This review summarised research studies comparing different types of pharmacologic maintenance treatments for pregnant women with opioid dependence
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.
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.
The evidence is current to 18 February 2020.
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.
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.
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.
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.
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.
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).
Randomised controlled trials which assessed the efficacy of any pharmacological maintenance treatment for opiate-dependent pregnant women.
We used the standard methodological procedures expected by Cochrane.
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).