In pregnancy, untreated opioid addiction is associated with adverse maternal and perinatal complications.1 The principle treatment strategy for opioid addiction is a combination of medication-assisted treatment and counseling, which has led to improved obstetric outcomes.2,3 However, medication-assisted treatment during pregnancy may cause neonatal abstinence syndrome, a condition characterized by a constellation of physiologic changes, behaviors, and a poor adaptation process.4
Methadone has been used for medication-assisted treatment in pregnancy since the 1970s.5 Distribution of methadone for medication-assisted treatment of opioid use disorders is tightly controlled through federally regulated clinics in which daily visits are required. Buprenorphine was approved for medication-assisted treatment in the United States in 2002. Benefits of buprenorphine over methadone include its availability through an office prescription, less overdose potential, fewer drug interactions, and a milder neonatal abstinence syndrome.6–9 Buprenorphine is also available in combination with the opioid antagonist naloxone, which has poor oral bioavailability but when injected will precipitate withdrawal.10 In nonpregnant individuals, the buprenorphine and naloxone combination product is preferred for medication-assisted treatment because of the reduced diversion potential compared with buprenorphine monotherapy.11 The literature is limited on pregnancy outcomes among women taking the combination therapy with two publications reporting on a total of 10 patients.12,13
The aim of this study is to report on the outcomes of neonates whose mothers were treated prenatally with buprenorphine and naloxone compared with outcomes of neonates born to mothers treated with methadone with emphasis on measures of neonatal abstinence syndrome.
MATERIALS AND METHODS
We performed a retrospective, cohort analysis on mother–neonate dyads treated for maternal opioid dependence with either buprenorphine and naloxone or methadone during pregnancy. All patients were delivered at the University of North Carolina at Chapel Hill Hospitals between January 1, 2011, and November 30, 2013. Most women in our sample received care through the University of North Carolina at Chapel Hill Horizons Program, a gender-specific treatment program for women with substance use disorders; the timeframe for the study reflects the introduction of buprenorphine and naloxone as a treatment option for these patients. A team involving social workers, counselors, physicians, and a nurse practitioner work together with the aim of assisting women through treatment and recovery. Both residential and outpatient treatment are available. Daycare and transportation are provided. Goals at Horizons include helping women remain with their children and become independent and self-supportive. Opioid-dependent women are cotreated with local methadone clinics or treated on-site with buprenorphine and naloxone whether pregnant or nonpregnant.
We identified patients in an electronic database using the North Carolina Translational and Clinical Sciences Institute Data Warehouse. Patient lists were generated by searching International Classification of Disease, 9th Revision (ICD-9) codes for pregnancy cross-referenced with pharmacies dispensing for either methadone or buprenorphine and naloxone and by cross-referencing International Classification of Disease, 9th Revision codes for pregnancy with those for opioid dependence. Additional patients were found through the Horizons Clinic database at the University of North Carolina at Chapel Hill. Patient charts were then reviewed for inclusion and exclusion criteria.
We excluded patients with methadone or buprenorphine and naloxone treatment less than 30 days before delivery, delivery at an outside hospital, multiple gestations, intrauterine fetal demise or stillbirth, or an anomalous fetus or newborn. Patients were included if there was documentation of maternal methadone or buprenorphine and naloxone treatment for 30 or more days before and including up to delivery, delivery at the University of North Carolina at Chapel Hill, and a live singleton nonanomalous neonate. After eligible patients were identified, maternal and neonate data were extracted from charts utilizing a standardized data collection form. Primary neonatal outcomes included diagnosis of neonatal abstinence syndrome, neonatal abstinence syndrome peak scores, total amount of morphine used to treat neonatal abstinence syndrome in milligrams, and duration of treatment for neonatal abstinence syndrome (days). A standardized 13-item Modified Finnegan opioid weaning score (total score possible 1–25) based on objective neonatal data was utilized by clinical nursing staff to assess neonatal abstinence syndrome.14 Neonates were assessed every 2–4 hours. Higher scores indicate a more severe withdrawal state. We diagnosed neonatal abstinence syndrome with three consecutive scores of 8 or more or any two scores of 12 or more. Neonatal abstinence syndrome scores were assessed as part of routine clinical care; therefore, assessors were not blinded to maternal opioid treatment. Secondary neonatal outcomes and data of interest were: head circumference, birth weight, body length, total length of hospitalization, prematurity (less than 37 0/7 weeks of gestation at delivery), Apgar scores at 1 and 5 minutes, and neonatal intensive care unit admission. At our hospital, neonates with neonatal abstinence syndrome are not routinely admitted to the neonatal intensive care unit; thus, these admissions occurred for nonopiate-related indications. Standard treatment for neonatal abstinence syndrome at the University of North Carolina at Chapel Hill is through oral morphine titrated to achieve normal neonatal abstinence syndrome scores followed by a taper. Additional data collected included maternal race and age, marital status, education (years), parity, smoking status, gestational age at delivery (weeks), dose of opioid medication at delivery (mg), use of other illicit substances at delivery (determined through urine drug screen), psychiatric diagnoses, indication for maternal opioid use, selective serotonin reuptake inhibitor use, and use of benzodiazepines at delivery. Maternal outcome data collected included: mode of delivery, type of analgesia during labor, total weight gain as determined from initial and final clinic appointment recordings, and the number of prenatal care visits.
Statistical analysis was performed utilizing descriptive statistics and unadjusted and adjusted bivariate analysis. A formal power calculation was not performed because this was a retrospective study with a fixed number of patients. The study period was conceived as the start of our facility's treatment of patients with the medication being examined (buprenorphine and naloxone) and therefore there is an inability to increase the sample size. The differences between the methadone and buprenorphine and naloxone groups were assessed for all categorical variables and outcomes using two-sided Fisher's exact tests of association, whereas exact Wilcoxon rank-sum tests were used for all continuous variables and outcomes. Primary and secondary neonatal outcomes were analyzed utilizing log-binomial regression for categorical variables and multiple linear regression for continuous variables. Normality of residuals in the linear regression models was tested to assure validity of the adjusted β-coefficients. All outcomes were adjusted for gestational age at delivery and maternal indication for opioids. Additional regression models were performed, including variables that are thought to affect the diagnosis and severity of neonatal abstinence syndrome, such as maternal smoking, benzodiazepine use, and illicit drug use at delivery. These covariates were retained in the model if they altered the parameter estimate for the β-coefficient or odds ratio (OR) by more than 10%. All data were analyzed utilizing SAS 9.3.
This study was approved by the institutional review board at the University of North Carolina at Chapel Hill.
From January 1, 2011, to November 30, 2013, we identified 64 women who were treated with either methadone or buprenorphine and naloxone and delivered a liveborn neonate at the University of North Carolina at Chapel Hill. A total of 62 women were included in this analysis; one woman was excluded because she gave birth to twins, and one was excluded because her fetus had a myelomeningocele and in utero repair.
The maternal baseline characteristics of patients from each medication group were similar except for indication for opioid treatment (Table 1). Women in the buprenorphine and naloxone group were treated almost exclusively for addiction (93.6%) compared with pain (0%) or pain and addiction combined (6.5%). Nearly two-thirds of the women in the methadone group were treated for addiction (61.3%) compared with pain (16.1%) or both (22.6%).
The mean maternal dose of methadone at delivery was 77.1±36.4 mg (range 5.0–180.0 mg), and the mean maternal dose of buprenorphine at delivery was 14.1±6.5 mg (range 2.0–24.0 mg). Neonates in the methadone-exposed group were born at an earlier gestational age compared with women in the buprenorphine and naloxone group (38.1±2.9 weeks compared with 39.7±1.8 weeks, P=.01). Neonatal sex and feeding method were not different.
Neonatal outcomes are presented in Table 2. The percentage of neonates treated for neonatal abstinence syndrome in the methadone group was 51.6%, and within the buprenorphine and naloxone group, it was 25.1% adjusted (gestational age and maternal indication for opiates; OR 2.55, 95% confidence interval [CI] 1.31–4.98). Peak neonatal abstinence syndrome scores were lower within the buprenorphine and naloxone group; however, the amount of morphine used to treat the neonates for neonatal abstinence syndrome and duration of treatment for neonatal abstinence syndrome between groups was not statistically different. Sixteen percent of the neonates from the methadone group were born prematurely compared with 3% in the buprenorphine and naloxone group, (OR 5.0, 95% CI 0.62–40.36, P=.20).
Neonatal head circumference, birth weight, and length measured less within the methadone group, but these differences were nonsignificant after adjustment for gestational age and maternal indication for opiates. Overall hospitalization was shorter for the buprenorphine and naloxone group, 5.6±5.0 days compared with 9.8±7.4 days, remaining significant after adjustment for gestational age and maternal indication for opiates (multivariate-adjusted mean difference=−3.90 days, 95% CI −7.13 to −0.67, P=.02). Treatment group was not associated with neonatal intensive care unit admission or Apgar scores at 1 and 5 minutes. Inclusion of maternal smoking, benzodiazepine use, and illicit drug use at delivery in multivariable-adjusted models changed parameter estimates by less 10%, so these covariates were not included.
Table 3 shows maternal outcomes according to treatment group; no significant differences were noted with regard to mode of delivery, analgesia during labor, gestational weight gain, or number of prenatal care visits.
In a population of pregnant women treated with either methadone or buprenorphine and naloxone who delivered at a large state teaching hospital, we found that there was less frequent neonatal abstinence syndrome, lower peak neonatal abstinence syndrome scores, and a shorter overall hospitalization for the newborns of mothers treated with buprenorphine and naloxone.
Our studies confirm and extend earlier work on outcomes after medication-assisted treatment in pregnancy; prior reports on 10 patients treated with buprenorphine and naloxone demonstrated maternal and neonatal outcomes consistent with historical data regarding methadone and buprenorphine monotherapy.12,13 Neonatal abstinence syndrome incidence rates in neonates born to mothers treated with methadone range from 45 to 65%15,16 and from 22 to 63% with buprenorphine,11,16,17 consistent with the neonatal abstinence syndrome rates within our two treatment groups. We hypothesized that the percentage of neonates with the diagnosis of neonatal abstinence syndrome would be the same between groups, but we found that the adjusted OR within our methadone group was more than twice that of the buprenorphine and naloxone group.
Overall the methadone group was born earlier and had correspondingly smaller head circumferences, birth weights, and body lengths but with means appropriate for gestational age.18
The most notable difference between the two groups was the length of newborn hospitalization. Newborns in the methadone group spent a mean hospital duration of 9.8±7.4 days compared with 5.6±5.0 days for those in the buprenorphine and naloxone group. This is best explained by the number of newborns who were treated for neonatal abstinence syndrome combined with the number of premature neonates. However, after adjusting for gestational age at delivery and indication for maternal opioid treatment, duration of hospitalization remained significantly longer for the methadone group.
Our findings must be interpreted within the context of our study design. The primary limitation is the observational and retrospective nature of the study with the potential for uncontrolled confounding. The groups differed in their indications for medication-assisted treatment and these differences may have influenced our results. All patients in our study who were treated with buprenorphine and naloxone received care through the Horizons Program with a multidisciplinary care approach not received by all of the patients within the methadone group. Clinicians assigning neonatal abstinence syndrome scores were not blinded to maternal opiate type and dose, which may have biased assessment. However, neonatal abstinence syndrome scoring among multiple observers has been validated in other studies, making it less susceptible to bias.19,20
Data were missing for several important outcomes. Two neonates diagnosed with neonatal abstinence syndrome within the methadone group did not have morphine treatment doses calculated because one was treated with methadone and one was transferred to another facility after 21 days of hospitalization. Two neonates within the methadone group were transferred to other facilities; therefore, their days of hospitalization were not included in this analysis; both were hospitalized for more than 21 days—one for treatment of neonatal abstinence syndrome and one for prematurity (no neonatal abstinence syndrome).
Our sample size was small, limiting our power to detect differences in outcomes such as rate of preterm birth. The additional reporting of larger number of pregnancies exposed to the combination medication buprenorphine and naloxone will further inform practitioners of its acceptability as a treatment for maternal opioid dependence, because these initial reports are reassuring but limited. Additionally, it would be helpful to explore maternal obstetric outcomes including treatment acceptance and adherence. This study helps to strengthen the suggestion that buprenorphine and naloxone may be a reasonable alternative to methadone for the treatment of opioid dependence in pregnancy.
1. Kaltenbach K, Berghella V, Finnegan L. Opioid dependence during pregnancy. Effects and management. Obstet Gynecol Clin North Am 1998;25:139–51.
2. Committee on Health Care for Underserved Women, American Society of Addiction Medicine. Opioid abuse, dependence, and addiction in pregnancy. Committee Opinion No. 524. American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;119:1070–6.
3. Center for Substance Abuse Treatment. Medication assisted treatment for opioid addiction during pregnancy. In: SAHMSA/CSAT treatment improvement protocols. Rockville (MD): Substance Abuse and Mental Health Services Administration; 2008.
4. Jansson LM, Velez M. Neonatal abstinence syndrome. Curr Opin Pediatr 2012;24:252–8.
5. Jones HE, Martin PR, Heil SH, Kaltenbach K, Selby P, Coyle MG, et al.. Treatment of opioid-dependent pregnant women: clinical and research issues. J Subst Abuse Treat 2008;35:245–59.
6. Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE. Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther 1994;55:569–80.
7. Ariëns EJ. Intrinsic activity: partial agonists and partial antagonists. J Cardiovasc Pharmacol 1983;5(suppl 1):S8–15.
8. Johnson RE, Jones HE, Fischer G. Use of buprenorphine in pregnancy: patient management and effects on the neonate. Drug Alcohol Depend 2003;70(2 suppl):S87–101.
9. Jones HE, Heil SH, Baewert A, Arria AM, Kaltenbach K, Martin PR, et al.. Buprenorphine treatment opioid-dependent pregnant women: a comprehensive review. Addiction 2012;107(suppl 1):5–27.
10. Fudala PJ, Bridge TP, Herbert S, Williford WO, Chiang CN, Jones K, et al.. Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med 2003;349:949–58.
11. Johnson RE, McCagh JC. Buprenorphine and naloxone for heroin dependence. Curr Psychiatry Rep 2000;2:519–26.
12. Debelak K, Morrone WR, O'Grady KE, Jones HE. Buprenorphine + naloxone in the treatment of opioid dependence during pregnancy-initial patient care and outcome data. Am J Addict 2013;22:252–4.
13. Lund IO, Fischer G, Welle-Strand GK, O'Grady KE, Debelak K, Morrone WR, et al.. A Comparison of Buprenorphine + Naloxone to Buprenorphine and Methadone in the Treatment of Opioid Dependence during Pregnancy: Maternal and Neonatal Outcomes. Subst Abuse 2013;7:61–74.
14. Finnegan LP, Connaughton JF Jr, Kron RE, Emich JP. Neonatal abstinence syndrome: assessment and management. Addict Dis 1975;2:141–58.
15. Metz V, Jagsch R, Ebner N, Würlz J, Pribasniq A, Aschauer C, et al.. Impact of treatment approach on maternal and neonatal outcome in pregnant opioid-maintained women. Hum Psychopharmacol 2011;26:412–21.
16. Jones HE, Johnson RE, Jasinski DR, O'Grady KE, Crisholm CA, Choo RE, et al.. Buprenorphine versus methadone in the treatment of pregnant opioid-dependent patients: effects on the neonatal abstinence syndrome. Drug Alcohol Depend 2005;79:1–10.
17. Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, et al.. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med 2010;363:2320–31.
18. Olsen IE, Groveman SA, Lawson ML, Clark RH, Zemel BS. New intrauterine growth curves based on United States data. Pediatrics 2010;125:e214–24.
19. Maguire D, Cline GC, Parnell L, Tai CY. Validation of the Finnegan neonatal abstinence syndrome tool-short form. Adv Neonatal Care 2013;13:430–7.
20. Lucas K, Knobel RB. Implementing practice guidelines and education to improve care of infants with neonatal abstinence syndrome. Adv Neonatal Care 2012;12:40–5.