The case series presented is unique in that two different opioid maintenance medications were investigated in opioid-dependent pregnant women using a within-subject design. The analysis of data from three women who had consecutive pregnancies during the study, whilst maintained on double-blind methadone or buprenorphine, provided a unique opportunity to control for factors such as maternal metabolism and personal constitution, which may influence the appearance, severity and duration of NAS.
Both methadone and buprenorphine were effective maintenance medication for all three women in both pregnancies in terms of retaining all three women in treatment for the duration of both pregnancies and in keeping consumption of illicit substances to a minimum. All six neonates were healthy and birth outcome measurements were within a normal range for each baby, regardless of study medication, demonstrating fetal safety of both methadone and buprenorphine.
Compared to previous populations, the cohort evaluated in this study over a long period (average duration of study participation: 23 weeks) was characterized by very low rates of concomitant consumption of illicit substances (approximately 10% of urine toxicology samples were positive), possibly due to the use of daily clinical contacts including supervised dosing and voucher incentives, a form of contingency management shown to improve retention rates especially during pregnancy [20
]. In order to answer the scientific questions posed in the MOTHER study regarding the safety and efficacy of prenatal exposure to methadone or buprenorphine, a highly rigorous design was required. Such rigid scientific protocols are important on the one hand but limit the ability to generalize from these results to the broader population of opioid-dependent pregnant patients such as those who have concurrent benzodiazepine and/or alcohol abuse or dependence.
Although all three women were heavy smokers, there were no significant differences in smoking behaviour between the two pregnancies. The majority of opioid dependent women are co-dependent on nicotine, [23
] but few studies have controlled for nicotine dependence. [11
] Collectively, these factors suggest that comparisons of neonatal outcomes for methadone and buprenorphine-exposed neonates in this unique cohort may have been less susceptible to several known confounding influences.
Consistent with previous reports, [7
] our results revealed a trend in favour of buprenorphine for a milder neonatal abstinence syndrome, lower scores and less days in treatment. Two of three women had milder NAS occurrence altogether under buprenorphine with one buprenorphine exposed neonate not requiring any NAS treatment. Compared to methadone-exposed neonates, those exposed to buprenorphine had fewer NAS symptoms. Differences of NAS treatment doses though were too small to reach statistical significance. This might be explained by the medication dosing protocol used, which followed an escalating regimen that started treatment of neonates only when the predefined cut-off score of the adapted Finnegan scale was surpassed.
Looking at the results for birth outcome measurements, all six neonates were comparable to a non-opioid but nicotine-dependent population. Interestingly, methadone-exposed neonates had a higher birth weight compared to buprenorphine exposed ones, possibly due to the same mechanism responsible for the weight gain commonly observed in methadone-maintained patients. A recent prospective survey of 41 pregnant women found a higher birth weight for the methadone group, approximately 200g above average findings, however, differences in birth weight means were not statistically significant. [28
] In fact, the majority of prior studies in the field report the opposite of our finding, all showing a trend for a higher birth weight for buprenorphine exposed neonates. Kakko et al. reported a significantly higher birth weight for buprenorphine exposed neonates [27
] while other studies found a similar yet insignificant trend [7
] or no differences [8
Previous authors have questioned whether higher opioid maintenance doses will lead to a milder occurrence of NAS by minimizing illicit substance abuse. [27
] In our study, the use of a flexible dosing schedule, with average maximum doses in the upper range (methadone 80 mg, buprenorphine 13 mg), was associated with minimal rates of concomitant consumption. To date, only a few studies reported a correlation between maternal dose and NAS severity; [29
] other reports have found no such correlation [7
]so that findings, so far, have been inconclusive. A recent systematic review and meta-analysis including 67 studies on methadone dose and neonatal abstinence syndrome concluded that the severity of NAS is not associated with maternal maintenance dose. [33
These results are in-line with prior research, suggesting that both methadone and buprenorphine are effective and safe in the treatment of opioid dependent pregnant women. Little has been known about whether one or the other might be beneficial to one individual based on biological determinants such as metabolism. Rather than restricting opioid dependent pregnant women to the “gold standard” of methadone for treatment, especially in light of the more favourable NAS occurrence for buprenorphine, each woman should have the choice between buprenorphine or methadone as an effective and safe treatment of opioid dependence during pregnancy. So far neither medication has FDA/EMEA approval for the treatment of pregnant women.
Up to this point, most medication research conducted on pregnant women with chronic medical conditions such as HIV, psychiatric disorders or hypertension has been observational, retrospective, or epidemiological [1
]. Furthermore, most trials did not evaluate different classes of medical drugs for the same condition. However, there is a strong need and an ethical justification for further research specifically targeting pregnant women based on existing concepts for the criteria of initiating early-phase investigations and controlled trials, and to evaluate when an experimental intervention should become standard of care [4
]. The MOTHER trial may serve as a role model for randomized controlled trials involving pregnant women in the future.