Opioid antagonists in pregnancy: Naltrexone or not?

 

With the increasing concern about rising rates of opioid abuse in the general population, including women of reproductive age and pregnant and breastfeeding women, clear guidelines regarding treatment in pregnancy and lactation are needed.

The Committee on Obstetric Practice of the American College of Obstetricians and Gynecologists and the American Society of Addiction Medicine addressed this issue comprehensively in the ACOG Committee Opinion issued in August 2017.¹ In this document, universal screening and medication-assisted treatment for opioid use disorder were recommended. Opioid agonists including methadone and buprenorphine were considered the treatments with the most evidence of benefit, and limited concern about adverse fetal effects, other than predictable and treatable neonatal abstinence syndrome.

BackyardProduction/Thinkstock

However, comfort levels are less secure with the safety of treatment with opioid antagonists such as naltrexone, a nonselective opioid receptor antagonist that blocks the euphoric effects of opioids. While there are apparent concerns with daily-use naltrexone for treatment retention and adherence outside of direct-monitoring centers, long-acting injectable doses or implants seem to result in improved abstinence rates. It is presumed that naltrexone crosses the human placenta, and animal studies have suggested that pregnancy exposure, depending on the dosing regimen, can affect growth and behavior of the offspring. Interestingly, in experimental animal studies, continued prenatal dosing was associated with accelerated fetal somatic and brain growth, while intermittent dosing was linked to reduced growth rates.²

Two types of scenarios make this topic relevant. In the first, a woman who has been successful in avoiding relapse by naltrexone treatment, although advised not to become pregnant, could inadvertently conceive. She would then be at risk of relapse if treatment were discontinued. In the second, a woman who overdoses with an opioid in pregnancy might require rapid detoxification with naltrexone in order to survive. In either case, there are quite limited data on potential fetal consequences.

In a 2001 report, Hulse et al. described a series of fetal outcomes following prenatal naltrexone exposure. In one set of cases accumulated from three countries, rapid opiate detoxification with naltrexone was performed for 18 pregnant women. One woman received two detoxification treatments. Two treatments occurred in the first trimester, 11 in the second, and 6 in the third. Maternal and fetal outcomes were said to be unremarkable, except for two cases of low birth weight infants (less than 2,500 g). In another set of cases, seven opioid-dependent women in Australia who had been maintained on 50 mg naltrexone per day became pregnant. In six of the seven cases, naltrexone was discontinued at 7 weeks’ gestation because of the unknown risks of teratogenicity. Of these, three restarted naltrexone maintenance therapy in the second trimester. One mother continued naltrexone throughout pregnancy. One of the seven women delivered at 36 weeks by induction for high blood pressure, and the infant was less than 2,500 g. One other term infant was small at 2,625 g. Otherwise, outcomes were considered normal.³

In two subsequent reports by some of the same authors, pregnancy outcomes in 9 and 17 heroin users with naltrexone implants were unremarkable and comparable to those of women on methadone maintenance therapy.^4,5

Finally, a recent report by Kelty and Hulse described the largest study of naltrexone treatment in pregnancy published to date.⁶ This was a record-linkage study in which data on 1,976 opioid-dependent women were abstracted prior to and during pregnancy between 2001 and 2010 in a clinic in Western Australia. Rates of pregnancy and outcomes were compared with those for 1,976 age-matched controls. In 7 years of follow-up, 99 women became pregnant who were treated with naltrexone implants, 200 became pregnant who were treated with methadone, and 182 became pregnant who were treated with buprenorphine; 343 had no treatment. There were significantly higher rates of pregnancy in the naltrexone-exposed group. Among those who became pregnant, there were more elective terminations and more ectopic pregnancies in the naltrexone group. Overall rates of complications during pregnancy with the naltrexone implant were not significantly different, compared with those in the methadone and buprenorphine groups, but were higher than in control women.

While the very limited data on naltrexone safety in pregnancy have not suggested substantial increased risks, the numbers are too small to provide strong reassurance, and the animal data remain concerning. Long-term behavioral outcome studies are also lacking. More research in this area is needed to weigh the safety of naltrexone for the fetus against the risk of relapse with discontinuation of this drug.
 

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures.

 

References

1. Obstet Gynecol. 2017 Aug;130(2):e81-e94.

2. Curr Neuropharmacol. 2008 Jun;6(2):125–50.

3. Aust N Z J Obstet Gynaecol. 2001 Nov;41(4):424-8.

4. Aust N Z J Obstet Gynaecol. 2002 Feb;42(1):104-5.

5. Int J Gynaecol Obstet. 2004 May;85(2):170-1.

6. Drugs. 2017 Jul;77(11):1211-9.
 

 

With the increasing concern about rising rates of opioid abuse in the general population, including women of reproductive age and pregnant and breastfeeding women, clear guidelines regarding treatment in pregnancy and lactation are needed.

The Committee on Obstetric Practice of the American College of Obstetricians and Gynecologists and the American Society of Addiction Medicine addressed this issue comprehensively in the ACOG Committee Opinion issued in August 2017.¹ In this document, universal screening and medication-assisted treatment for opioid use disorder were recommended. Opioid agonists including methadone and buprenorphine were considered the treatments with the most evidence of benefit, and limited concern about adverse fetal effects, other than predictable and treatable neonatal abstinence syndrome.

BackyardProduction/Thinkstock

However, comfort levels are less secure with the safety of treatment with opioid antagonists such as naltrexone, a nonselective opioid receptor antagonist that blocks the euphoric effects of opioids. While there are apparent concerns with daily-use naltrexone for treatment retention and adherence outside of direct-monitoring centers, long-acting injectable doses or implants seem to result in improved abstinence rates. It is presumed that naltrexone crosses the human placenta, and animal studies have suggested that pregnancy exposure, depending on the dosing regimen, can affect growth and behavior of the offspring. Interestingly, in experimental animal studies, continued prenatal dosing was associated with accelerated fetal somatic and brain growth, while intermittent dosing was linked to reduced growth rates.²

Two types of scenarios make this topic relevant. In the first, a woman who has been successful in avoiding relapse by naltrexone treatment, although advised not to become pregnant, could inadvertently conceive. She would then be at risk of relapse if treatment were discontinued. In the second, a woman who overdoses with an opioid in pregnancy might require rapid detoxification with naltrexone in order to survive. In either case, there are quite limited data on potential fetal consequences.

In a 2001 report, Hulse et al. described a series of fetal outcomes following prenatal naltrexone exposure. In one set of cases accumulated from three countries, rapid opiate detoxification with naltrexone was performed for 18 pregnant women. One woman received two detoxification treatments. Two treatments occurred in the first trimester, 11 in the second, and 6 in the third. Maternal and fetal outcomes were said to be unremarkable, except for two cases of low birth weight infants (less than 2,500 g). In another set of cases, seven opioid-dependent women in Australia who had been maintained on 50 mg naltrexone per day became pregnant. In six of the seven cases, naltrexone was discontinued at 7 weeks’ gestation because of the unknown risks of teratogenicity. Of these, three restarted naltrexone maintenance therapy in the second trimester. One mother continued naltrexone throughout pregnancy. One of the seven women delivered at 36 weeks by induction for high blood pressure, and the infant was less than 2,500 g. One other term infant was small at 2,625 g. Otherwise, outcomes were considered normal.³

In two subsequent reports by some of the same authors, pregnancy outcomes in 9 and 17 heroin users with naltrexone implants were unremarkable and comparable to those of women on methadone maintenance therapy.^4,5

Finally, a recent report by Kelty and Hulse described the largest study of naltrexone treatment in pregnancy published to date.⁶ This was a record-linkage study in which data on 1,976 opioid-dependent women were abstracted prior to and during pregnancy between 2001 and 2010 in a clinic in Western Australia. Rates of pregnancy and outcomes were compared with those for 1,976 age-matched controls. In 7 years of follow-up, 99 women became pregnant who were treated with naltrexone implants, 200 became pregnant who were treated with methadone, and 182 became pregnant who were treated with buprenorphine; 343 had no treatment. There were significantly higher rates of pregnancy in the naltrexone-exposed group. Among those who became pregnant, there were more elective terminations and more ectopic pregnancies in the naltrexone group. Overall rates of complications during pregnancy with the naltrexone implant were not significantly different, compared with those in the methadone and buprenorphine groups, but were higher than in control women.

While the very limited data on naltrexone safety in pregnancy have not suggested substantial increased risks, the numbers are too small to provide strong reassurance, and the animal data remain concerning. Long-term behavioral outcome studies are also lacking. More research in this area is needed to weigh the safety of naltrexone for the fetus against the risk of relapse with discontinuation of this drug.
 

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures.

 

References

1. Obstet Gynecol. 2017 Aug;130(2):e81-e94.

2. Curr Neuropharmacol. 2008 Jun;6(2):125–50.

3. Aust N Z J Obstet Gynaecol. 2001 Nov;41(4):424-8.

4. Aust N Z J Obstet Gynaecol. 2002 Feb;42(1):104-5.

5. Int J Gynaecol Obstet. 2004 May;85(2):170-1.

6. Drugs. 2017 Jul;77(11):1211-9.
 

 

With the increasing concern about rising rates of opioid abuse in the general population, including women of reproductive age and pregnant and breastfeeding women, clear guidelines regarding treatment in pregnancy and lactation are needed.

The Committee on Obstetric Practice of the American College of Obstetricians and Gynecologists and the American Society of Addiction Medicine addressed this issue comprehensively in the ACOG Committee Opinion issued in August 2017.¹ In this document, universal screening and medication-assisted treatment for opioid use disorder were recommended. Opioid agonists including methadone and buprenorphine were considered the treatments with the most evidence of benefit, and limited concern about adverse fetal effects, other than predictable and treatable neonatal abstinence syndrome.

BackyardProduction/Thinkstock

However, comfort levels are less secure with the safety of treatment with opioid antagonists such as naltrexone, a nonselective opioid receptor antagonist that blocks the euphoric effects of opioids. While there are apparent concerns with daily-use naltrexone for treatment retention and adherence outside of direct-monitoring centers, long-acting injectable doses or implants seem to result in improved abstinence rates. It is presumed that naltrexone crosses the human placenta, and animal studies have suggested that pregnancy exposure, depending on the dosing regimen, can affect growth and behavior of the offspring. Interestingly, in experimental animal studies, continued prenatal dosing was associated with accelerated fetal somatic and brain growth, while intermittent dosing was linked to reduced growth rates.²

Two types of scenarios make this topic relevant. In the first, a woman who has been successful in avoiding relapse by naltrexone treatment, although advised not to become pregnant, could inadvertently conceive. She would then be at risk of relapse if treatment were discontinued. In the second, a woman who overdoses with an opioid in pregnancy might require rapid detoxification with naltrexone in order to survive. In either case, there are quite limited data on potential fetal consequences.

In a 2001 report, Hulse et al. described a series of fetal outcomes following prenatal naltrexone exposure. In one set of cases accumulated from three countries, rapid opiate detoxification with naltrexone was performed for 18 pregnant women. One woman received two detoxification treatments. Two treatments occurred in the first trimester, 11 in the second, and 6 in the third. Maternal and fetal outcomes were said to be unremarkable, except for two cases of low birth weight infants (less than 2,500 g). In another set of cases, seven opioid-dependent women in Australia who had been maintained on 50 mg naltrexone per day became pregnant. In six of the seven cases, naltrexone was discontinued at 7 weeks’ gestation because of the unknown risks of teratogenicity. Of these, three restarted naltrexone maintenance therapy in the second trimester. One mother continued naltrexone throughout pregnancy. One of the seven women delivered at 36 weeks by induction for high blood pressure, and the infant was less than 2,500 g. One other term infant was small at 2,625 g. Otherwise, outcomes were considered normal.³

In two subsequent reports by some of the same authors, pregnancy outcomes in 9 and 17 heroin users with naltrexone implants were unremarkable and comparable to those of women on methadone maintenance therapy.^4,5

Finally, a recent report by Kelty and Hulse described the largest study of naltrexone treatment in pregnancy published to date.⁶ This was a record-linkage study in which data on 1,976 opioid-dependent women were abstracted prior to and during pregnancy between 2001 and 2010 in a clinic in Western Australia. Rates of pregnancy and outcomes were compared with those for 1,976 age-matched controls. In 7 years of follow-up, 99 women became pregnant who were treated with naltrexone implants, 200 became pregnant who were treated with methadone, and 182 became pregnant who were treated with buprenorphine; 343 had no treatment. There were significantly higher rates of pregnancy in the naltrexone-exposed group. Among those who became pregnant, there were more elective terminations and more ectopic pregnancies in the naltrexone group. Overall rates of complications during pregnancy with the naltrexone implant were not significantly different, compared with those in the methadone and buprenorphine groups, but were higher than in control women.

While the very limited data on naltrexone safety in pregnancy have not suggested substantial increased risks, the numbers are too small to provide strong reassurance, and the animal data remain concerning. Long-term behavioral outcome studies are also lacking. More research in this area is needed to weigh the safety of naltrexone for the fetus against the risk of relapse with discontinuation of this drug.
 

Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is also director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures.

 

References

1. Obstet Gynecol. 2017 Aug;130(2):e81-e94.

2. Curr Neuropharmacol. 2008 Jun;6(2):125–50.

3. Aust N Z J Obstet Gynaecol. 2001 Nov;41(4):424-8.

4. Aust N Z J Obstet Gynaecol. 2002 Feb;42(1):104-5.

5. Int J Gynaecol Obstet. 2004 May;85(2):170-1.

6. Drugs. 2017 Jul;77(11):1211-9.