Intrauterine exposure to opioids or other psychopharmacological medications can produce NAS in the neonate in the first hours and days after delivery. Signs of NAS are usually referable to the central nervous system, autonomic nervous system, gastrointestinal tract, and respiratory system. Intrauterine exposure to buprenorphine during pregnancy also results in NAS in more than 50% of exposed newborns 62
. The onset, nature, and treatment of buprenorphine-associated NAS are comparable but somewhat milder than that associated with methadone62,86
The severity and duration of NAS should be assessed by close clinical observation and monitoring of the newborn using an “abstinence scoring system.” This system assigns points to each abstinence-associated sign and serves as a guide to treatment. Once a predetermined minimum score is reached, treatment, usually with replacement opiate therapy, is begun. Weaning can begin once the neonate is assessed to be clinically stable on a set dosage for at least 48 hours60
. Seminal work with regards to perinatal addiction has been published over decades by Finnegan and colleagues with an in-depth focus on the neonatal consequences of intrauterine substance exposure, resulting in the widespread adoption of the ,,Finnegan-scoring-system“ for neonates87
The concomitant use of legal and illegal substances such as opiates, nicotine, cocaine, alcohol and other specific medications such as antidepressants play a key role among the factors influencing NAS appearance, severity and duration.
The onset of buprenorphine-associated NAS is usually observed within the first 12 to 72 hours after delivery, reaching its peak severity within 66 to 96 hours, and lasting approximately 120 to 168 hours. Considerable individual variability in abstinence exists; a reported protracted withdrawal syndrome has been seen in a few infants who exhibited withdrawal signs for 6 to 10 weeks following delivery. This extended withdrawal could be due to both the NAS medication and the regimen used to treat withdrawal rather than a direct effect of buprenorphine 74
The debate as to whether a correlation exists between the maternal maintenance dosage of opioids and the occurrence and severity of NAS began in the late 1960s, when methadone was first accepted as a method of treatment for opioids-dependent pregnant women. Based on existing data, Ostrea et al. made the recommendation in 1976, that at least one month before delivery mothers should be placed on a low-dose regiment of less than 20mg methadone per day to help prevent serious neonatal withdrawal 88
. The controversy continued, and in 2002, Dashe et al. reported that 90% of infants whose mothers had taken more than 40mg/d methadone required treatment for NAS, compared to 44% of infants when mothers had taken 20–39mg/d methadone, and 12% of infants when mothers took less than 20mg/day.89
However, this finding lacked a clear research design, was retrospective and no standardized urine toxicology was performed to examine the concomitant consumption of illicit drugs. In contrast, Berghella et al. published a report on 100 methadone maintained pregnant women and their neonates, which found no correlation between methadone dosage (doses of more than 80mg/ day and less than 80mg/d) and both the need for and duration of NAS treatment90
. As in many previous studies, however, results should not be considered conclusive since concomitant use of legal and illegal substances was not taken into account.
In a very recent retrospective study of 66 methadone-maintained patients, Lim studied the relationship between maternal dosage at delivery and neonatal abstinence. Dosage groups included (1) < 70 mg in 23 women, (2) 71–139 mg in 26 women, and (3) >140 mg in 17 women. A higher dosage of methadone was associated with a higher incidence and duration of NAS; every increase of 5.5 mg of methadone in the mother was coupled statistically with 1 additional day of NAS treatment for the infant. Studies suggest that the main variable affected by higher dosage may not be appearance of NAS itself, but rather its duration, and that both the occurrence and duration of NAS may be mitigated by a reduction of methadone dosages in motivated mothers.91
However, conclusions drawn from this study are also limited because it is retrospective and no standardized urine toxicology was collected for assessing concomitant substances consumed.
The debate over maternal methadone treatment may be considered in one major context: which has the greater impact on NAS, high dosages of maternal maintenance opioids or the often-seen concomitant illicit use of other substances when women are treated with an inadequate dose of methadone to achieve clinical stability? In one study, McCarthy et al92
reported that pregnant patients receiving mean daily methadone doses of 132 mg had less illicit drug use at delivery and their neonates had no more severe NAS than expectant mothers receiving mean doses of 62 mg of methadone. Higher incidences of illicit drug abuse occurred in women who were receiving less than 80mg/day than in women receiving more than 80mg/day. It is generally felt that concomitant use of illicit drugs increases the severity of NAS, one factor cited in promoting the use of higher maintenance dosages for pregnant women.
Fewer reports exist on the correlation between maternal buprenophine dosages and the incidence, severity, and duration of NAS in exposed neonates. In a recent population-based comparison of 47 consecutive, prospectively followed buprenorphine-exposed pregnancies to 35 retrospectively analyzed consecutive methadone-exposed pregnancies, Kakko et al. reported significant advantages with buprenorphine treatment in terms of birth weight and incidence of NAS requiring pharmacological treatment compared to methadone. The average maternal dosage was 15.4mg +/− 6.4mg buprenorphine and 71.3 +/− 27.3mg methadone and 14.9% of the buprenorphine-exposed group vs. 52.8% of the methadone maintained group developed NAS requiring pharmacological treatment. Kakko argues that the key to lowering NAS rates is the successful clinical management of substance use, which usually involves higher maintenance dosage. 93
Further supporting this viewpoint, a Finnish study (Kahila et al, 2007) of 67 women maintained on buprenorphine where tapering doses or even abstinence from buprenorpine was encouraged (mean dose of buprenorphine at time of birth 4.3 mg), resulted in a NAS incidence of 76%, with 57% requiring treatment. 94
This low maintenance dosage was linked to a low retention rate and higher rates of illicit use, both of which are unfavourable to NAS occurrence. To date, only one report has found a positive correlation between maternal buprenorphine dose and the severity of the NAS 95
; this finding pertained only to the maximum Lipsitz score. Other more recent reports 60,61
and one that included a large sample size 62
have reported no such correlation.
In summary, all of these results strongly suggest that pregnant women should be treated with dosages of methadone or buprenorphine that adequately treat their addiction. Concerns regarding the impact of higher therapeutic dosages on NAS do not seem to be warranted, based on available clinical data. The variability of NAS, however, mandates that close clinical surveillance of the neonate and infant should be maintained. It is hoped that the MOTHER study comparing methadone and buprenorphine in pregnant women, will shed further light on this subject.