METHODS: This was a retrospective cohort study of pregnant women with opioid addiction who delivered live-born singletons between April 1990 and April 2001. Inpatient detoxification or outpatient methadone maintenance therapy was offered. Women who had a positive drug screen or whose neonate tested positive for opioids were considered to be supplementing. We evaluated indices of neonatal withdrawal according to the maximum daily methadone dosage in the last week of pregnancy.
RESULTS: Seventy women with opioid addiction were followed. Median methadone dosage was 20 mg (range 0–150 mg), and 32 infants (46%) were treated for narcotic withdrawal. Among women who received less than 20 mg per day, 20–39 mg per day, and at least 40 mg per day of methadone, treatment for withdrawal occurred in 12%, 44%, and 90% of infants, respectively (P < 0.02). Methadone dosage was also correlated with both duration of neonatal hospitalization and neonatal abstinence score (rs = .70 and .73 respectively, both P < .001). Neonates were more likely to experience withdrawal if their mothers were supplementing with heroin, 68% versus 35% (P = .01). Regardless of supplementation, there was a significant relationship between methadone dosage and neonatal withdrawal (P < .05).
CONCLUSION: Maternal methadone dosage was associated with duration of neonatal hospitalization, neonatal abstinence score, and treatment for withdrawal. Heroin supplementation did not alter this dose–response relationship. In selected pregnancies, lowering the maternal methadone dosage was associated with both decreased incidence and severity of neonatal withdrawal.
Each year, more than 7000 infants are born to women who use heroin or methadone.1 Methadone maintenance therapy has been routinely offered to pregnant opioid users since the 1970s. The benefit of methadone was to obviate uncontrolled maternal narcotic withdrawal, which was associated with fetal death.2 Treatment with methadone during pregnancy was also reported to decrease illicit drug use and improve perinatal outcomes, though study findings varied considerably.3–5 Early research suggested an effective methadone dosage during pregnancy of approximately 80–120 mg per day.6 Subsequently, lower dosages were often employed. In recent years, however, heroin has improved in purity and the cost has decreased, such that many pregnant women have required greater amounts of methadone to alleviate withdrawal.3,7
The untoward effect of methadone treatment in pregnancy is neonatal narcotic withdrawal, also called neonatal abstinence.8 Some form of withdrawal occurs in 60%–90% of neonates exposed in utero.9–11 As many as 70% of newborns with neonatal abstinence syndrome have central nervous system irritability, which may progress to seizure activity if untreated. In addition, up to 50% may experience tachypnea, episodes of apnea, poor feeding, and failure to thrive.12 Studies of the relationship between maternal methadone dosage and neonatal withdrawal have had varied results. Some investigators have reported a significant relationship,13,14 even suggesting that withdrawal may be minimized by keeping the methadone dosage below 20 mg/day.15 Others have found no correlation.3,16,17
The controversy surrounding the neonatal consequences of maternal methadone treatment has become particularly problematic: As heroin potency has increased, so has the amount of methadone required to control maternal withdrawal symptoms.7 Given the uncertainty of the relationship of maternal methadone dosage to neonatal withdrawal, reducing the methadone dosage has been advocated. We have found opioid detoxification to be a safe alternative to maintenance therapy in selected women.18 Meanwhile, others have proposed raising the methadone dosage, in an attempt to improve fetal growth, pregnancy duration, and neonatal outcome. Kaltenbach and colleagues have further suggested that lowering the maternal methadone dosage might promote supplemental maternal drug use and increase fetal risk.7
Our objective in this study was to evaluate the relationship between maternal methadone dosage and various indices of neonatal narcotic withdrawal. We also sought to evaluate heroin supplementation among methadone users according to the methadone dosage received, to determine how such supplementation might affect neonatal withdrawal.
 | MATERIALS AND METHODS |
We conducted a retrospective cohort study of pregnant women with opioid addiction who delivered live-born singletons of at least 25 weeks’ gestation between April 1, 1990 and April 30, 2001. Pregnancies were prospectively followed by the Parkland Hospital Perinatal Intervention Program, a multidisciplinary medical and social case management team of physicians, nurse practitioners, drug counselors, and social workers whose services are available to any pregnant woman in Dallas County with a history of drug use. Through this program, detoxification was offered to pregnant women with otherwise uncomplicated pregnancies who reported use of heroin or other opioid or who were enrolled in methadone maintenance programs. Women were excluded from detoxification if there was evidence of fetal growth restriction (estimated fetal weight below the fifth percentile) or oligohydramnios (amniotic fluid index of 5 cm or less).18 All detoxification was conducted in the hospital using methadone and/or clonidine, according to a previously published protocol that included fetal surveillance after 24 weeks’ gestation.18 Those who elected not to undergo detoxification or who were not able to complete detoxification were maintained on methadone and received all of the program’s support services, including the same antepartum care. This study was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center.
Women were admitted to the hospital for one of two reasons: either they had been using narcotics and were experiencing withdrawal, or they were already on methadone and wanted to undergo detoxification. For the former, methadone was administered whenever there were objective signs of withdrawal, such as nausea, vomiting, abdominal discomfort, or uterine contractions. Methadone was chosen because it has a relatively long half-life (24–36 hours) and effectively blocks cravings without producing intoxication. The usual initial dosage was 20 mg per day, with half in the morning and half at bedtime, given as tablets crushed in orange juice to blind each woman to the amount she was receiving. The methadone dosage was increased 5 mg every 6 hours as needed. If a woman opted for detoxification, the dosage was tapered by no more than 20% every 3 days. For the latter group, those already on methadone maintenance, the detoxification protocol was started at the maintenance dosage. Clonidine was offered only to those who reported sporadic opioid use and had mild cravings, for the purpose of alleviating withdrawal symptoms produced by noradrenergic hyperactivity. A 0.2-mg transdermal dosage of clonidine was supplemented by 0.1 mg orally every 4–6 hours. Women were observed in the hospital for several days after all medication was discontinued. Those who did not elect detoxification, were unable to complete detoxification, or who returned to heroin use were maintained on outpatient methadone therapy.
At each prenatal visit following discharge, nurse practitioners and drug counselors from the Perinatal Intervention Program saw each woman in conjunction with obstetricians. Toxicology screens were performed periodically, particularly when there was suspicion (or admission) of intercurrent drug use, a missed prenatal appointment, or sign of intoxication. For study purposes, any woman who admitted to heroin use, had a positive toxicology screen for opioids other than methadone, or whose neonate tested positive for opioids other than methadone, was considered to be supplementing.
Neonates remained hospitalized for 5–7 days for observation. This period was selected because of methadone’s relatively long half-life. The decision to treat with paregoric, phenobarbital, or neonatal opium solution was left to the discretion of the attending pediatrician. Neonates were evaluated using the neonatal abstinence score.8 The neonatal abstinence score is made up of three components: central nervous system disturbances, metabolic–vasomotor–respiratory disturbances, and gastrointestinal disturbances, each of which has between three and eight subscales, scored 0 to 1 through 8 (depending on the subscale). Typically, a score exceeding 8 on two occasions was the indication for treatment. Various indices of neonatal withdrawal were evaluated, including need for treatment, duration of hospitalization, and maximum neonatal abstinence score. These outcomes were correlated with the maximum maternal methadone dosage in the last week of pregnancy. For the neonate with signs of withdrawal, hospitalization was continued while the infant was slowly weaned from drug therapy and social evaluation was completed. The infant was discharged when remaining free of withdrawal for 1–2 days off of therapy.
To facilitate comparisons, pregnancies were stratified according to methadone dosage, using three comparably sized groups of less than 20 mg per day, 20–39 mg per day, and 40 mg per day or more. Withdrawal was also evaluated according to whether the woman was considered to be supplementing with heroin. Other outcomes included preterm birth, birth weight below the tenth percentile for gestational age,19 cesarean delivery, meconium-stained amniotic fluid, 5-minute Apgar score below 7, and neonatal toxicology. Statistical analyses were performed using 
2, analysis of variance, Mantel-Haenszel 2 for trend,20 Spearman correlation coefficient, and Kruskal-Wallis test, where appropriate. P values < 0.05 were judged statistically significant.
| RESULTS |
Seventy pregnancies were followed by the Perinatal Intervention Program during the study period. Twenty-seven women (39%) underwent opioid detoxification, and 43 (61%) chose methadone maintenance. The median daily methadone dosage (maximum for the week prior to delivery) was 20 mg, ranging from none to 150 mg.
Maternal demographic characteristics are presented in Table 1
, stratified by maximum methadone dosage in the week prior to delivery. Seventy-nine percent of the group tested was positive for hepatitis C virus, and 77% reported a history of cocaine use. No differences were noted between the methadone dosage groups with respect to maternal age, ethnicity, hepatitis C seropositivity, or reported substance abuse history. Women receiving higher methadone dosages, however, were significantly more likely to be supplementing with heroin (P = .04).
(graph TABLE 1, view at website)
Selected pregnancy and neonatal outcomes are shown in Table 2, again stratified by maternal methadone dosage. No differences were noted between dosage groups with respect to gestational age at delivery, preterm birth, birth weight, cesarean delivery, meconium staining of the amniotic fluid, or low Apgar score. No infant suffered meconium aspiration syndrome. Increasing methadone dosage was significantly associated with birth weight below the tenth percentile, positive neonatal toxicology screen for opioids, and positive neonatal toxicology screen for cocaine (all P < .05).
(graph 2)
Indices of neonatal withdrawal are presented in Table 3 and Figures 1 and 2. Overall, 46% of neonates were treated for withdrawal, increasing from 12% whose mothers received less than 20 mg per day of methadone to 90% whose mothers received 40 mg per day or more. Among the 25 women who received less than 20 mg per day of methadone, only three infants were treated for withdrawal; moreover, in each case the woman had completed opioid detoxification less than 48 hours prior to delivery. As shown in Figures 1 and 2, both the maximum neonatal abstinence score and duration of neonatal hospitalization were significantly correlated with increasing maternal methadone dosage.
(graph 3)
Twenty-two women (31%) were found to be supplementing with heroin, and their neonates were more likely to require treatment for withdrawal, 68% compared with 35% of those with no evidence of illicit heroin use. Higher maternal methadone dosage was significantly associated with treatment for neonatal abstinence syndrome among infants whose mothers supplemented with opioids as well as among those with no evidence of supplementation (both P < .05). Regardless of opioid supplementation, the rate of treatment for withdrawal was more than 80% if the mother had received at least 40 mg per day of methadone.
| DISCUSSION |
We found a significant correlation between the amount of methadone a pregnant woman receives shortly before delivery and her neonate’s likelihood of withdrawal. This topic has been controversial for more than a quarter century, with a number of investigators unable to demonstrate any dose–response relationship,3,9,10,16,17 and others reporting results similar to ours.13–15 A MEDLINE search from 1996 through 2001 for the terms "methadone" and "pregnancy" confirms that this is the largest series to date in which detoxification was conducted with fetal heart rate monitoring. Because we were able to evaluate methadone detoxification in a controlled setting, our encouraging results may counter a commonly held opinion—that maintenance is preferable to any detoxification.21 We hope this information may be useful for counseling pregnant women enrolled in methadone maintenance programs, particularly those women who are motivated to decrease their methadone usage.
The relationship between methadone dosage and illicit heroin abuse is particularly important whenever detoxification is considered. In our cohort, 31% of pregnant women resorted to heroin supplementation, similar to 37% in a series by Berghella and colleagues ( Berghella V, Lim P, Cherpes J, Hill MK, Kaltenbach K, Wapner RJ. Maternal methadone dose and neonatal withdrawal [abstract]. Am J Obstet Gynecol 2000;182:S154) and 41% reported by Brown et al.3 Interestingly, we found heroin supplementation to be more common among women receiving greater amounts of methadone. These women may have had the most severe addiction, as they were unable to refrain from heroin despite higher methadone dosages. We suspect that, once women were found to be supplementing, the methadone dosage was also increased. Traditionally, there has been concern that decreasing a woman’s methadone dosage may make her more likely to abuse heroin. In our series, however, women able to undergo detoxification or tapering of their methadone to less than 20 mg per day were the least likely to be supplementing with heroin. All of these pregnancies were provided with intensive medical and social support, which may have kept supplemental drug use to a minimum.
In attempting to establish a relationship between maternal methadone dosage and neonatal withdrawal, the dosage range is likely a key factor. For example, Brown et al followed 32 pregnancies in methadone users and found no significant difference in neonatal withdrawal when women receiving at least 50 mg per day of methadone were compared with those receiving a lower dosage.3 Berghella et al ( Berghella V, et al. Am J Obstet Gynecol 2000;182:S154) found no difference in likelihood of neonatal withdrawal when comparing infants whose mothers received more than 80 mg per day of methadone with those who received less. In our cohort, women were frequently on lower dosages of methadone, which may reflect a combination of milder habit and the fact that our group encourages methadone tapering and detoxification. Our findings are similar to a series of 110 pregnancies published 25 years ago by Madden et al, in which neonatal withdrawal occurred in 18% of infants with maternal methadone dosage below 20 mg but developed in 63% when the methadone dosage was higher.15 In a study of 21 cases, Doberczak et al also found a significant relationship between the maternal methadone dosage and neonatal plasma methadone level, and between the decline in neonatal methadone level and severity of withdrawal.13 The mean maternal methadone dosage in that series was only 47 mg per day, with a range of 20–80 mg.13
Other limitations of this series are of note. Because it was retrospective, it was neither blinded nor randomized. Decisions regarding duration of neonatal hospitalization, need for treatment, and neonatal abstinence score are generally considered to be objective, but clinicians were aware of maternal drug use and methadone dosage. Unfortunately, we do not have information about pregnancies not delivered in our hospital; however, because we are the county hospital, it is likely that the majority of narcotic users delivered with us. Our study did not address heroin users not on methadone, and so if women left methadone programs altogether and used heroin we would not have been able to assess them. In addition, to obtain a fairly large number of pregnancies, the series spanned a decade, during which time both the amount of methadone and the aggressiveness of neonatal withdrawal treatment have tended to increase; however, our results concur with series in which neonatal methadone levels were considered, and the likelihood of neonatal withdrawal in our study is comparable to that reported by others at similar dosages.3,13
Based on our findings, we continue to recommend detoxification and tapering of methadone dosage to motivated pregnant women, in an effort to decrease the incidence and severity of neonatal withdrawal. (!!)
*I will continue to post more studies as the blog gets up and running!!! Anyone considering a taper must know that they are going up against severe "group think" from clinic personnel, and you will be assumed to be uneducated unless you come armed with your own research!!
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MATERIALS AND METHODS
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