Author:  John McCarthy, M.D. Executive/Medical Director
Bi-Valley Medical Clinic, Inc.


High Dose Methadone Maintenance in Pregnancy

Introduction

            Methadone maintenance treatment in opiate addicted pregnant women reduces maternal morbidity and mortality and promotes fetal stability and growth, compared to mothers using heroin^1,2.  It is associated with better compliance with obstetrical care, and better preparation for parenting responsibilities³.  The baby, however, is at risk for symptoms of neonatal abstinence syndrome (NAS) potentially associated with withdrawal from methadone at birth.   Abstinence symptomatology can occur in gastrointestinal, metabolic, and neurologic domains. Mild symptoms may not require medication management, while moderate or severe symptoms usually require medication assisted withdrawal during 3-5 weeks of hospital monitoring.

            There are conflicting studies on whether the higher methadone doses often needed to eliminate maternal withdrawal symptoms and drug abuse may increase the level of fetal pharmacologic dependence, leading to more severe NAS ^4-9.  Berghella et al., in a retrospective review of 100 pregnant women maintained on methadone, found no difference in severity, duration, or treatment of NAS between infants of mothers on <80mg/day of methadone and those on ≥80mg/day¹⁰.  In contrast, Dashe et al. in their retrospective review of 70 women (mean dose = 20mg/day) who were withdrawn or tapered just prior to delivery found significant correlations between methadone dose and NAS¹¹.

            Therapeutic response to methadone is dose-related.  Higher doses are associated with better treatment outcomes in non-pregnant patients; and federal guidelines recommend increasing methadone doses in pregnant patients with withdrawal symptoms^12-15.  Pregnant patients have required 50-150 mg/day to suppress withdrawal symptoms¹⁶.

            We retrospectively reviewed mothers and infants in a specialized methadone maintenance pregnancy program using individualized dosing to assess whether higher doses of methadone were associated with adverse neonatal outcomes.

Materials and Methods

            The study’s narcotic treatment program (NTP) maintains an active census of approximately 1100 methadone maintenance patients in a California metropolitan area with a population of 1.5 million.  It is the only specialized provider of pregnancy services for opiate addicted women in the area.  Women in the program are assigned to a specially-trained counselor, are all linked with obstetrical care, and give written consent for providers to share information.  All participate in and receive a psychiatric assessment, supportive psychotherapy, one hour of individual drug treatment counseling per week, and participate in a weekly support group for both pregnant and early post-partum patients.  All patients provide random weekly urine drug screens.  As part of the clinic’s on-going Quality Assurance program, maternal and infant data are collected from program entry until one month post-partum.

            Patients are maintained on BID or TID methadone regimens, since the sustained plasma levels achieved with split dosing are associated with fewer withdrawal symptoms and less illicit drug use during pregnancy^{17, 18}.  As a quality control measure, methadone trough serum levels are measured after women reach stable methadone dosing, and repeated in patients requiring unusually high doses.  Although there is a therapeutic range for methadone trough levels in non-pregnant patients of 150-600 ng/ml¹⁹, there is no attempt to achieve ‘target ‘serum levels.  Methadone doses are clinically adjusted, without arbitrary limits, in response to illicit opiate use, withdrawal symptoms, or side effects.

            NAS was evaluated using an objective scoring system²⁰ and treatment of the infant was initiated clinically when repeated scores were in the 6-8 range.

            The study was approved by the University of California, Davis, Institutional Review Board.  SPSS version 11.5 was used for all analyses and p values >0.05 were selected for statistical significance. Data were analyzed using Independent Samples (Between-Subjects) 2-tailed t-tests, Chi-Square analyses, and Mann-Whitney tests.

Results

            There were 94 admissions to the pregnancy program from February 1999 to May 2003.  Thirteen subjects were excluded:  4 miscarried, 3 decided to terminate pregnancy, 2 left treatment, 2 requested to taper off methadone, and 2 had unavailable outcome information.  Eight women had two pregnancies during the study; each pregnancy was considered a separate admission.  Data was analyzed for 81 admissions and 81 offspring.

The study group was 64% White, 25% Mexican/Hispanic, 6% Black, 4% Asian, 1% other. The average maternal age on admission was 32 ± 6.4 years.  The average age of first opiate use was 23 ± 5.6 years, and the average years of use was 10 ± 6.5 years. Twenty-five admissions had conceived while on methadone maintenance.  All others (N=56) were acutely addicted to heroin (N=49), prescription opiates (N=5), or opium (N=2).  Seventy-seven percent of the women were cigarette smokers, with 28 % of the smokers using greater than 1 pack/day.  Polydrug abuse (alcohol, cocaine, methamphetamine, or marijuana) was reported by 38% of the women on admission. Seventy-eight percent (N=1188/1528) of all maternal urine toxicology screens prior to delivery were negative for illicit drugs.

            The average maternal methadone dose at delivery was 101mg/day (range 14-190mg/day).  Trough serum methadone levels were obtained at different gestational ages on only 59 of 81 women during pregnancy due to the difficulty of peripheral venous access in heroin injectors.  The mean trough serum level was 146ng/ml (median 115, std dev 101.5, range 20-478ng/ml).  Forty-six percent of mothers nursed their babies.  Figure 1 depicts the number of babies treated for NAS at each maternal dose range.

            The infants had a mean gestational age at delivery of 37.3 weeks and a mean birth weight of 2792 grams.  No major developmental abnormalities were noted.  Eighty one percent (N=66/81) of infant toxicology screens at the time of delivery were negative for illicit drugs.  The 15 positive screens detected opiates (N=4), amphetamines (N=9), cocaine (N=4), diazepam (N=2), marijuana (N=1), and alcohol (N=1).  Six infants were positive for 2 drugs.  Thirty-seven babies (46%) required medication for management of NAS symptoms. Infants were treated with paregoric (N=20), phenobarbital (N=10), both paregoric and phenobarbital (N=4), methadone (N-1), ativan (N=1), and both paregoric and ativan (N=1).

            Because of custody issues, length of stay (LOS) information was not available on 10 infants.  The median LOS for the 71 infants on whom data was available was 10.0 days (range 1-105).  There was no significant correlation between maternal dose and LOS (Pearson correlation co-efficient .066, p=.586).  When divided into NAS-treated (N=37) and untreated (N=44) groups, the untreated babies spent a median 3 days (range 1-44) in the hospital, while babies treated for NAS spent a median 25 days (range 8-105).  We observed no cases of post-hospitalization NAS in untreated babies during the 1-month post-partum period.

            To assess whether higher doses resulted in increased risks of NAS, the cohort was divided into 2 dose groups:  mothers treated with <100mg of methadone (N=36) and those treated with ≥100mg (N=45).  The cut-off of 100mg for the groups was chosen to achieve approximately equal cohort size.  Comparison of maternal dose groups revealed a mean dose in the ≥100mg group of 132mg, and 62mg in the <100mg group.  Independent samples t-tests showed no significant differences between groups in maternal age, age of onset of drug use or time in treatment, while the high dose group had significantly longer histories of opiate abuse (mean 11.6 years versus 7.8 years in the low dose group; t=-2.6(66.6), p<.05).  Chi-Square analyses showed no significant differences between groups in ethnicity, polydrug use history, and smoking history.

            Table I shows infant outcome data by maternal dose group.  Chi-Square analyses revealed that the higher dose group had significantly less drug use at delivery:  11% of infant toxicology screens were positive for illicit drugs in the high dose group vs. 27% positive screens in the low dose group (p=.05).  There were no significant differences in the incidence of treated NAS between infants of high- and low methadone-dose mothers:  51% of the high-dose babies and 49% of the low-dose babies required treatment.  Mann-Whitney tests for non-normal distributions revealed no significant differences in gestational age (U=735, N₁=36, N₂=45, p=.47), birth weight (U=775, N ₁=36, N ₂=45, p=74), or days of infant hospitalization (U=600, N₁=31, N₂=40, p=81) between high- and low-dose groups.

Comment

            This retrospective records review of methadone-maintained pregnant women and their offspring found no evidence of an increased incidence of adverse outcomes in babies exposed to higher, clinically-determined methadone doses.  The rate of treatment for NAS and length of infant hospitalization was similar for both high-dose (mean 132mg/day) and low-dose (mean 62mg/day) groups studied.  Our results extend the findings of Berghella et al., mentioned in the introduction, to higher average dose ranges.

            Importantly, our high-dose group had significantly less detected illicit drug use at delivery, even though this group had significantly longer histories of addiction.  Berghella et al. found a trend toward less drug use at doses >80mg.  Our study suggests that, as in non-pregnant populations, higher doses of methadone do lead to less drug use¹³.   Any theoretical goal of reducing NAS by using low doses or tapering schedules may well be off-set by the adverse effects of more illicit drug use.  For example, Brown et al. reported on a low dose methadone-treated pregnant population (41% were maintained on less than 50mg) in which 84% of newborn infants tested positive for illicit drugs at the time of delivery, leading them to question the efficacy of methadone treatment⁷.

            The dose range (14-190mg/day) in our cohort was quite wide, possibly reflecting individual differences in methadone metabolism²¹.  Accelerated methadone metabolism and decreases in methadone bioavailability occur during pregnancy^{22, 23}.  Consistent with these metabolic effects, the mean maternal methadone serum level during pregnancy in this study was in the low range for methadone, despite the high average dose.

            The overall 46% rate of treated NAS for the infants is comparable to, or better than, studies where lower doses were used.  Doberczak et al. reported a 78% rate of treated NAS where the average maternal dose was 50mg/day ⁵.  The overall rate of treatment in the Dashe et al. study (median of 20mg/day) was 46%¹¹.

     We used treated NAS as an outcome measure.  We did not assess other variables that might affect the severity of NAS since our study relied on readily-available measures used in routine clinical practice.  Doberczak et al. found that the severity of NAS was related to the decline of the neonatal plasma methadone level from day 1 to day 4 of life⁵.  Kushel et al. confirmed this finding and further found that both low maternal and low cord methadone concentrations at delivery were associated with more severe NAS^9.  These studies underscore the importance of infant variables in determining risks of NAS.  Furthermore, almost half of our mothers nursed their babies.  Methadone levels in milk are small and normally not sufficient to prevent NAS²⁴.  However, Ballard found that frequent small feedings in the neonatal period were associated with reduced symptoms of NAS ²⁵.  Finally, it is speculative, but the more stable serum levels achieved by split doses may have some protective effect against NAS.  Mothers on inadequate doses of methadone or on single dose regimes often experience repeated episodes of withdrawal, which could possibly sensitize the fetus to the withdrawal state.  Further study of the effect of split doses of methadone on NAS is warranted.

            The role of non-opiate fetal drug exposure (alcohol, cocaine, amphetamine, and benzodiazepine) in effecting the expression of NAS has not been systematically studied, and remains a potential confound in our study, as in others^4-9.

            Maternal recovery from illicit drug abuse is critical for the long-term health and safety of both the mother and the child.  Using adequate doses of methadone during pregnancy in a specialized program such as the one described in this study can increase the likelihood of the mother achieving recovery early in treatment.  Continued methadone maintenance after delivery may further reduce risks of maternal relapse during the critical and often stressful period of parenting a newborn child.

            Acknowledgements

We thank Genelle Smith, MSW, for her significant contributions to patient care and data collection, and to Kimberly S. Tyda, MA, for her help with data analysis.

Figure 1. Number of infants treated for NAS, by maternal dose range

Table 1. Infant outcomes by maternal methadone dose group

^* Mean ±SD

¹ Independent Samples t-test

² Mann-Whitney tests

³ Chi-Square

References

1)        Kaltenbach KA, Berghella V, Finnegan L.  Opioid dependence during pregnancy: effects and management.  Clin Obstet Gynaecol. 1998;25:139-151.

2)        Kandell SR, Doberczak TM, Jantunen M, Stein J.  The methadone-maintained pregnancy.  Clin Perinatol. 1999;26:173-183.

3)        Wilson GS, Desmond MM, Wait RB.  Follow-up of methadone-treated and untreated narcotic-dependent women and their infants: health, developmental, and social implications.  J Ped.  1981;98:716-722.

4)        Doberczak TM, Kandall SR, Wilets I.  Neonatal opiate abstinence syndrome in term and preterm infants.  J Ped.  1991;118:933-937.

5)        Doberczak TM, Kandall SR, Friedmann P.  Relationship between maternal methadone dosage, maternal-neonatal methadone levels, and neonatal withdrawal.  J Obstet Gynecol. 1993;81:936-940.

6)        Madden JD, Chappel JN, Zuspan F, Gumpel J, Mejia A, and Davis R.  Observation and treatment of neonatal narcotic withdrawal.  Am J Obstet Gynecol.  1977;127:199-201.

7)        Brown HL, Britton KA, Mahaffey D, Brizendine E, Hiett AK, Turnquest MA.  Methadone maintenance in pregnancy: a reappraisal.  Am J Obstet Gynecol. 1998;179:459-463.

8)        Blinnick G, Jerez E, Wallach RC.  Methadone maintenance, pregnancy, and progeny.  JAMA. 1973;225:477-479.

9)        Kushel CA, Austerberry L, Cornwell M, Couch R, Rowley, RSH. Can methadone concentrations predict the severity of withdrawal in infants at risk of neonatal abstinence syndrome?  Arch Dis Child Fetal Neonatal Ed 2004;89:F390-393.

10)    Berghella V, Lim PJ, Cherpes J, Chennat J, Kaltenbach K.  Maternal methadone dose and neonatal withdrawal.  Am J Obstet Gynecol.  2003;189:312-317.

11)    Dashe JS, Sheffield JS, Olscher DA, Todd SJ, Jackson GL, Wendel GD.  Relationship between maternal methadone dosage and neonatal withdrawal. Obstet Gynecol. 2002;100:1244-1249.

12)    Leavitt SG, Shinderman M, Maxwell S, Eap CB, and Paris P.  When enough is not enough: new perspectives on optimal methadone maintenance dose.  J Mt Sinai Hosp NY. 2000; 67:404-411.

13)    D’Aunno T, Pollack HA. Changes in methadone treatment practices. JAMA. 2002;288:850-856.

14)    National Institutes of Health Consensus statement 108: Effective Medical Treatment of Opiate Addiction 1997. Available at http://odp.od.nih.gov/cosensus/cons/108/108_statement.htm.

15)    Kaltenbach K, Silverman N, Wepner RJ: Methadone maintenance during pregnancy. In State Methadone Treatment Guidelines, Center for Substance Abuse Treatment. Rockville, MD, US Department of Health and Human Services, 1992, pp85-93..

16)    Drozdick J 3^rd, Berghella V, Hill M, Kaltenbach K.  Methadone trough levels in pregnancy.  Am J Obstet Gynecol.  2002;187:1184-1188.

17)    Swift RM, Dudley M, DePetrillo P, Camara P, and Griffiths W.  Altered methadone pharmacokinetics in pregnancy: implications for dosing.  J Subst Abuse.  1989;1:453-460.

18)    DePetrillo PB and Rice J.  Methadone dosing and pregnancy: Impact on program compliance. Internat J of Addictions.  1995;30:207-217.

19)    Dole, V. Implications of methadone maintenance for theories of narcotic addiction. JAMA. 1988;260:3025-3029.

20)    Finnegan LP, Kron RE, Connaughton, JF, Emidl, JP.  Assessment and treatment of abstinence in the infant of the drug-dependent mother.  Int J Clin Pharmacol Biopharm.  1975;12:19-32.

21)    Eap CB, Buclin T, and Baumann P.  Interindividual variability of the clinical pharmacokinetics of methadone: Implications for the treatment of opioid dependence.  Clin Pharmacokinet. 2002;41:1153-1193.

22)    Pond SM, Kreek MJ, Tong TG, Raghunath J, and Benowitz NL.  Altered methadone pharmacokinetics in methadone-maintained pregnant women.  J Pharmacol Exp Ther. 1985;233:1-6.

23)    Jarvis MA, Wu-Pong S, Kniseley JS, and Schnoll SH.  Alterations in methadone metabolism during late pregnancy.  J Addict Dis. 1999;18 (4):51-61.

24)    Jansson LM, Velez M, Harrow C. Methadone maintenance and lactation: A review of the literature and current management guidelines. J Hum Lact 2004; 20:62-70.

25)   Ballard, JL. Treatment of neonatal abstinence syndrome with breast milk containing methadone. J Perinat Neonat Nurs 2002; 15: 76-85.