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Outcomes of neonates conceived on methadone maintenance therapy
Journal of Substance Abuse Treatment 35 (2008) 202 – 206
Regular article
Outcomes of neonates conceived on methadone maintenance therapy John J. McCarthy, (M.D.) a,b,⁎, Martin H. Leamon, (M.D.) b , Garrett Stenson, (M.S.W.) a , Lagen A. Biles, (Ph.D.) c a
b
Bi-Valley Medical Clinic, Sacramento, CA 95816, USA Department of Psychiatry and Behavioral Science, University of California, Davis, Sacramento, CA 95817, USA c The Permanente Medical Group, Inc. Gilroy, CA 95020, USA Received 9 May 2007; received in revised form 21 September 2007; accepted 30 September 2007
Abstract To assess potential risks related to the duration or total amount of fetal methadone exposure during gestation, we compared babies of women who conceived and maintained on methadone throughout pregnancy with babies of women who began methadone treatment during the second or third trimester. Babies conceived on methadone were exposed to the medication for a mean of 37.4 weeks at a mean dose of 110 mg/day, whereas comparison babies were exposed for a mean of 13.1 weeks at a mean dose of 93 mg/day. There were no significant betweengroup differences in the frequency of treatment of neonatal abstinence, days hospitalized, birth weight, or gestational age. Babies conceived on methadone were significantly less likely to test positive for illicit drugs at delivery as compared with babies conceived off methadone (positive toxicology, 9.1% vs. 34.3%, respectively). Methadone exposure during the entire gestational period was associated with better drugtreatment outcomes but was not associated with more severe neonatal abstinence. © 2008 Elsevier Inc. All rights reserved. Keywords: Methadone; Pregnancy; Conception; Neonatal abstinence; Drug treatment
1. Introduction Methadone maintenance therapy (MMT) for opiate addiction during pregnancy is associated with a number of positive maternal outcomes, including reduced perinatal morbidity, recovery from illicit drug use, and better preparation for parenting (Kandall, Doberczak, Jantunen, & Stein, 1999; McCarthy, Leamon, Parr, & Anania, 2005; Wilson, Desmond, & Wait, 1981). Methadone has potential therapeutic benefit for the developing fetus by minimizing cycles of intoxication and withdrawal associated with variable timing and amounts of illicit opiate use (Kaltenbach, Berghella, & Finnegan, 1998). Maintaining a pregnant woman on methadone continues the opiate-dependent state of the fetus and delays the eventual opiate abstinence syndrome until delivery. There ⁎ Corresponding author. Tel.: +1 916 442 4985. E-mail addresses: [email protected] (J.J. McCarthy), [email protected] (M.H. Leamon), [email protected] (G. Stenson), [email protected] (L.A. Biles). 0740-5472/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.jsat.2007.09.009
has been concern expressed about the frequency and severity of the neonatal abstinence syndrome (NAS), a constellation of central nervous system, gastrointestinal, and metabolic disturbances that occurs in methadone-dependent neonates (Dashe, Jackson, Olsher, Zane, & Wendell, 1998). These symptoms require medication management in 46% to 81% of babies (Doberczak, Kandall, & Friedman, 1993; McCarthy et al., 2005). Babies that require medications are usually hospitalized for 3 to 4 additional weeks after delivery. Although relapse rates as high as 90% have been reported when women are withdrawn from methadone during pregnancy (Luty, Nikolaou, & Bearn, 2003) and not being on MMT has been associated with early treatment dropout (Kissin, Svikis, Moylan, Haug, & Stitzer, 2004), concerns about NAS have led some authors to attempt methadone withdrawal or dose reductions during pregnancy. Luty et al. (2003) reported on 101 women who underwent a 21-day methadone withdrawal and found no increased risk of miscarriage or prematurity. Dashe et al. (1998) reported successful withdrawal from methadone in selected low-risk cases without evidence of fetal distress on sonographic or
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fetal heart rate monitoring. Maas, Katner, Weingart-Jesse, Shafer, and Obladen (1990) reported on 17 women who were successfully withdrawn from heroin using methadone and found that gestational age, birth weight, head circumference, and symptoms of NAS were all improved as compared with a larger number of women who continued to use heroin during the attempted withdrawal. Because all three of these studies had high rates of relapse to illicit drug use and detox failures, the practice remains controversial (Newman, 2004). In a case study reflective of the potential dangers of intrauterine withdrawal, Zuspan, Gumpel, Mejia-Zelaya, Madden, and Davis (1975) used serial amniocenteses during an attempted second-trimester methadone withdrawal and described marked increases in fetal epinephrine and norepinephrine, an apparent stress effect of the withdrawal that was reversed by increasing the maternal methadone dose. These authors also reported knowledge of five intrauterine deaths caused by detoxification during the second and third trimesters. Some earlier studies suggested that higher maternal methadone doses caused more severe NAS (Dashe et al., 2002; Doberczak et al., 1993). More recent studies, across the wider range of doses used in current clinical practice, suggest that this is not the case (Berghella et al., 2003; McCarthy et al., 2005). However, it is possible that the duration of exposure (e.g., initiation of MMT in the first trimester vs. third trimester) or total amount of methadone administered could be associated with more severe NAS or other problems. Most pregnant women receiving MMT begin the therapy after conception, most commonly in the second or third trimester (Dashe et al., 1998; Hagopian et al., 1996). However, women who are already receiving MMT do conceive while on methadone and remain on methadone for the entire pregnancy. There have been many studies of neonatal outcomes for babies of women on MMT. We are aware of only three published studies, however, that looked at outcomes of babies of women who specifically conceived on and maintained on MMT throughout the pregnancy. Kemplova and Okruhlica (2005) compared birth weight, length, and gestational ages of 10 infants conceived on MMT to population norms and found no differences between the two groups. Kandall et al. (1976) compared outcomes of 40 women confirmed to be on methadone during the entire pregnancy with those of heroin users and controls. The birth weights of the methadone-exposed infants were significantly greater than those of infants of heroin-using mothers but less than those of a community control group. These authors also found a correlation between higher methadone doses in the first trimester and higher birth weights. Sharpe and Kushel (2004) used a control group of 24 pregnant patients in MMT that appear to have conceived on methadone in a study of women on short-term methadone treatment for pain. In the MMT patients, they found a median gestational age of 39 weeks and that 58% of the infants required treatment of NAS. The authors state that the “infants born to mothers
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receiving methadone for addiction had very little morbidity.” Although these three studies support the use of MMT in pregnancy in general, only Sharpe and Kushel (2004) examined NAS as an outcome. It is therefore reasonable to ask whether longer or shorter periods of methadone exposure result in differences in severity of NAS. The ideal study for this question would compare babies of women who conceived on methadone, did not use any other drugs, and remained on the medication through delivery with those of women who conceived while abstinent and not on methadone and were then placed on methadone later in the pregnancy. Such a study would clearly not be ethical in addiction treatment, although such a study might be feasible in a pain management setting. Therefore, this study reports on neonatal outcomes, including NAS, for babies of women who conceived and maintained on methadone for the entire pregnancy compared with those for babies of mothers who entered MMT in their second or third trimester. We believe this is the first such study in the English literature.
2. Methods The participants for this analysis are a subgroup of a cohort previously studied for the effect of maternal methadone dose on the severity of neonatal abstinence symptoms. Data for this study were collected between February 1999 and May 2003. All women in the study were enrolled in an MMT program with enhanced pregnancyrelated services that included individual counseling, psychiatric care, weekly random urine drug screens, and coordination with obstetrical care providers. Patients attended a mandatory weekly support group for pregnant and early postpartum women, led by the clinic physician (J.M.) and a pregnancy counselor specialist, which focused on education on methadone dosing, NAS, nursing, drug use effects on the fetus, and other pregnancy-related topics. Methadone doses were individualized and increased in response to either maternal reports of withdrawal symptoms or maternal drug use. All women were maintained on a twice-daily methadone-dosing schedule to achieve more constant maternal and fetal blood levels over 24 hours and prevent any maternal withdrawal symptoms. To maximize the potential for identifying outcome differences based on duration of methadone exposure, we chose to compare two groups with very different levels and timing of methadone exposure: those who conceived on methadone (conceived on) and those who were initiated on methadone in the second and third trimesters (conceived off). Because of the inherent uncertainty in determining the estimated date of conception (EDC), only women who were in MMT 2 or more weeks prior to their EDC were included in the conceived-on methadone group. Women who began MMT at more than 12 weeks from their EDC were included in the conceived-off group. In addition, for both groups, only
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women who remained on MMT continuously through delivery were included. An approximation of total methadone exposure for the two groups was achieved by multiplying the days pregnant on methadone by the average daily dose at delivery. This method overestimates the methadone exposure in both groups to some small degree because after initial stabilization, the methadone dose is at times increased during pregnancy. All infants born to mothers on methadone are considered high risk and are monitored initially in a neonatal intensive care unit. NAS was assessed using the standard Finnegan rating scale, and babies were treated when they had repeated scores above 8 (Finnegan, Kron, Connaughton, & Emich, 1975). The data for this study were collected as part of a routine internal quality improvement program. The institutional review board at the University of California, Davis, approved the study without requiring informed consent. Statistical analyses were carried out using SPSS software (version 12.0; SPSS Inc, Chicago, IL) using a significance cutoff of b.05. Specific analyses included comparison of means via two-tailed independent sample t tests, measures of association via chi-square and Mann–Whitney's U, as well as linear regression analyses. 3. Results Twenty-two participants were in the conceived-on group, and 35 were in the conceived-off group. Ethnic distribution for the whole cohort was as follows: Caucasian, 63%; Hispanic, 25%; African American, 5%; Asian American, 5%; and other, 2%. There were no significant differences in ethnicity between groups. Other maternal demographic variables are presented in Table 1. There were no significant differences for maternal age, methadone dose at delivery, or smoking history. Women who conceived on methadone had a mean continuous exposure to methadone of 104.5 weeks, including their time on methadone prior to conception.
Table 1 Maternal demographics and outcomes
Variables Maternal age at delivery Years of opiate use % smoking on admission Mother's dose at delivery (mg) Total weeks on methadone % positive toxicology during pregnancy ⁎ p b .10. ⁎⁎ p b .05. ⁎⁎⁎ p b .0001.
Conceived on methadone (n = 22)
Conceived off methadone (n = 35)
t tests
34.3 12.7 81.8 110
31.3 7.7 77.1 93
t = 0.44 ⁎ t = 1.84 ⁎⁎ ns ns
104.5 18.8
13.1 40.2
t = 8.04 ⁎⁎⁎ t = 0.08 ⁎
Table 2 Infant outcomes
Variables Weeks on methadone Gestational age (weeks) Birth weight (g) Days hospitalized % treated for NAS % positive toxicology at delivery % nursing
Babies conceived on methadone (n = 22)
Babies conceived off methadone (n = 35)
Statistic
37.4 37.4 2856 16.1 45.5 9.1
13.1 36.7 2622 18.3 51.4 34.3
t = 13.64 ⁎⁎ ns ns ns ns χ2(1) = 4.63 ⁎⁎
54.5
31.4
χ2(1) = 2.99 ⁎
⁎ p b .10. ⁎⁎ p b .05.
Women in the conceived-on group had significantly longer histories of addiction, 12.7 versus 7.7 years (p = .0001). Although weekly urine drug tests were ordered, results were not available if the patient did not provide a sample or if she were incarcerated at the time a sample was to be provided. There was no significant difference between groups in the percentage of samples tested (conceived on = 458 of 491 [93.3%]; conceived off = 343 of 394 [87.1%]). Of 885 possible tests for the entire cohort, 801 samples (90.5%) were collected and tested. For the whole cohort, 72% (n = 577/801) of urine drug screens during pregnancy were negative for illicit drugs. Positive tests were for opiates (19.4%), amphetamines (6.1%), and cocaine (5.9%). Of these positive tests, 4.9% were positive for two drugs. Comparing the groups, 18.2% of tests (n = 86/458) in the conceived-on group were positive for drugs versus 40.2% (n = 138/343) in the conceived-off group (p b .1). For opiate tests specifically, 10.5% of tests (n = 48/458) in the conceived-on group were positive versus 31.2% (n = 107/ 343) in the conceived-off group. Infant outcomes (Table 2) showed significant differences for positive toxicology for illicit drugs at birth. The conceived-on group had significantly fewer positive tests than the conceived-off group (9.1% vs. 34.3%, respectively; p b .05). Twenty-eight babies required treatment for NAS with medications. The percentage of babies treated in the conceived-on group was 45.5% versus 51.4% in the conceived-off group. Specific medications used to treat NAS were paregoric (n = 17), phenobarbital (n = 11), morphine (n = 3), and lorazepam (n = 2). Six babies were treated with two medications. The average birth weight of full-term babies was 3,047 g versus 2,179 g in premature babies. There was a 38.6% (n = 22/57) incidence of prematurity (b37 weeks' gestation) in the infants. There was a 35% incidence (n = 20/57) of low birth weight (b2500 g). Average birth length was 18.58 in. There were no significant intergroup differences in rates of treatment for NAS, birth weight, length, gestational age, or days of infant hospitalization after delivery.
J.J. McCarthy et al. / Journal of Substance Abuse Treatment 35 (2008) 202–206
There were eight mothers in the conceived-on group who had no evidence on weekly drug screens of illicit drug use during the entire pregnancy. The average gestational age of these babies was 38.3 weeks, and the average birth weight was 2,931 g. Five of these women smoked cigarettes. For comparison purposes, local county birth data for comparable years (averages of years 1999–2003) showed an average birth weight of 3,369 g and average gestational age of 40.0 weeks (Sacramento County Department of Public Health, personal communication, 2003). Because smoking has an adverse effect on birth weight and gestational age, even this group with no illicit drug use does not reflect the ideal of methadone-only exposure. Nursing was encouraged in this population, and 40% of the women nursed. There was a trend for a greater percentage of babies breast-fed in the conceived-on group versus the conceived-off group, 54.5% versus 31.4%, respectively (p b .10). Babies conceived on methadone had an approximate total gestational exposure of 28.8 g (110 mg/day × 37.4 weeks). Those in the conceived-off group had an approximate exposure of 8.5 g (93 mg/day × 13.1 weeks). The conceived-on group had approximately 20 g greater methadone exposure and an average duration of exposure 24.3 weeks longer.
4. Conclusions This study found no evidence that the timing, duration, or total amount of prenatal methadone exposure was associated with increased risk for treatment of neonatal abstinence or for longer hospitalization when compared with a cohort of women placed on methadone in the second and third trimesters. Our study also extends the results of two earlier studies in a similar population showing no adverse effects of extended methadone exposure versus shorter exposure on birth weight or gestational age (Kandall et al., 1976; Kemplova & Okruhlica, 2005). We found a significant difference between groups in infant toxicologies at delivery (p b .05) and a trend for less drug use in the conceived-on group in maternal drug tests during pregnancy (p b .1). Our small sample size may have reduced the statistical significance of the 22% difference between groups in positive maternal drug tests. Mothers who conceived on methadone had less drug use, and babies conceived on methadone were significantly more likely to have negative urine drug screens at delivery, findings that are consistent with the known relationship between duration of substance abuse treatment and positive treatment outcomes (National Institutes of Health, 1997). We did note a 38.6% rate of late preterm births and a 35% incidence of low birth weight in our cohort with no differences between groups. There was a high rate of smoking (81% and 78%) in the two groups, and smoking is associated with both prematurity and low birth weight.
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Kandall et al. (1976) reported that heroin use caused fetal growth retardation and that methadone promoted fetal growth in heroin-exposed babies. These authors also found evidence that the growth-retarding effect of heroin may persist beyond the period of addiction and affect a subsequent pregnancy. There is no evidence from our study that cumulative dose or duration of methadone treatment had any adverse effect on weight or gestational age. The overall rate of breast-feeding in this population was 40%. The conceived-on group was more likely to nurse. Nursing while on methadone is approved by the American Academy of Pediatrics (AAP, 2001) without restrictions on maternal dose based on evidence that the amounts of methadone in milk are very small and unlikely to involve risks (Jansson, Velez, & Harrow, 2004; McCarthy & Posey, 2000). Nursing is the optimal form of infant nutrition providing many health benefits, including benefits specific to drug-exposed babies such as reduction of NAS symptoms and protection against sudden infant death syndrome (AAP, 1982; Ballard, 2002; McVea, Turner, & Peppler, 2000). Our study does not support a need to advise women to reduce doses or duration of treatment during pregnancy to reduce the risks of NAS at delivery or to improve gestational age or birth weight. Withdrawal during pregnancy obviously can reduce the risks of postpartum NAS by precipitating the withdrawal syndrome in utero. It is interesting that none of the authors reporting on the apparent safety of methadone withdrawal during pregnancy report any signs of a fetal abstinence syndrome using routine fetal monitoring (Dashe et al., 1998; Luty et al., 2003; Maas et al., 1990). Jansson, DiPietro, and Elko (2005) have demonstrated differences in fetal movement and heart rate associated with peak and trough maternal methadone serum levels using a fetal actocardiograph to monitor fetal movements and heart rate with more sensitivity than ultrasound visualization, although these mothers were not undergoing withdrawal. It seems likely that fetal behavioral functions would become more abnormal during an actual methadone withdrawal. There may be other biochemical abnormalities in addition to those found by Zuspan et al. (1975). Routine fetal-monitoring measures used may not be sensitive enough to detect evidence of significant behavioral or neuroendocrine changes occurring during an intrauterine withdrawal. Furthermore, because most intrapartum withdrawals are likely to result in relapse or early treatment dropout, such babies may be exposed to two episodes of precipitated abstinence, in utero and after birth, in addition to the potential adverse effects of relapses to illicit drug use. However, a very important factor in decisions about attempted withdrawal from methadone during pregnancy is maternal preference. This is often motivated by fear of the stigma and social disapproval associated with methadone treatment. Information about evidence of the safety and benefits of methadone treatment throughout pregnancy should be part of discussions with women who feel pressured to withdraw during pregnancy.
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In summary, the lack of demonstrable adverse effects on the baby of prolonged gestational exposure to methadone coupled with reduction of risks from illicit drugs from prolonged participation in an MMT program supports continuation of methadone treatment as the standard of care for substance-addicted pregnant women. This study is limited by relatively small numbers with insufficient power to study other variables that might affect neonatal outcome measures, such as the amount of exposure to nicotine, other drugs, or alcohol. Our fetal outcome measures are limited to those that are easily obtainable in the immediate postpartum period. In addition, exposure to counseling and obstetrical care, which may affect outcomes, was not measured. The generalizability of outcomes of this and many studies of pregnant women is limited by small numbers. A more accurate measure of the effects of methadone exposure on the fetus would be in patients who had no drug use for the duration of the pregnancy. We found only eight patients who met this criterion, but five of these women smoked cigarettes, showing how difficult it is to isolate the effects of methadone exposure alone. There was also a significant difference in baseline characteristics between groups in terms of duration of addiction, the potential impact of which is unknown. A large multisite study of this unique population is needed to further assist clinicians in advising women on issues related to methadone and pregnancy. Because methadone is being used with increasing frequency for chronic pain, another group of women will conceive while on methadone. Although the results and implications of this study may not be generalizable to a pain population, as noted by Sharpe and Kushel (2004), it is important that all women placed on methadone for addiction or for chronic pain be given detailed information about the fetal dependence that occurs if they conceive on maintenance therapy. Knowing these risks, physicians should advise on the use of contraception during methadone therapy to avoid this complication. However, some women will choose to conceive on methadone, at times due to previous relapses when not in MMT. The evidence to date suggests that we can safely support such decisions.
References American Academy of Pediatrics. (1982). The promotion of breastfeeding. Pediatrics, 69, 654. American Academy of Pediatrics. (2001). The transfer of drugs and other chemicals into human milk. Pediatrics, 108, 776−789. Ballard, J. L. (2002). Treatment of neonatal abstinence syndrome with breast milk containing methadone. Journal of Perinatal and Neonatal Nursing, 15, 76−85. Berghella, V., Lim, P. J., Cherpes, J., Chennat, J., Hill, M. K., & Kaltenbach, K. (2003). Maternal methadone dose and neonatal withdrawal. American Journal of Obstetrics and Gynecology, 189, 312−317. Dashe, J. S., Jackson, G. L., Olscher, D. A., Zane, E. H., & Wendel, G. D. (1998). Opioid detoxification in pregnancy. Journal of Obstetrics and Gynecology, 92, 854−858.
Dashe, J. S., Sheffield, J. S., Olscher, D. A., Todd, S. J., Jackson, G. L., & Wendel, G. D. (2002). Relationship between maternal methadone dosage and neonatal withdrawal. Journal of Obstetrics and Gynecology, 100, 1244−1249. Doberczak, T. M., Kandall, S. R., & Friedmann, P. (1993). Relationship between maternal methadone dosage, maternal-neonatal methadone levels, and neonatal withdrawal. Journal of Obstetrics and Gynecology, 81, 936−940. Finnegan, L. P., Cron, R. E., Connaughton, J. F., & Emich, J. P. (1975). Assessment and treatment of abstinence in the infant of the drugdependent mother. International Journal of Clinical Pharmacology and Biopharmacy, 12, 19−32. Hagopian, G. S., Wolfe, H. M., Sokol, R. J., Ager, J. W., Wardell, J. N., & Cepeda, E. E. (1996). Neonatal outcome following methadone exposure in utero. Journal of Maternal-Fetal Medicine, 5, 348−354. Jansson, L. M., DiPietro, J., & Elko, A. (2005). Fetal response to maternal methadone administration. American Journal of Obstetrics and Gynecology, 193, 611−617. Jansson, L. M., Velez, M., & Harrow, C. (2004). Methadone maintenance and lactation: A review of the literature and current management guidelines. Journal of Human Lactation, 20, 62−71. Kaltenbach, K., Berghella, V., & Finnegan, L. (1998). Opioid dependence during pregnancy. Obstetric and gynecology clinics of North America, 25, 139−151. Kandall, S. R., Albin, S., Lowinson, J., Berle, B., Eidelman, A. I., & Gartner, L. M. (1976). Differential effects of maternal heroin and methadone use on birth weight. Pediatrics, 58, 681−685. Kandall, S. R., Doberczak, T. M., Jantunen, M., & Stein, J. (1999). The methadone-maintained pregnancy. Clinics in Perinatology, 26, 173−183. Kemplova, D., & Okruhlica, L. (2005). No intrauterine growth retardation in babies of mothers stabilized on methadone before conception and throughout their pregnancies. Heroin Addiction and Related Clinical Problems, 8, 25−30. Kissin, W. B., Svikis, D. S., Moylan, P., Haug, N., & Stitzer, M. (2004). Identifying pregnant women at risk for early attrition from substance abuse treatment. Journal of Substance Abuse Treatment, 27, 31−38. Luty, J., Nikolaou, V., Bearn, J., et al. (2003). Is opiate detoxification unsafe in pregnancy? Journal of Substance Abuse Treatment, 24, 363−367 (Comment in Luty, J. (2004). Journal of Substance Abuse Treatment, 26, 65–66.). Maas, U., Kattner, E., Weingart-Jesse, B., Schäfer, A., & Obladen, M. (1990). Infrequent neonatal withdrawal following maternal methadone detoxification during pregnancy. Journal of Perinatal Medicine, 18, 111−118. McCarthy, J. J., Leamon, M. L., Parr, M. S., & Anania, B. A. (2005). High dose methadone maintenance in pregnancy: Maternal and neonatal outcomes. American Journal of Obstetrics and Gynecology, 193, 606−610. McCarthy, J. J., & Posey, B. L. (2000). Methadone levels in human milk. Journal of Human Lactation, 16, 115−120. McVea, K. L., Turner, P. D., & Peppler, D. K. (2000). The role of breastfeeding in sudden infant death syndrome. Journal of Human Lactation, 16, 13−20. National Institutes of Health Consensus Statement. (1997). Effective medical treatment of opiate addiction. Available at: http://odp.od.nih. gov/cosensus/cons/108/108_statement.htm. Newman, R. (2004). Letter to the editor. Journal of Substance Abuse Treatment, 26, 65−66. Sharpe, C., & Kushel, C. (2004). Outcomes of infants born to mothers receiving methadone for pain management in pregnancy. Archives of Diseases of Child Fetal and Neonatal Education, 89, F33−F36. Wilson, G. S., Desmond, M. M., & Wait, R. B. (1981). Follow-up of methadone-treated and untreated narcotic-dependent women and their infants: Health, developmental, and social implications. Journal of Pediatrics, 98, 716−722. Zuspan, F. P., Gumpel, J. A., Mejia-Zelaya, A., Madden, J., & Davis, R. (1975). Fetal stress from methadone withdrawal. American Journal of Obstetrics and Gynecology, 122, 43−46.
Regular article
Outcomes of neonates conceived on methadone maintenance therapy John J. McCarthy, (M.D.) a,b,⁎, Martin H. Leamon, (M.D.) b , Garrett Stenson, (M.S.W.) a , Lagen A. Biles, (Ph.D.) c a
b
Bi-Valley Medical Clinic, Sacramento, CA 95816, USA Department of Psychiatry and Behavioral Science, University of California, Davis, Sacramento, CA 95817, USA c The Permanente Medical Group, Inc. Gilroy, CA 95020, USA Received 9 May 2007; received in revised form 21 September 2007; accepted 30 September 2007
Abstract To assess potential risks related to the duration or total amount of fetal methadone exposure during gestation, we compared babies of women who conceived and maintained on methadone throughout pregnancy with babies of women who began methadone treatment during the second or third trimester. Babies conceived on methadone were exposed to the medication for a mean of 37.4 weeks at a mean dose of 110 mg/day, whereas comparison babies were exposed for a mean of 13.1 weeks at a mean dose of 93 mg/day. There were no significant betweengroup differences in the frequency of treatment of neonatal abstinence, days hospitalized, birth weight, or gestational age. Babies conceived on methadone were significantly less likely to test positive for illicit drugs at delivery as compared with babies conceived off methadone (positive toxicology, 9.1% vs. 34.3%, respectively). Methadone exposure during the entire gestational period was associated with better drugtreatment outcomes but was not associated with more severe neonatal abstinence. © 2008 Elsevier Inc. All rights reserved. Keywords: Methadone; Pregnancy; Conception; Neonatal abstinence; Drug treatment
1. Introduction Methadone maintenance therapy (MMT) for opiate addiction during pregnancy is associated with a number of positive maternal outcomes, including reduced perinatal morbidity, recovery from illicit drug use, and better preparation for parenting (Kandall, Doberczak, Jantunen, & Stein, 1999; McCarthy, Leamon, Parr, & Anania, 2005; Wilson, Desmond, & Wait, 1981). Methadone has potential therapeutic benefit for the developing fetus by minimizing cycles of intoxication and withdrawal associated with variable timing and amounts of illicit opiate use (Kaltenbach, Berghella, & Finnegan, 1998). Maintaining a pregnant woman on methadone continues the opiate-dependent state of the fetus and delays the eventual opiate abstinence syndrome until delivery. There ⁎ Corresponding author. Tel.: +1 916 442 4985. E-mail addresses: [email protected] (J.J. McCarthy), [email protected] (M.H. Leamon), [email protected] (G. Stenson), [email protected] (L.A. Biles). 0740-5472/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.jsat.2007.09.009
has been concern expressed about the frequency and severity of the neonatal abstinence syndrome (NAS), a constellation of central nervous system, gastrointestinal, and metabolic disturbances that occurs in methadone-dependent neonates (Dashe, Jackson, Olsher, Zane, & Wendell, 1998). These symptoms require medication management in 46% to 81% of babies (Doberczak, Kandall, & Friedman, 1993; McCarthy et al., 2005). Babies that require medications are usually hospitalized for 3 to 4 additional weeks after delivery. Although relapse rates as high as 90% have been reported when women are withdrawn from methadone during pregnancy (Luty, Nikolaou, & Bearn, 2003) and not being on MMT has been associated with early treatment dropout (Kissin, Svikis, Moylan, Haug, & Stitzer, 2004), concerns about NAS have led some authors to attempt methadone withdrawal or dose reductions during pregnancy. Luty et al. (2003) reported on 101 women who underwent a 21-day methadone withdrawal and found no increased risk of miscarriage or prematurity. Dashe et al. (1998) reported successful withdrawal from methadone in selected low-risk cases without evidence of fetal distress on sonographic or
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fetal heart rate monitoring. Maas, Katner, Weingart-Jesse, Shafer, and Obladen (1990) reported on 17 women who were successfully withdrawn from heroin using methadone and found that gestational age, birth weight, head circumference, and symptoms of NAS were all improved as compared with a larger number of women who continued to use heroin during the attempted withdrawal. Because all three of these studies had high rates of relapse to illicit drug use and detox failures, the practice remains controversial (Newman, 2004). In a case study reflective of the potential dangers of intrauterine withdrawal, Zuspan, Gumpel, Mejia-Zelaya, Madden, and Davis (1975) used serial amniocenteses during an attempted second-trimester methadone withdrawal and described marked increases in fetal epinephrine and norepinephrine, an apparent stress effect of the withdrawal that was reversed by increasing the maternal methadone dose. These authors also reported knowledge of five intrauterine deaths caused by detoxification during the second and third trimesters. Some earlier studies suggested that higher maternal methadone doses caused more severe NAS (Dashe et al., 2002; Doberczak et al., 1993). More recent studies, across the wider range of doses used in current clinical practice, suggest that this is not the case (Berghella et al., 2003; McCarthy et al., 2005). However, it is possible that the duration of exposure (e.g., initiation of MMT in the first trimester vs. third trimester) or total amount of methadone administered could be associated with more severe NAS or other problems. Most pregnant women receiving MMT begin the therapy after conception, most commonly in the second or third trimester (Dashe et al., 1998; Hagopian et al., 1996). However, women who are already receiving MMT do conceive while on methadone and remain on methadone for the entire pregnancy. There have been many studies of neonatal outcomes for babies of women on MMT. We are aware of only three published studies, however, that looked at outcomes of babies of women who specifically conceived on and maintained on MMT throughout the pregnancy. Kemplova and Okruhlica (2005) compared birth weight, length, and gestational ages of 10 infants conceived on MMT to population norms and found no differences between the two groups. Kandall et al. (1976) compared outcomes of 40 women confirmed to be on methadone during the entire pregnancy with those of heroin users and controls. The birth weights of the methadone-exposed infants were significantly greater than those of infants of heroin-using mothers but less than those of a community control group. These authors also found a correlation between higher methadone doses in the first trimester and higher birth weights. Sharpe and Kushel (2004) used a control group of 24 pregnant patients in MMT that appear to have conceived on methadone in a study of women on short-term methadone treatment for pain. In the MMT patients, they found a median gestational age of 39 weeks and that 58% of the infants required treatment of NAS. The authors state that the “infants born to mothers
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receiving methadone for addiction had very little morbidity.” Although these three studies support the use of MMT in pregnancy in general, only Sharpe and Kushel (2004) examined NAS as an outcome. It is therefore reasonable to ask whether longer or shorter periods of methadone exposure result in differences in severity of NAS. The ideal study for this question would compare babies of women who conceived on methadone, did not use any other drugs, and remained on the medication through delivery with those of women who conceived while abstinent and not on methadone and were then placed on methadone later in the pregnancy. Such a study would clearly not be ethical in addiction treatment, although such a study might be feasible in a pain management setting. Therefore, this study reports on neonatal outcomes, including NAS, for babies of women who conceived and maintained on methadone for the entire pregnancy compared with those for babies of mothers who entered MMT in their second or third trimester. We believe this is the first such study in the English literature.
2. Methods The participants for this analysis are a subgroup of a cohort previously studied for the effect of maternal methadone dose on the severity of neonatal abstinence symptoms. Data for this study were collected between February 1999 and May 2003. All women in the study were enrolled in an MMT program with enhanced pregnancyrelated services that included individual counseling, psychiatric care, weekly random urine drug screens, and coordination with obstetrical care providers. Patients attended a mandatory weekly support group for pregnant and early postpartum women, led by the clinic physician (J.M.) and a pregnancy counselor specialist, which focused on education on methadone dosing, NAS, nursing, drug use effects on the fetus, and other pregnancy-related topics. Methadone doses were individualized and increased in response to either maternal reports of withdrawal symptoms or maternal drug use. All women were maintained on a twice-daily methadone-dosing schedule to achieve more constant maternal and fetal blood levels over 24 hours and prevent any maternal withdrawal symptoms. To maximize the potential for identifying outcome differences based on duration of methadone exposure, we chose to compare two groups with very different levels and timing of methadone exposure: those who conceived on methadone (conceived on) and those who were initiated on methadone in the second and third trimesters (conceived off). Because of the inherent uncertainty in determining the estimated date of conception (EDC), only women who were in MMT 2 or more weeks prior to their EDC were included in the conceived-on methadone group. Women who began MMT at more than 12 weeks from their EDC were included in the conceived-off group. In addition, for both groups, only
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women who remained on MMT continuously through delivery were included. An approximation of total methadone exposure for the two groups was achieved by multiplying the days pregnant on methadone by the average daily dose at delivery. This method overestimates the methadone exposure in both groups to some small degree because after initial stabilization, the methadone dose is at times increased during pregnancy. All infants born to mothers on methadone are considered high risk and are monitored initially in a neonatal intensive care unit. NAS was assessed using the standard Finnegan rating scale, and babies were treated when they had repeated scores above 8 (Finnegan, Kron, Connaughton, & Emich, 1975). The data for this study were collected as part of a routine internal quality improvement program. The institutional review board at the University of California, Davis, approved the study without requiring informed consent. Statistical analyses were carried out using SPSS software (version 12.0; SPSS Inc, Chicago, IL) using a significance cutoff of b.05. Specific analyses included comparison of means via two-tailed independent sample t tests, measures of association via chi-square and Mann–Whitney's U, as well as linear regression analyses. 3. Results Twenty-two participants were in the conceived-on group, and 35 were in the conceived-off group. Ethnic distribution for the whole cohort was as follows: Caucasian, 63%; Hispanic, 25%; African American, 5%; Asian American, 5%; and other, 2%. There were no significant differences in ethnicity between groups. Other maternal demographic variables are presented in Table 1. There were no significant differences for maternal age, methadone dose at delivery, or smoking history. Women who conceived on methadone had a mean continuous exposure to methadone of 104.5 weeks, including their time on methadone prior to conception.
Table 1 Maternal demographics and outcomes
Variables Maternal age at delivery Years of opiate use % smoking on admission Mother's dose at delivery (mg) Total weeks on methadone % positive toxicology during pregnancy ⁎ p b .10. ⁎⁎ p b .05. ⁎⁎⁎ p b .0001.
Conceived on methadone (n = 22)
Conceived off methadone (n = 35)
t tests
34.3 12.7 81.8 110
31.3 7.7 77.1 93
t = 0.44 ⁎ t = 1.84 ⁎⁎ ns ns
104.5 18.8
13.1 40.2
t = 8.04 ⁎⁎⁎ t = 0.08 ⁎
Table 2 Infant outcomes
Variables Weeks on methadone Gestational age (weeks) Birth weight (g) Days hospitalized % treated for NAS % positive toxicology at delivery % nursing
Babies conceived on methadone (n = 22)
Babies conceived off methadone (n = 35)
Statistic
37.4 37.4 2856 16.1 45.5 9.1
13.1 36.7 2622 18.3 51.4 34.3
t = 13.64 ⁎⁎ ns ns ns ns χ2(1) = 4.63 ⁎⁎
54.5
31.4
χ2(1) = 2.99 ⁎
⁎ p b .10. ⁎⁎ p b .05.
Women in the conceived-on group had significantly longer histories of addiction, 12.7 versus 7.7 years (p = .0001). Although weekly urine drug tests were ordered, results were not available if the patient did not provide a sample or if she were incarcerated at the time a sample was to be provided. There was no significant difference between groups in the percentage of samples tested (conceived on = 458 of 491 [93.3%]; conceived off = 343 of 394 [87.1%]). Of 885 possible tests for the entire cohort, 801 samples (90.5%) were collected and tested. For the whole cohort, 72% (n = 577/801) of urine drug screens during pregnancy were negative for illicit drugs. Positive tests were for opiates (19.4%), amphetamines (6.1%), and cocaine (5.9%). Of these positive tests, 4.9% were positive for two drugs. Comparing the groups, 18.2% of tests (n = 86/458) in the conceived-on group were positive for drugs versus 40.2% (n = 138/343) in the conceived-off group (p b .1). For opiate tests specifically, 10.5% of tests (n = 48/458) in the conceived-on group were positive versus 31.2% (n = 107/ 343) in the conceived-off group. Infant outcomes (Table 2) showed significant differences for positive toxicology for illicit drugs at birth. The conceived-on group had significantly fewer positive tests than the conceived-off group (9.1% vs. 34.3%, respectively; p b .05). Twenty-eight babies required treatment for NAS with medications. The percentage of babies treated in the conceived-on group was 45.5% versus 51.4% in the conceived-off group. Specific medications used to treat NAS were paregoric (n = 17), phenobarbital (n = 11), morphine (n = 3), and lorazepam (n = 2). Six babies were treated with two medications. The average birth weight of full-term babies was 3,047 g versus 2,179 g in premature babies. There was a 38.6% (n = 22/57) incidence of prematurity (b37 weeks' gestation) in the infants. There was a 35% incidence (n = 20/57) of low birth weight (b2500 g). Average birth length was 18.58 in. There were no significant intergroup differences in rates of treatment for NAS, birth weight, length, gestational age, or days of infant hospitalization after delivery.
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There were eight mothers in the conceived-on group who had no evidence on weekly drug screens of illicit drug use during the entire pregnancy. The average gestational age of these babies was 38.3 weeks, and the average birth weight was 2,931 g. Five of these women smoked cigarettes. For comparison purposes, local county birth data for comparable years (averages of years 1999–2003) showed an average birth weight of 3,369 g and average gestational age of 40.0 weeks (Sacramento County Department of Public Health, personal communication, 2003). Because smoking has an adverse effect on birth weight and gestational age, even this group with no illicit drug use does not reflect the ideal of methadone-only exposure. Nursing was encouraged in this population, and 40% of the women nursed. There was a trend for a greater percentage of babies breast-fed in the conceived-on group versus the conceived-off group, 54.5% versus 31.4%, respectively (p b .10). Babies conceived on methadone had an approximate total gestational exposure of 28.8 g (110 mg/day × 37.4 weeks). Those in the conceived-off group had an approximate exposure of 8.5 g (93 mg/day × 13.1 weeks). The conceived-on group had approximately 20 g greater methadone exposure and an average duration of exposure 24.3 weeks longer.
4. Conclusions This study found no evidence that the timing, duration, or total amount of prenatal methadone exposure was associated with increased risk for treatment of neonatal abstinence or for longer hospitalization when compared with a cohort of women placed on methadone in the second and third trimesters. Our study also extends the results of two earlier studies in a similar population showing no adverse effects of extended methadone exposure versus shorter exposure on birth weight or gestational age (Kandall et al., 1976; Kemplova & Okruhlica, 2005). We found a significant difference between groups in infant toxicologies at delivery (p b .05) and a trend for less drug use in the conceived-on group in maternal drug tests during pregnancy (p b .1). Our small sample size may have reduced the statistical significance of the 22% difference between groups in positive maternal drug tests. Mothers who conceived on methadone had less drug use, and babies conceived on methadone were significantly more likely to have negative urine drug screens at delivery, findings that are consistent with the known relationship between duration of substance abuse treatment and positive treatment outcomes (National Institutes of Health, 1997). We did note a 38.6% rate of late preterm births and a 35% incidence of low birth weight in our cohort with no differences between groups. There was a high rate of smoking (81% and 78%) in the two groups, and smoking is associated with both prematurity and low birth weight.
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Kandall et al. (1976) reported that heroin use caused fetal growth retardation and that methadone promoted fetal growth in heroin-exposed babies. These authors also found evidence that the growth-retarding effect of heroin may persist beyond the period of addiction and affect a subsequent pregnancy. There is no evidence from our study that cumulative dose or duration of methadone treatment had any adverse effect on weight or gestational age. The overall rate of breast-feeding in this population was 40%. The conceived-on group was more likely to nurse. Nursing while on methadone is approved by the American Academy of Pediatrics (AAP, 2001) without restrictions on maternal dose based on evidence that the amounts of methadone in milk are very small and unlikely to involve risks (Jansson, Velez, & Harrow, 2004; McCarthy & Posey, 2000). Nursing is the optimal form of infant nutrition providing many health benefits, including benefits specific to drug-exposed babies such as reduction of NAS symptoms and protection against sudden infant death syndrome (AAP, 1982; Ballard, 2002; McVea, Turner, & Peppler, 2000). Our study does not support a need to advise women to reduce doses or duration of treatment during pregnancy to reduce the risks of NAS at delivery or to improve gestational age or birth weight. Withdrawal during pregnancy obviously can reduce the risks of postpartum NAS by precipitating the withdrawal syndrome in utero. It is interesting that none of the authors reporting on the apparent safety of methadone withdrawal during pregnancy report any signs of a fetal abstinence syndrome using routine fetal monitoring (Dashe et al., 1998; Luty et al., 2003; Maas et al., 1990). Jansson, DiPietro, and Elko (2005) have demonstrated differences in fetal movement and heart rate associated with peak and trough maternal methadone serum levels using a fetal actocardiograph to monitor fetal movements and heart rate with more sensitivity than ultrasound visualization, although these mothers were not undergoing withdrawal. It seems likely that fetal behavioral functions would become more abnormal during an actual methadone withdrawal. There may be other biochemical abnormalities in addition to those found by Zuspan et al. (1975). Routine fetal-monitoring measures used may not be sensitive enough to detect evidence of significant behavioral or neuroendocrine changes occurring during an intrauterine withdrawal. Furthermore, because most intrapartum withdrawals are likely to result in relapse or early treatment dropout, such babies may be exposed to two episodes of precipitated abstinence, in utero and after birth, in addition to the potential adverse effects of relapses to illicit drug use. However, a very important factor in decisions about attempted withdrawal from methadone during pregnancy is maternal preference. This is often motivated by fear of the stigma and social disapproval associated with methadone treatment. Information about evidence of the safety and benefits of methadone treatment throughout pregnancy should be part of discussions with women who feel pressured to withdraw during pregnancy.
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In summary, the lack of demonstrable adverse effects on the baby of prolonged gestational exposure to methadone coupled with reduction of risks from illicit drugs from prolonged participation in an MMT program supports continuation of methadone treatment as the standard of care for substance-addicted pregnant women. This study is limited by relatively small numbers with insufficient power to study other variables that might affect neonatal outcome measures, such as the amount of exposure to nicotine, other drugs, or alcohol. Our fetal outcome measures are limited to those that are easily obtainable in the immediate postpartum period. In addition, exposure to counseling and obstetrical care, which may affect outcomes, was not measured. The generalizability of outcomes of this and many studies of pregnant women is limited by small numbers. A more accurate measure of the effects of methadone exposure on the fetus would be in patients who had no drug use for the duration of the pregnancy. We found only eight patients who met this criterion, but five of these women smoked cigarettes, showing how difficult it is to isolate the effects of methadone exposure alone. There was also a significant difference in baseline characteristics between groups in terms of duration of addiction, the potential impact of which is unknown. A large multisite study of this unique population is needed to further assist clinicians in advising women on issues related to methadone and pregnancy. Because methadone is being used with increasing frequency for chronic pain, another group of women will conceive while on methadone. Although the results and implications of this study may not be generalizable to a pain population, as noted by Sharpe and Kushel (2004), it is important that all women placed on methadone for addiction or for chronic pain be given detailed information about the fetal dependence that occurs if they conceive on maintenance therapy. Knowing these risks, physicians should advise on the use of contraception during methadone therapy to avoid this complication. However, some women will choose to conceive on methadone, at times due to previous relapses when not in MMT. The evidence to date suggests that we can safely support such decisions.
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