Neonatal outcomes following in utero exposure to methadone or buprenorphine: A National Cohort Study of opioid-agonist treatment of Pregnant Women in Norway from 1996 to 2009

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Abstract

Background

In Norway, most opioid-dependent women are in opioid maintenance treatment (OMT) with either methadone or buprenorphine throughout pregnancy. The inclusion criteria for both medications are the same and both medications are provided by the same health professionals in any part of the country. International studies comparing methadone and buprenorphine in pregnancy have shown differing neonatal outcomes for the two medications.

Method

This study compared the neonatal outcomes following prenatal exposure to either methadone or buprenorphine in a national clinical cohort of 139 women/neonates from 1996 to 2009.

Results

After adjusting for relevant covariates, buprenorphine-exposed newborns had larger head circumferences and tended to be heavier and longer than methadone-exposed newborns. The incidence of neonatal abstinence syndrome (NAS) and length of treatment of NAS did not differ between methadone- and buprenorphine-exposed newborns. There was little use of illegal drugs and benzodiazepines during the pregnancies. However, the use of any drugs or benzodiazepines during pregnancy was associated with longer lasting NAS-treatment of the neonates.

Conclusions

The clinical relevance of these findings is that both methadone and buprenorphine are acceptable medications for the use in pregnancy, in line with previous studies. If starting OMT in pregnancy, buprenorphine should be considered as the drug of choice, due to more favorable neonatal growth parameters. Early confirmation of the pregnancy and systematic follow-up throughout the pregnancy are of importance to encourage the women in OMT to abstain from the use of tobacco, alcohol, illegal drugs or misuse of prescribed drugs.

Introduction

Opioid maintenance treatment (OMT) involves long-term prescription of opioid-agonist medication, as well as the provision of a variety of psychosocial supportive measures. Methadone is a full μ-opioid agonist and has been prescribed to opioid-dependent pregnant women for many years (Kandall et al., 1977, Newman et al., 1975). Methadone maintenance treatment (MMT), given in a multidisciplinary setting, has become the international standard of care for opioid-dependent pregnant women (Fischer et al., 1998a, Jansson et al., 2007, Jones et al., 2008, Kaltenbach et al., 1998, WHO, 2009, Winklbaur et al., 2008). MMT in pregnancy is associated with better prenatal care, higher birth weights, longer gestational ages and fewer complications for the infants than if the woman were using heroin during her pregnancy (Doberczak et al., 1987, Finnegan et al., 1977, Hulse et al., 1997).

In contrast, buprenorphine is a partial μ-opioid agonist and κ-antagonist and has been prescribed to pregnant women since the nineties (Fischer et al., 1998b, Fischer et al., 2000, Johnson et al., 2001, Kahila et al., 2007). Generally, studies of buprenorphine maintenance treatment (BMT) in pregnancy have shown similar maternal, birth and neonatal outcomes as MMT (Johnson et al., 2003, Jones et al., 2008).

Both medications have been associated with a neonatal abstinence syndrome (NAS) following prenatal exposure, e.g. (Fischer et al., 2006, Johnson et al., 2003, Jones et al., 2005, Lejeune et al., 2006). NAS is observed in 40–90% of neonates prenatally exposed to methadone or buprenorphine, and is characterized by symptoms of hyperirritability of the central-nervous, the gastrointestinal, the respiratory and the autonomic nervous systems (Finnegan et al., 1975, Fischer et al., 1998b). In a recent review of the relationship between the maternal dose of methadone and NAS in 67 studies, Cleary concludes that the severity of NAS does not appear to differ whether the woman is on low or high dose of methadone at delivery (Cleary et al., 2010). The use of illicit drugs in addition to MMT is associated with a greater likelihood of needing NAS-treatment (Jansson et al., 2012) and a longer duration of treatment for NAS (Seligman et al., 2008) than for the use of methadone alone.

Prospective clinical studies comparing MMT and BMT during pregnancy have shown differing neonatal outcomes in neonates prenatally exposed to either medication. A French multicenter study did not report any significant differences in either NAS parameters or neonatal growth (Lejeune et al., 2006). In contrast, a Swedish study found that BMT during pregnancy was significantly related to a lower incidence of NAS and higher average birth weights (Kakko et al., 2008) than MMT. Another French multicenter study found similar NAS results as did Kakko in 2008 (Lacroix et al., 2011). In all three studies, MMT was provided from specialized clinics and BMT was provided mainly by general practitioners. Results of randomized clinical trials (RTCs) indicate that BMT yields a milder abstinence syndrome for the neonate than does MMT (Fischer et al., 2006, Jones et al., 2005, Jones et al., 2010). The MOTHER study (Jones et al., 2010), an international multi-center RCT, found no significant difference in the incidence of NAS, but in the prenatally buprenorphine-exposed condition, the duration of NAS-treatment was shorter.

Opioid withdrawal in pregnancy is associated with increased risks of abortion, preterm birth and use of illegal drugs (Luty et al., 2003, McCarthy, 2012). Transferring a methadone maintained pregnant woman to buprenorphine also puts the fetus at risk through withdrawal (Jones et al., 2006, McCarthy, 2012). OMT is important in pregnancy, despite the possible effects of methadone or buprenorphine, to stabilize the woman and improve the neonatal outcomes compared to the untreated condition or opioid withdrawal in pregnancy.

The aim of the present study was to compare the neonatal outcomes following prenatal exposure to either methadone or buprenorphine. The design was a national clinical cohort study in which pregnant women were prescribed either methadone or buprenorphine. We wanted to ensure that the women in MMT and BMT were comparable: firstly, MMT and BMT were given according to the same national inclusion criteria; secondly, both medications were provided by the same health professionals in any part of the country; thirdly, only the first child of the women in OMT was included in the study; and lastly, we wanted to control for relevant covariates. We hypothesized that buprenorphine-exposed newborns would have higher birth weights, larger head circumferences, lower incidence of NAS needing medication, and shorter length of treatment for NAS than methadone-exposed neonates.

Section snippets

Methods

This study included a national cohort of pregnant women in opioid maintenance treatment (OMT) in Norway from 1996 to 2009.

Participant characteristics

The women in MMT did not differ from the women in BMT on most variables (Table 2). Significant difference between the medication groups was only found in the length of opioid dependency prior to OMT, with women in MMT having longer opioid dependency.

Table 2 also shows that 81% and 74% of the MMT and BMT pregnancies were unplanned, respectively. The pregnancies were confirmed early, between week six and seven of the pregnancy. Approximately 90% of the women were in OMT when they conceived, and

Study participants

The women in our study appear comparable to women in other studies of MMT and BMT in pregnancy. In our sample the women are slightly older than in the MOTHER study and the first French study, but of similar ages as in the Swedish and the second French study (Kakko et al., 2008, Lacroix et al., 2011). Furthermore, the doses of methadone and buprenorphine used during pregnancy in our study are higher than in the French studies, but comparable to the other two studies (Jones et al., 2010, Kakko et

Role of funding source

The Norwegian Directorate of Health has made it possible for Gabrielle Welle-Strand to conduct research part-time since 2007. The Norwegian Directorate of Health had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. The Norwegian Centre for Addiction Research has provided a work-place and supervision through the whole study period and has also financed part of

Contributors

Gabrielle Welle-Strand has designed the study, written the protocol, collected most of the data, undertaken the statistical analysis and written all the drafts of the manuscript. Svetlana Skurtveit has helped out with the statistical analysis, the interpretation of the results and reading through several drafts of the manuscript. Hendreé Jones has helped out in suggesting further statistical analysis, interpreting the results and putting them into an international context and carefully reading

Conflict of interest

Welle-Strand has received travel grant from Schering-Plough prior to 2005. Jones has received reimbursement for time and travel from Reckitt Benckiser Pharmaceuticals.

Acknowledgements

First of all, we would like to thank all the women who participated in the study and sheared their experience with us. Secondly, I am grateful to the Norwegian Directorate of Health for giving me the opportunity to do research and to my colleagues at the Norwegian Centre for Addiction Research for inspiring me throughout the course of the study.

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