What is known about treatment with buprenorphine (Subutex) during pregnancy?

Fråga: What is known about treatment with buprenorphine (Subutex) during pregnancy?

Sammanfattning: Buprenorphine is not known to induce teratogenic or embryotoxic effects in animals or humans. However, mild neonatal withdrawal syndromes have been reported in a number of cases. According to published reports buprenorphine seems to be a safe and effective alternative in the treatment of opioid-dependent pregnant women. However, close follow-up for neonatal withdrawal syndromes after birth is recommended.

Svar: Buprenorphine (Subutex) is used as maintenance treatment of opioid addiction. Although no clinical studies so far have included pregnant women, the advantages of buprenorphine over methadone during gestation may include less respiratory depression at high doses, less toxicity from overdose, less severe withdrawal symptoms, and potentially less abuse liability (1,2).

In general, pre-clinical data suggest that buprenorphine is not embryotoxic or teratogenic, nor impair fertility or reproductive function at relevant doses (1).

A number of reports on opiod-dependent pregnant women treated with buprenorphine (0.8-10mg/day) have been located in the literature. No fetal abnormalities were reported in these cases (35 children) and the majority of the children had no withdrawal syndrome. During treatment urine tests of almost all mothers were negative for opiates (3-8). The first report describes a pregnant woman addicted to heroin who was treated with buprenorphine (4 mg/day) during the second and third trimester of pregnancy. A weak withdrawal syndrome (agitation, sleep disorders, tremor, yawing, noisy breathing, slight fever) occurred approximately 48 hours after birth and lasted for four days. The symptoms resolved without therapy. The concentration of buprenorphine was six times higher in the newborn´s serum (1.9 ng/ml) than in the mother´s serum (0.3 ng/ml) whereas the active metabolite norbuprenorphine was on similar levels (3). The higher serum concentration of the drug in the newborn compared with the mother does not necessarily indicate a neonatal risk since at the time of sampling the absolute concentration might be lower than the pharmacological active concentration. In an open labelled prospective study where three opioid-dependent pregnant women received with 8 or 12 mg buprenorphine per day for 12-15 weeks prior to delivery, the infants exhibited mild neonatal withdrawal syndrome. The onset of signs occurred within the first 12 hours after birth, peaked by 72 hours and disappeared by 12 hours. No pharmacological treatment was required (4). Four additional reports including in total 30 children exposed to buprenorphine in utero (maternal dose 0.8-10 mg/day) describe a history of the mothers and a pattern of the newborns similar to the cases cited above; 22 neonates had no withdrawal syndrome, five had mild withdrawal syndrome that resolved without treatment and three children had moderate syndrome that required pharmacological treatment. The mean duration of neonatal withdrawal syndrome was one day. (5-8).

In a study of 15 subjects, no correlation was observed between the intensity of the withdrawal symptoms and the mean daily buprenorphine dose or dose in mg per kg at delivery or total dos (6). Neither were there any differences in the mean total buprenorphine dose of the mothers whose neonates required or not required treatment for withdrawal syndrome.

In a report published 2001, Johnson et al (4) cited 13 reports including 97 infants who have been exposed to buprenorphine in utero. Some of these are referred to above, whereas others are published in Journals not available in Sweden. The reports also include cases in which buprenorphine (Temgesic) have been used as analgesics (recommended doses 0.6-1.2 mg/day).

In the Swedish Medical Birth register (9,10), there are 10 reports on children exposed to Temgesic (buprenorphine as analgesics) in utero. One of these children had a minor congenital heart defect. Only one child, who had no malformations, is reported to have been exposed Subutex (buprenorphine for maintenance of opioid addiction) during early pregnancy, but there are 1753 children whose mothers have stated use of some kind of opiates. The frequency of malformations does not differ from what could be expected in a normal population.

In vitro studies of transplacental transfer and metabolism of buprenorphine in a model system of dual perfusion of placental lobule indicated that less than 10% of the buprenorphine dose was transferred to the fetal circulation and the most of the remainder was retained by the tissue (11). Less than 5% of the perfused buprenophine was metabolised to norbuprenophine during 4 hours of perfusion. Further, therapeutic levels of buprenorphine in the maternal circulation did not show any in vitro effects on placental tissue viability and functional parameters (hCG release, O2 consumption, glucose consumption lactate production). However, it is difficult to predict an in vivo situation from these data.