studies. In the MOTHER Study, there were 14/89 (16%) serious adverse events in the methadone group and 8/86 (9%) in the buprenorphine group (RR 1.69, 95% CI 0.75 to 3.83) (Analysis 1.9). There were fewer non‐serious adverse events in the buprenorphine group (66/86; 77%) compared to methadone (83/89; 93%) (RR 1.22, 95% CI 1.07 to 1.38, low quality evidence) (Analysis 1.10).
8. Side effects for the child
No side effects for the child were reported in the Jones 2005 and Fischer 2006 studies. In the MOTHER Study, there were more serious adverse events (6/73; 8%) in the methadone group than in the buprenorphine group (1/58; 2%) (RR 1.22, 95% CI 1.07 to 1.38) (Analysis 1.11). There was no significant difference in the frequency of non‐serious adverse events: 34/73 (47%) in the methadone group and 29/58 (50%) in the buprenorphine group (RR 1.08, 95% CI 0.74 to 1.59, low quality evidence). There was no evidence of a difference between treatments.
Comparison 2: Methadone versus oral slow‐release morphine
See summary of findings Table 2. This comparison included one study (Fischer 1999) with 48 participants.
Primary outcomes: for the woman
1. Dropouts from treatment
No participants dropped out from either group, low quality evidence.
2. Use of primary substance of abuse
2.1 During or at the end of treatment
The result for the number of participants who used heroin in the third trimester was RR 2.40 (95% CI 1.00 to 5.77) low quality evidence, in favour of oral slow‐release morphine (Analysis 2.1).
2.2 At follow‐up
The study did not consider this outcome.
3. Obstetric outcomes
3.1 Third trimester bleeding
Data were not reported.
3.2 Preterm delivery
One woman delivered at 31 weeks due to early amniotic rupture, but it was not reported to which group she was allocated. No other gynaecological problems occurred during the study period. The mean week of delivery was as follows: methadone: 38.92 (SD 1.74), morphine: 37.79 (SD 2.55). There was no evidence of a difference between treatments.
3.3 Fetal distress and meconium aspiration
Data were not reported.
3.4 Caesarean section
The percentage of caesarean sections was 25% in both groups.
3.5 Abnormal presentation
Data were not reported.
3.6 Medical complications at delivery
The percentage of vacuum extractions was 8.3% in both groups.
3.7 Breastfeeding following delivery
Data were not reported.
3.8 Puerperal morbidity
Data were not reported.
Primary outcomes: for the child
4. Health status
4.1 Birth weight
There was no evidence of a difference between treatments (MD 124 g, 95% CI ‐186 to 434, low quality evidence) (Analysis 2.2).
4.2 APGAR score
The study did not consider this outcome.
4.3 Neonatal abstinence syndrome
There was no evidence of a difference between treatments in the mean duration of neonatal abstinence syndrome (MD ‐5.00, 95% CI ‐10.97 to 0.97, low quality evidence) (Analysis 2.3).
4.4 Prenatal and neonatal mortality
There was no prenatal or neonatal mortality in either group.
Secondary outcomes
5. Nicotine consumption
Fischer 1999 measured the difference in the mean number of cigarettes smoked per day before and at the end of treatment. At the start of the trial, the mean number of cigarettes smoked per day was 27.56 (SD 16.28) and 31.30 (SD 22.56) for the methadone and morphine group, respectively. At delivery, it was 15.89 (SD 12.24) and 15.20 (SD 8.24), respectively (MD ‐4.43, 95% CI ‐1.47 to 10.33); There was no evidence of a difference between treatments (Analysis 2.4).
6. Use of other substances
The study only reported the percentage of negative urine testing during each week of treatment for methadone and slow‐release morphine in a graph: the mean percentages for the whole study period were about 95% and 90%, respectively, for cocaine and 54% and 89% for benzodiazepines.
7. Side effects for the mother
No side effects for the mother were reported;(low quality evidence) .
8. Side effects for the child
No severe complications were noted in any of the neonates as monitored by polysomnography, although one child in the methadone group had central apnoea, and one child in the morphine group had obstructive apnoea; (low quality evidence) .
Sensitivity analysis
The only difference among the trials in terms of risk of bias was in random sequence generation (we judged one as at low risk and two as at unclear risk of bias). No differences were found in the results when studies were stratified for risk of bias for random sequence generation. Therefore, we did not perform sensitivity analyses.
Assessment of reporting bias
We did not use a funnel plot to explore publication bias because only four studies were included, all with small sample sizes. In fact, the power of this method is very limited when meta‐analysis comprises only a few small studies (Higgins 2011).
Discussion
Summary of main results
Only four trials with 271 pregnant women satisfied the criteria for inclusion in the review. Three (Fischer 2006; Jones 2005; MOTHER Study) compared methadone with buprenorphine (223 participants), and one (Fischer 1999) compared methadone with oral slow‐release morphine (48 participants).
In the comparison of methadone versus buprenorphine, we found moderate‐quality evidence of little or no difference in the dropout rate of the mothers. We also found low‐quality evidence of no difference in the use of the primary substance between the methadone and buprenorphine groups. Birth weight was higher in the buprenorphine group in the two trials that repoterd data, but the quality of evidence is very low. The third study reported that there was no evidence of a difference between treatments. For the APGAR score, none of the studies found a significant difference, with low‐quality evidence. Many measures were used in the studies to assess neonatal abstinence syndrome. For the number of newborns treated for neonatal abstinence syndrome, the most critical outcome, we found low‐quality evidence of no significant difference.
In the comparison of methadone versus oral slow‐release morphine, we found no difference in the dropout rate, whereas slow‐release morphine seemed to be superior to methadone for abstinence of women from the use of heroin. The study did not find evidence of a difference between treatments in birth weight or mean duration of neonatal abstinence syndrome. The APGAR score was not considered in the study. We judged the quality of evidence to be low for all outcomes.
Only one study which compared methadone with buprenorphine reported side effects. For the mother, there was no significant difference between groups in the frequency of serious adverse events, while the non‐serious adverse events were fewer in the buprenorphine groups. There were no significant differences in the frequency of severe or non‐severe adverse events for the newborn. The quality of evidence was low.
In the comparison of methadone versus slow‐release morphine, no side effects were reported for the mother, whereas one child in the methadone group had central apnoea, and one child in the morphine group had obstructive apnoea.
The difficulty of determining whether the opioid substitution is associated with better outcomes for newborns always needs to be considered in relation to the direct effects of cigarette smoking. Only one study (Fischer 1999) reported data on cigarette consumption at the start of the study and at delivery. Women smoked a mean of 29 cigarettes per day at enrollment in the study and a mean of 14 cigarettes per day at delivery. There was no statistically significant difference between groups in the reduction of cigarettes smoked. This seems to be a relevant outcome and was not considered by the majority of the included studies. The level of nicotine exposure during pregnancy does affect birth weight and could affect neonatal abstinence syndrome.
Overall completeness and applicability of evidence
The number of included studies and participants is too small to allow definite conclusions. Although, from a clinical point of view, it is well recognised that, for both women opiate addicts and their infants, agonist treatment during pregnancy is protective, but many questions remain unanswered. Which is the most effective drug treatment and at what dosage? What is the most appropriate type of setting? In particular, is it useful or not to associate any type of psychosocial intervention with pharmacological treatment?
Furthermore, it would be useful to know, both for maternal and child health, whether the mothers continued to use maintenance treatments after their delivery.
Quality of the evidence
Three out of four studies had adequate allocation concealment and were double‐blind. The major flaw of the studies was attrition bias: three out of four had a high dropout rate (30% to 40%), and this was unbalanced between groups. In the comparison of methadone versus buprenorphine, quality of the evidence ranged from moderate to very low and was downgraded for risk of attrition bias, inconsistency and imprecision of the estimate. In the comparison of methadone versus slow‐release morphine, quality of the evidence was low and was downgraded for imprecision in the estimate due to a very small sample size.
Potential biases in the review process
To lower the risk of bias in the review process, two review authors independently screened abstracts, assessed full texts, rated risk of bias for included studies and extracted data from primary studies. None of the review authors has any personal, scientific or financial conflicts of interest or expected advantages from significant results in terms of reviewer decisions or raising funds, We could not inspect funnel plots for risk of possible publication bias due to the small number of studies included in the meta‐analyses; however, we did not find any unpublished studies, despite contacting all of the first authors of the included studies and searching conference proceedings.so the likelihood of publication bias can be considered low" .
Agreements and disagreements with other studies or reviews
We did not find any other systematic reviews on this topic. One narrative review published in 2008 (Winklbaur 2008) considered all types of treatment for pregnant opioid‐dependent women and included both randomised and non‐randomised studies. This review cited the three randomised controlled trials (RCTs) published before 2006 and concluded that buprenorphine and methadone are substantially equivalent but may attenuate neonatal abstinence syndrome. A mixed‐method systematic review of interventional and observational systematic reviews identified 3 RCTs (n = 223), and 15 cohort observational (OBS) (n = 1923) studies to assess the safety of buprenorphine compared with methadone to treat pregnant women with opioid use disorder (Zedler 2016). Considering methadone as comparator, buprenorphine was found to be associated with lower risk of preterm birth (RCT risk ratio (RR) 0.40, 95% CI 0.18 to 0.91; OBS RR 0.67, 95% CI 0.50 to 0.90), and greater birth weight (RCT weighted mean difference (MD) 277 g, 95% CI 104 to 450; OBS MD 265 g, 95% CI 196 to 335). Authors concluded that methadone presents with a lower risk of preterm birth, and greater birth weight compared with buprenorphine treatment of maternal opioid use disorder during pregnancy.
An older published narrative review (Jones 2012) compared buprenorphine with methadone and included the same three RCTs together with observational studies but did not pool the data in a meta‐analysis. This review reached the same conclusions, reporting that there was no significant difference between methadone and buprenorphine for maternal outcomes, whereas buprenorphine "...results in a clinically significant less severe neonatal abstinence syndrome (NAS) than treatment with methadone". They also stated, "...concluding that buprenorphine is an effective treatment for opioid dependence during pregnancy does not mean that methadone should no longer be considered a useful and effective medication for opioid dependence, nor does it mean that all opioid‐dependent pregnant women should be treated with buprenorphine without regard to their preferences and life circumstances."
Study flow diagram September 2013.
Study flow diagram February 2020.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1: Methadone versus buprenorphine, Outcome 1: Dropout rate
Comparison 1: Methadone versus buprenorphine, Outcome 2: Use of primary substance
Comparison 1: Methadone versus buprenorphine, Outcome 3: Birth weight
Comparison 1: Methadone versus buprenorphine, Outcome 4: APGAR score
Comparison 1: Methadone versus buprenorphine, Outcome 5: Number treated for NAS
Comparison 1: Methadone versus buprenorphine, Outcome 6: Mean duration of NAS treatment
Comparison 1: Methadone versus buprenorphine, Outcome 7: Length of hospital stay
Comparison 1: Methadone versus buprenorphine, Outcome 8: Total amount of morphine for NAS
Comparison 1: Methadone versus buprenorphine, Outcome 9: Serious AE for the mother
Comparison 1: Methadone versus buprenorphine, Outcome 10: Serious AE for the child
Comparison 1: Methadone versus buprenorphine, Outcome 11: Non‐serious AE for the mother
Comparison 1: Methadone versus buprenorphine, Outcome 12: Non‐serious AE for the child
Comparison 2: Methadone versus oral slow‐release morphine, Outcome 1: Use of primary substance
Comparison 2: Methadone versus oral slow‐release morphine, Outcome 2: Birth weight
Comparison 2: Methadone versus oral slow‐release morphine, Outcome 3: NAS mean duration
Comparison 2: Methadone versus oral slow‐release morphine, Outcome 4: Nicotine consumption
| Methadone compared to buprenorphine for opiate‐dependent pregnant women | ||||||
| Patient or population: opiate‐dependent pregnant women | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with buprenorphine | Risk with methadone | |||||
| Dropout rate | Study population | RR 0.66 | 223 | ⊕⊕⊕⊝ | ||
| 318 per 1000 | 210 per 1000 | |||||
| Use of primary substance | Study population | RR 1.81 | 151 | ⊕⊕⊝⊝ | ||
| 75 per 1000 | 135 per 1000 | |||||
| Birth weight | The mean birth weight ranged from 3.093 g to 3530 gr | MD ranged from ‐530.00 gr (662.78,lower to 397.22 lower) to ‐215.00 gr (238.93, lower to 191.07 lower) | ‐ | 19 and 131 participants | ⊕⊝⊝⊝ | |
| APGAR score | The mean APGAR score was 8.95 | MD 0 | ‐ | 163 | ⊕⊕⊝⊝ | |
| Number treated for NAS | Study population | RR 1.19 | 166 | ⊕⊕⊝⊝ | ||
| 447 per 1000 | 532 per 1000 | |||||
| Serious adverse events for the mother | Study population | RR 1.69 | 175 | ⊕⊕⊝⊝ | ||
| 93 per 1000 | 157 per 1000 | |||||
| Serious adverse events for the child | Study population | RR 4.77 | 131 | ⊕⊕⊝⊝ | ||
| 17 per 1000 | 82 per 1000 | |||||
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 downgraded one level due to imprecision: optimal information size not met 2 downgraded one level due to study limitations: high risk of attrition bias 3 downgraded one level due to inconsistency: high heterogeneity: I2 95% 4 downgraded one level due to imprecision: fewer than 400 participants | ||||||
| Methadone compared to oral slow‐release morphine for opiate‐dependent pregnant women | ||||||
| Patient or population: opiate‐dependent pregnant women | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with oral slow‐release morphine | Risk with methadone | |||||
| Dropout rate from treatment | No dropouts from either group | 48 | ⊕⊕⊝⊝ | |||
| Use of substance | Study population | RR 2.40 | 48 | ⊕⊕⊝⊝ | ||
| 208 per 1000 | 500 per 1000 | |||||
| Birth weight | The mean birth weight was 2912 g | MD 124 higher | ‐ | 48 | ⊕⊕⊝⊝ | |
| APGAR score (APGAR score ) | The study did not assess this outcome | ‐ | ||||
| Adverse events for the mother follow‐up: mean 15 weeks | No side effects for the mother were reported | 48 | ⊕⊕⊝⊝ | |||
| Serious adverse events for the child follow‐up: mean 15 weeks | No severe complications were noted in any of the neonates as monitored by polysomnography, although one child in the methadone group had central apnoea and one child in the morphine group had obstructive apnoea. | 48 | ⊕⊕⊝⊝ | |||
| *The risk in the intervention group (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 not applicable 2 downgraded two levels: fewer than 100 participants 3 downgraded two level: optimal information size not met | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Dropout rate Show forest plot | 3 | 223 | Risk Ratio (M‐H, Random, 95% CI) | 0.66 [0.37, 1.20] |
| 1.2 Use of primary substance Show forest plot | 2 | 151 | Risk Ratio (M‐H, Random, 95% CI) | 1.81 [0.70, 4.68] |
| 1.3 Birth weight Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 1.4 APGAR score Show forest plot | 2 | 163 | Mean Difference (IV, Random, 95% CI) | 0.00 [‐0.03, 0.03] |
| 1.5 Number treated for NAS Show forest plot | 3 | 166 | Risk Ratio (M‐H, Random, 95% CI) | 1.19 [0.87, 1.63] |
| 1.6 Mean duration of NAS treatment Show forest plot | 2 | 145 | Mean Difference (IV, Random, 95% CI) | 0.00 [‐0.03, 0.03] |
| 1.7 Length of hospital stay Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 1.8 Total amount of morphine for NAS Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 1.9 Serious AE for the mother Show forest plot | 1 | 175 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.69 [0.75, 3.83] |
| 1.10 Serious AE for the child Show forest plot | 1 | 131 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.77 [0.59, 38.49] |
| 1.11 Non‐serious AE for the mother Show forest plot | 1 | 175 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.22 [1.07, 1.38] |
| 1.12 Non‐serious AE for the child Show forest plot | 1 | 131 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.08 [0.74, 1.59] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Use of primary substance Show forest plot | 1 | 48 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.40 [1.00, 5.77] |
| 2.2 Birth weight Show forest plot | 1 | 48 | Mean Difference (IV, Fixed, 95% CI) | 124.00 [‐186.94, 434.94] |
| 2.3 NAS mean duration Show forest plot | 1 | 48 | Mean Difference (IV, Fixed, 95% CI) | ‐5.00 [‐10.97, 0.97] |
| 2.4 Nicotine consumption Show forest plot | 1 | 48 | Mean Difference (IV, Fixed, 95% CI) | 4.43 [‐1.47, 10.33] |
