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Neonatal abstinence syndrome in methadone-exposed infants is altered by level of prenatal tobacco exposure
Drug and Alcohol Dependence 75 (2004) 253–260
Neonatal abstinence syndrome in methadone-exposed infants is altered by level of prenatal tobacco exposure Robin E. Choo a , Marilyn A. Huestis a , Jennifer R. Schroeder b , Angela S. Shin a , Hendrée E. Jones c,d,∗ a
c
Chemistry and Drug Metabolism Section, Clinical Pharmacology and Therapeutics Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institute of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224-6823, USA b Treatment Section, Clinical Pharmacology and Therapeutics Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institute of Health, Baltimore, MD 21224-6823, USA Center for Addiction and Pregnancy, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, D4 East 442, Baltimore, MD 21224-6823, USA d Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21224-6823, USA Received 4 September 2003; received in revised form 10 March 2004; accepted 15 March 2004
Abstract Maternal tobacco consumption during pregnancy has been associated with lower birth weight infants, preterm births, intrauterine growth retardation, smaller head circumference and increase in morbidity, yet few studies have examined the role tobacco has on the opiate neonatal abstinence syndrome (NAS). This study examined the effect of prenatal tobacco exposure on NAS for infants born to mothers maintained on methadone during gestation. Twenty-nine pregnant women and their newborn infants participated in this study. Tobacco exposure was based on maternal self-report with 16 women reporting cigarette consumption of 10 or less per day and 13 reporting smoking 20 cigarettes or more a day. The onset, peak, and duration of NAS were examined. Results showed that infants born to mothers who reported smoking 20 or more cigarettes per day had significantly higher NAS peak scores of 9.8 versus 4.8, and took longer to peak (113.0 h versus 37.8 h), than light smokers of 10 or fewer cigarettes per day. We concluded that tobacco use in conjunction with methadone plays an important role in the timing and severity of NAS in prenatally exposed infants. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Perinatal; Methadone; Nicotine; Withdrawal
1. Introduction Opioid dependence during pregnancy is a growing concern in today’s society, especially since the non-medical use of analgesics is rapidly increasing among women in their childbearing years. While methadone remains the recommended treatment for illicit opioid dependence based on its low teratogenic potential and association with improved birth outcome (Kandall et al., 1976; Connaughton et al., 1977; Finnegan, 1991; Kaltenbach and Finnegan, 1986), it is not without disadvantages. Of most concern is the risk that the neonate will undergo neonatal abstinence syndrome (NAS). NAS is characterized by signs and symptoms indicated by dysfunction of the autonomic nervous system, ∗ Corresponding author. Tel.: +1-410-550-7684; fax: +1-410-550-7687. E-mail address: [email protected] (H.E. Jones).
gastrointestinal tract, and respiratory system (Kaltenbach and Finnegan, 1989; Connaughton et al., 1975; Blinick et al., 1969). While the association between methadone dose and NAS has been examined, the literature is inconsistent, with eight studies suggesting a relationship between methadone dose and NAS (Dashe et al., 2002; Malpas et al., 1995; Doberczak et al., 1991; Doberczak et al., 1993; Harper et al., 1977; Madden et al., 1977; Strauss et al., 1976; Ostrea et al., 1976) and eight studies suggesting no relationship (Brown et al., 1998; Hagopian et al., 1996; Mack et al., 1991; Stimmel et al., 1982–83; Newman et al., 1975; Rosen and Pippenger, 1976; Rosen and Pippenger, 1975; Blinick et al., 1973). This inability to establish a clear dose–response relationship between methadone dose and NAS severity may be due to other factors, such as tobacco exposure that may contribute to the severity of NAS. As is true for opiates, abrupt cessation of chronic nicotine administration is associated with a withdrawal syndrome
0376-8716/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.drugalcdep.2004.03.012
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in adults. Symptoms include dysphoria or depressed mood, insomnia, irritability, anxiety, difficulty concentrating, restlessness, and decrease in heart rate (Heishman, 1999). Some of these symptoms are similar to those seen during opiate withdrawal (Martin et al., 1973). Similar to adults, it appears that neonates who undergo abrupt discontinuation of prenatal tobacco exposure also display withdrawal signs. Compared to controls, tobacco-exposed neonates have heightened Moro (startle) reflex, tremors, and impaired neonatal habituation, orientation, consolability, autonomic regulation, orientation to sound, and gastrointestinal and visual disturbances (Picone et al., 1982; Law et al., 2003). These signs are similar to those seen with opiate induced NAS (Finnegan et al., 1975). The withdrawal associated with tobacco exposure also appears to be dose-related, since neonatal abstinence was seen in women who were heavy smokers (i.e., consumed greater than 20 cigarettes/day) (Garcia-Algar et al., 2001). Most recently, the neurobehavioral alterations associated with abrupt cessation of in utero tobacco exposure following delivery have been reported when women smoked as few as 6.7 cigarettes/day (Law et al., 2003). Although prenatal exposure and abrupt cessation of both methadone and tobacco appear to produce withdrawal symptomatology, as yet no study has directly examined the role that the degree of tobacco exposure may have on NAS symptomatology in neonates of methadone-treated mothers. Given that approximately 90% of pregnant women treated with methadone report cigarette smoking during pregnancy (Svikis et al., 1997; Haug et al., 2001; Tuten et al., 2003), it is important to examine the role tobacco exposure plays in NAS associated with methadone. This study examines neonatal withdrawal in infants born to mothers maintained on methadone for their opiate addiction and who also smoked cigarettes during their pregnancy. This study specifically examines the onset, duration, and peak effects of neonatal withdrawal for infants born to mothers who were classified as either light or heavy smokers based on self-reported tobacco use at the time of enrollment into the study and at delivery.
2. Methods 2.1. Participants Thirty-eight pregnant women were recruited from the Center for Addiction and Pregnancy between June 2000 and July 2001. This project, part of a larger clinical trial, was approved by the Johns Hopkins Bayview Medical Center (JHBMC) and the National Institute on Drug Abuse (NIDA) Institutional Review Boards. All participants provided written informed consent and were compensated for their participation. Included in the study were women who (1) had a DSM-IV diagnosis of current opioid dependence and were treated with methadone pharmacotherapy (mean dose 77.0 mg/day ± 19.4) and (2) were less than 28 weeks
pregnant. A total of nine women were excluded from the study for either fetal demise (n = 2), not being methadone maintained (n = 2) or being non-smokers (n = 5). The 29 mother-infant dyads were divided into two groups based on maternal self-reported smoking habits. Light smokers (LS) (n = 16, 55%) were women who reported cigarette consumption of half a pack (i.e., 10 cigarettes/day) or less per day (mean 8.4 cigarettes/day ± 2.3), and had a mean smoking history of 201.6 months ± 72.0, range 36–288 months. Heavy smokers (HS) (n = 13, 45%) were women who reported smoking equal to (i.e., 20 cigarettes/day) or more than a pack a day (mean 21.5 cigarettes/day ± 5.5) and had a mean smoking history of 164.0 months ± 78.5, range 12–288 months. This light versus heavy smoking categorization is based on results of previous research (Kallén, 2001). Since we found the mean number of cigarettes smoked per day for the light group to be 8 and 21 for the heavy smoking group, we adopted similar cutoffs. Smoking histories were not significantly different between the two groups (t(27) = −1.59, P = 0.12). Since no significant differences were observed on baseline characteristics between the LS and HS, those from the overall sample are presented. The total sample mean age was 30 years ± 5.7, with a mean of 11 years of education ± 1.9, 88% were African American, 86% were single and 86% were unemployed. Medical co-morbid conditions included hepatitis C (38%), hepatitis B (14%), syphilis (10%), HIV (6%), and anxiety treatment with fluoxetine (17%). Concurrent drug use at the onset of the study was evident by urine toxicology screens and self-report for cocaine (93%), benzodiazepine (17%), ethanol (10%), and marijuana (10%). Participants enrolled in treatment at a mean estimated gestational age (EGA) of 17.1 ± 5.8 weeks and a mean dose of methadone at delivery of 75.6 mg/day ± 22.9 for LS and 78.8 mg/day ± 14.9 for HS. 2.2. Setting Participants were enrolled at the Center for Addiction and Pregnancy (CAP), a specialized comprehensive drug treatment facility for pregnant and recent post-partum women. Treatment included an initial seven-day residential stay followed by intensive outpatient treatment, observed urine drug screens, and daily methadone dosing. Ancillary services including obstetrical, medical, psychiatric, and pediatric care were provided (Jansson et al., 1996). 2.3. Procedure Participants were recruited for this study during the first days of their CAP residential treatment and were followed throughout pregnancy. Participants were expected to attend daily group sessions and weekly individual counseling. Methadone dosing occurred daily in late afternoon, or in the early morning and late afternoon for those on a split-dosing schedule. Primary care providers and CAP staff recorded participants’ smoking history at the time of enrollment and
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during the post-partum hospital stay. Smoking histories were obtained by questionnaires and interviews. Treatment (e.g., methadone pharmacotherapy and urine toxicology) and delivery outcome data were extracted from maternal and neonatal medical charts. 2.4. Outcome measures 2.4.1. Urine drug testing Observed urine specimens were collected every Monday, Wednesday, and Friday by CAP staff. The number of maternal prenatal urine specimens obtained was 1222 out of a possible 1644 specimens (74%). The number of urine specimens collected per participant depended on the duration of time enrolled in the study. On site urine analysis for opiates and cocaine was performed with the Abuscreen On-Trak Rapid Assays for Drug Abuse (Roche Diagnostic Systems® Indianapolis, Indiana). The cutoff for positive specimens was 300 ng/mL for cocaine (benzoylecogonine) and illicit opiates (morphine). Presumed positive specimens were confirmed by gas chromatography–mass spectrometry at an off-site certified drug laboratory. In addition, weekly random comprehensive drug screens were performed using thin layer chromatography (TLC) or enzyme multiplied immunoassay technique (EMIT). The compounds identified by TLC included: quinine (cutoff 200 ng/mL); ativan/dalmane, benzodiazepines, clonazepam and valium (cutoff 300 ng/mL); morphine (cutoff 500 ng/mL); barbiturates, codeine, dilaudid, meprobamate, PCP, phenmetrazine, phenobarbital (cutoff 1000 ng/mL); and amitriptyline/nortriptyline, demerol, doxepin, glutethimide, hydrocodone, hydroxyzine, imipramine, LAAM, methadone, morphine, and propoxyphene (cutoff 200 ng/mL). Cannabinoids (cutoff 100 ng/mL), cocaine (cutoff 300 ng/mL), and amphetamines (cutoff 1000 ng/mL) were detected using EMIT. The JHBMC laboratory performed maternal and infant drug screens at delivery or shortly thereafter. Specimens were screened using BioRad Liquichek Immunoassay (RioRad Laboratories® Hercules, California) for cannabinoids (cutoff 50 ng/mL), barbiturates and benzodiazepines (cutoffs 200 ng/mL), and cocaine and opiates (cutoffs 300 ng/mL). 2.4.2. Maternal delivery measures All maternal delivery measures were abstracted from the medical records as noted by the midwife/physician and nursing staff. EGA at delivery was based on the first day of the last menstrual cycle and calculated by the primary care provider and adjusted, if needed, after confirmation by ultrasound around the 20th week of gestation. Prematurity was defined as any infant born before 37 weeks of gestation. Type of birth (vaginal or cesarean section), and maternal urine toxicology (tested for opioids, cocaine, barbiturates, and benzodiazepines) were also collected. Maternal hospital stay was calculated from the date of maternal admission to the date of discharge.
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2.4.3. Birth outcome measures The birth weight (g), length (cm), head circumference (cm), and urine toxicology results were obtained at birth. Apgar scores were obtained at 1 and 5 min after birth, rating color, muscle tone, heart rate, respiratory effort, and reflex with a possible score ranging from 0 to 10. The need for specialized care (i.e., any night spent in the Neonatal Intensive Care Unit (NICU)) and length of NICU stay also were obtained from the medical records. Total length of hospital stay was calculated from the date of birth to the date of discharge. 2.4.4. NAS assessment Nursing staff on the post-partum unit assessed neonatal withdrawal every 4–12 h, depending on the intensity of withdrawal, during the first 4 days of life or until discharge from the hospital. Symptoms were recorded using a modified Finnegan neonatal abstinence syndrome scale (Kaltenbach and Finnegan, 1986). The minimum NAS score is zero and indicates no signs of withdrawal. The maximum obtainable score is 42. The NAS score is based on excessive crying, sleep habits, reflex, undisturbed, and disturbed tremors, muscle tone, excoriation, generalized seizure, fever, frequent yawning, sweating, nasal stuffiness, sneezing, tachypnea, poor feeding, vomiting, loose stools, failure to thrive, and excessive irritability. NAS was examined in several ways. First, the frequencies of NAS were tallied for each infant during the observation period. Each sign or symptom was given a score based on its presence and severity, with higher scores given for more severe symptoms. Infants were treated for withdrawal with tincture of opium medication if the infant scored 8 or above at any two consecutive time points. Second, the NAS peak score was based on the highest score recorded by the staff during the infant’s hospital stay. Third, the time to peak withdrawal was calculated from the time of birth to the time of the peak score. Fourth, the duration of NAS was calculated from the time of the first symptoms of withdrawal until the NAS score was 0 or the infant was discharged from the hospital. 2.4.5. Data analysis Participants were divided into light smokers (≤10 cigarettes/day) and heavy smokers (≥20 cigarettes/day). Two-sample t-tests were used to determine whether the following outcome variables were associated with smoking status (light or heavy): NAS peak score, onset time, and duration; gestational age at delivery; methadone dose; and birth weight and head circumference. Analysis of covariance (ANCOVA) was used to assess the relationship between smoking status and each birth outcome after adjusting for possible confounders. The covariates examined were those that could be associated with both smoking status and outcomes and thus confound the relationships: maternal age and ethnicity, maternal drug use, and maternal length of stay. Gestational age was included as a covariate for the outcome variables birth weight and head circumference; both gestational age and neonate opiate-positive at
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birth were included as covariates for the NAS outcome variables. Since premature delivery can affect NAS signs, the analyses using NAS variables as outcome measures were re-run for the subgroup of 19 participants whose babies were born at full term (gestational age at delivery was at least 37 weeks). Two-tailed tests of significance were used with a Type I error rate = 0.05; P-values greater than 0.05 but less than 0.10 are reported as trends. All analyses were conducted using SAS version 8.2.
3. Results 3.1. Urine drug testing results during treatment The average number of weeks enrolled in the study prior to delivery was similar for the groups: 20.1 ± 5.5 weeks and 17.3 ± 6.7 weeks for light and heavy smokers, respectively. The proportions of possible urine specimens obtained during treatment were also similar for both groups. The LS provided 73% of possible specimens with 21% positive for opiates and/or cocaine, compared to 81% of possible specimens with 17% positive for opiates and/or cocaine in the HS. No LS maternal urine samples were positive for barbiturates and/or benzodiazepines; however, HS had 8% positive for barbiturates and/or benzodiazepines. 3.2. Maternal delivery Mean gestational age at delivery was similar for LS (36.8 ± 4.3 weeks) and HS (38.3 ± 3.6 weeks) and not statistically different (t(27) = 1.03, P = 0.31). Two LS participants had a prior history of premature delivery and delivered their infants at 26 and 28 weeks. Four women in each group delivered between 30 and 37 weeks of gestation; therefore, 34% of the total study sample delivered prematurely. Three women (19%) in the LS group underwent cesarean sections while the rest of the women in both groups had vaginal deliveries. Maternal urine samples at the time of delivery were positive for illicit opioids (13 and 25% for LS and HS groups, respectively), for cocaine (20% for LS, 17% for HS), barbiturates (0% for LS, 8% for HS), and benzodiazepines (0% for LS, 8% for HS). There was no significant difference (t(27), P = 0.66) between the two groups regarding delivery toxicology. The average maternal hospital stay was not significantly different (t(27), P = 0.21) between the two groups with a mean stay of 5.2 ± 5.2 and 3.6 ± 1.2 days for light and heavy smokers, respectively. One participant in the LS group had an extended hospital stay of 24 days due to preterm labor. 3.3. Birth outcome The average birth weight for the LS was 2471.9 ± 853.3 g (range 675–4370 g) and 2784.6 ± 760.5 g (range 1505–4025 g) for the HS. Mean head circumference for
the infants in the LS group was 31.5 ± 2.4 cm (range 25.3–36.0 cm) and 32.3 ± 2.7 cm (range 26.0–35.5 cm) for the HS group. Differences in birth weight and head circumference by smoking amount were not statistically significant, both unadjusted and adjusted for gestational age. Neonatal urine drug screens showed the LS and the HS drug-positive rates of 13 and 31% for opioids, 19 and 23% for cocaine, and 0 and 8% for barbiturates, respectively; all urine specimens in both groups were negative for benzodiazepines. The mean Apgar scores at 1 and 5 min were 7.9 ± 1.6 and 8.7 ± 1.0 for light smokers, and 8.5 ± 0.7 and 8.8 ± 0.4 for heavy smokers, respectively. Three infants in the LS and 4 in the HS were treated in the NICU. For the LS group, the average number of days spent in the NICU was 49 ± 39.8 (range 6–83 days). Admission to the NICU for 2 of the 3 LS infants was due to prematurity (born at 28 and 26 weeks, they stayed 58 and 83 days, respectively). The other LS infant was admitted to the NICU due to a chromosomal abnormality (born at 35.2 weeks and stayed 6 days). The average number of days spent in the NICU for the four HS infants was 13.5 days ± 11.6 (range 3–25 days). One infant was admitted to the NICU due to prematurity (born at 30 weeks) and stayed 25 days. Another infant was admitted due to neonatal withdrawal and stayed 22 days. This infant was the only infant treated with phenobarbital and paregoric in addition to tincture of opium. The other two infants were admitted to the NICU due to meconium aspiration and sepsis and stayed 3 and 4 days, respectively. The average total hospital stay for LS infants was 14.8 days ± 22.6 (range 3–83 days) and 8.5 days ± 7.2 (range 4–26 days) for HS infants; the difference between groups was not statistically significant. 3.4. NAS The frequency of neonatal abstinence signs is presented in Table 1. The signs most frequently noted in LS and HS were disturbed tremors, increased muscle tone and hyperactive Moro reflex. Three infants (19%) from the LS displayed no NAS. However, all of these infants were premature (born at 26.0, 28.0, and 36.5 weeks of gestation), and prematurity can reduce NAS signs compared to those typically found in full term infants (Doberczak et al., 1991). In the LS group, 12.5% of the infants were treated for NAS symptoms and 23% were treated in the HS group. For the full sample (N = 29), mean NAS peak scores were 5.6 ± 3.8 (range 0–13) for LS and significantly higher (P = 0.014) for HS, having a peak score of 9.8±4.8 (range 4–19) (Fig. 1, top panel). There was a significant (P = 0.016) difference in time to peak between the LS (37.8 ± 33.8 h) and the HS (113.8 ± 90.0 h) (Fig. 1, middle panel). After adjusting for gestational age and opiate-positive neonatal toxicology, the association between smoking amount and NAS time to peak remained statistically significant (F(3,20) = 5.88, P = 0.025), while the relationship between smoking amount and NAS peak score represented only a trend
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Table 1 Frequency and percentage of neonatal abstinence syndrome (NAS) signs seen in the light smokers (LS) and heavy smokers (HS) NAS signs
LS Frequency
Percentage
Frequency
Percentage
Disturbed tremors Increased muscle tone Hyperactive moro reflex Undisturbed tremors Fever Sleep <3 h post-feed Marked hyperactive moro reflex Sneezing Stuffiness Sleep <2 h post-feed Tachypnea Excoriation Loose stools Excessive irritability Poor feeding Sweating Sleep <1 h post-feed Vomiting Yawning Generalized seizures Failure to thrive
265 257 124 79 59 53 49 42 32 28 18 16 14 14 10 4 4 4 0 0 0
24.5 23.7 11.4 7.3 5.4 4.9 4.5 3.9 3 2.6 1.7 1.5 1.3 1.3 1.0 0.37 0.37 0.37 0 0 0
495 474 300 163 109 115 11 90 38 63 33 152 62 35 88 26 25 12 18 0 0
20.5 19.6 12.4 6.7 4.5 4.8 0.45 3.7 1.6 2.6 1.4 6.3 2.6 1.4 3.6 1.1 1.0 0.5 0.74 0 0
(F(3,24) = 4.22, P = 0.051). The duration of NAS ranged from 0 to 18 days with a mean of 5.1 ± 4.6 for the LS, and from 4 to 24 days with a mean of 9.5 days ± 7.3 for the HS group; this difference showed a trend towards statistical significance (P = 0.054) (Fig. 1, lower panel). The relationship between smoking amount and NAS duration no longer represented a trend (F(3,24) = 2.35, P = 0.14) after adjusting for gestational age and neonatal opiate-positive toxicology. For the subsample who delivered at full term (N = 19), heavier smoking was significantly associated with a higher NAS peak score (6.8 ± 2.9 for LS, 11.0 ± 5.1 for HS, P = 0.039) as well as longer time to peak (42.9 ± 28.4 h for LS, 116.9 ± 89.9 h for HS, P = 0.042); there was no significant relationship between smoking and duration of NAS (5.9±4.3 days for LS, 10.6±8.7 days for HS, P = 0.15). No NAS variable remained significantly associated with smoking amount after adjusting for gestational age and neonatal opiate toxicology in this subsample.
4. Discussion This paper reports maternal and neonatal outcomes for women who received methadone therapy during pregnancy and were either light (n = 16) or heavy smokers (n = 13). This study showed that, relative to light smoker offspring, neonates of heavy smokers had peak NAS scores that were 57% higher, took 33% longer to peak and had 54% longer duration. The relationship between amount of smoking and NAS peak score and time to peak were statistically significant in the full sample, as well as in the sub-
HS
set of women who delivered at full term (n = 19). The relationship between amount of smoking and time to peak NAS score remained significant after adjusting for gestational age and neonatal opiate toxicology in the full sample; however, no NAS variables remained significantly associated with smoking amount after adjusting for these covariates in the subsample who delivered at full term. Although previous studies have separately examined the effects of tobacco (Garcia-Algar et al., 2001; Law et al., 2003) or methadone (Kaltenbach and Finnegan, 1989; Connaughton et al., 1975; Blinick et al., 1969) on neonatal abstinence, this is the first study to directly examine the role that the level of tobacco exposure may play in methadone-associated NAS. It is also noteworthy that after controlling for gestational age, birth weight between the light (2471.9 g) and heavy (2784.6 g) smokers was not statistically different. Although a clear relationship has been shown between number of cigarettes smoked and decreases in birth weight in non-illicit-drug using women smokers (as few as 6–8 cigarettes/day) (England et al., 2001; Law et al., 2003), the present data suggest that this relationship may not generalize to babies of methadone-treated women. It is possible that this lack of difference in birth weight may be due to the fact that infants in both groups were exposed to tobacco at levels high enough to affect infant birth weight. Another possibility may be that methadone effects override or exacerbate tobacco effects. Alternatively, one study has shown that regardless of tobacco use, increases in birth weight in the drug abusing population, who were receiving treatment, were due to improved nutrition and reduced drug use (Dashe et al., 2002). It is also possible that patterns in smoking topography
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NAS Peak Score
20
*
18 16 14 12 10 8 6 4 2 0 LS
300
Time to Peak (hr)
250
HS
*
200 150 100 50 0 LS
25
HS
NAS Duration (days)
20 15 10 5 0 LS
HS
Fig. 1. Neonatal abstinence syndrome (NAS) parameters for neonates of light (LS) and heavy (HS) smokers. The upper panel shows peak scores, the middle panel shows time to peak and the lower panel shows syndrome duration. (*) P ≤ 0.05.
(i.e., inhalation, nicotine yield, etc.) could have differed between the groups resulting in a similar amount of nicotine and cigarette additives, yielding similar birth weights between light and heavy smokers (Peacock et al., 1991). The present results are both timely and important since a large percentage (90%) of methadone-treated women smoke while pregnant (Svikis et al., 1997; Haug et al., 2001; Tuten et al., 2003), as compared to their non-drug-using counterparts (i.e., 20%) (NIDA, 1996). Given that methadone-treated women also are at elevated risk of adverse birth outcomes compared to non-drug using populations, this population is in dire need of smoking interventions. As yet, little is known about their smoking reduction or quitting behavior during pregnancy. Given these data, it may be that methadone-treated women who are able to reduce smoking to less than 10 cigarettes a day could reduce the incidence and severity of NAS, which carries substantial benefits for the neonate and mother, as well as for society.
It is possible that the level of tobacco smoking may ultimately be a useful predictor of NAS severity in methadoneexposed neonates. Although effort has been devoted to examining the relationship between maternal methadone dose and NAS severity, previous research has not been able to consistently show this association (Dashe et al., 2002; Malpas et al., 1995; Doberczak et al., 1991; Doberczak et al., 1993; Harper et al., 1977; Madden et al., 1977; Strauss et al., 1976; Ostrea et al., 1976; Brown et al., 1998; Hagopian et al., 1996; Mack et al., 1991; Stimmel et al., 1982–83; Newman et al., 1975; Rosen and Pippenger, 1976; Rosen and Pippenger, 1975; Blinick et al., 1973). Possible explanations for the discrepancy in results include restricted methadone dose range, bias in sample selection and lack of control of co-occurring drug exposure. In fact, only 3 of the 16 reports mentioned tobacco use in the description of the participants, and no report described controlling for this important potential confounding factor. Given the present results, level of tobacco exposure may be one critical factor obscuring the relationship between methadone dose and NAS severity. Several limitations should be noted when interpreting these results. First, the addition of an objective measure of maternal tobacco use (i.e., plasma or oral fluid cotinine) would improve the reliability of results and offer an opportunity to explore dose–response relations; however, the fact that dramatic differences in NAS were observed based on self-report of tobacco use, strengthen the confidence in the results and further refinement of smoking status should only enhance the differences observed. Second, repeated measurements of cotinine and methadone blood levels in the neonate at the time of NAS measurement would have provided valuable information to correlate the cotinine and methadone level with NAS symptomatology. This could be especially important since the fetus may be exposed to greater nicotine levels than the mother (Lambers and Clark, 1996; Luck et al., 1985) and NAS severity has been shown to correlate with the declining rate of neonatal plasma methadone level during the first 4 days of life (Doberczak et al., 1993). Third, the addition of a non-smoking methadone-treated comparison group would have added information about the effect that methadone alone has on NAS and allowed for a dose response curve to be established. In addition, maternal self-report can be unreliable. Even though the mothers provided detail accounts of their smoking habits at admission into the study and at the time of delivery, no data was collected on the amount, timing and patterns of nicotine use in the interim. Research has shown that the timing, duration and amount of in utero drug exposure can greatly affect neonatal outcome (Lester et al., 2001). Also, it is possible that other maternal factors not examined in this study may have contributed to the differences observed; however, it should be noted that the two groups did not differ significantly with respect to the baseline characteristics examined. Finally, the relatively small sample size could have reduced statistical power to observe differences in outcome measures associated with smoking: this
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limitation would have been most pronounced in the analysis of the subset of full term infants (N = 19). Replication of these findings in larger samples of methadone-exposed infants is warranted before firm conclusions can be drawn. The results from this study demonstrate the importance of the role that tobacco plays in the timing and severity of NAS of neonates of methadone-treated mothers. Future studies of opioid associated NAS should include the level of tobacco exposure as a variable in the analysis, since this may be a better predictor of NAS severity and need for treatment than the methadone dose alone.
Acknowledgements This study was supported by the National Institute on Drug Abuse Extramural Research Grant DA12403-02 and intramural research funds. We would like to acknowledge the staff at the Center for Addiction and Pregnancy, and labor & delivery and post-partum ward at Johns Hopkins Bayview Medical Center for all of their assistance during the course of this study.
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Neonatal abstinence syndrome in methadone-exposed infants is altered by level of prenatal tobacco exposure Robin E. Choo a , Marilyn A. Huestis a , Jennifer R. Schroeder b , Angela S. Shin a , Hendrée E. Jones c,d,∗ a
c
Chemistry and Drug Metabolism Section, Clinical Pharmacology and Therapeutics Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institute of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224-6823, USA b Treatment Section, Clinical Pharmacology and Therapeutics Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institute of Health, Baltimore, MD 21224-6823, USA Center for Addiction and Pregnancy, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, D4 East 442, Baltimore, MD 21224-6823, USA d Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21224-6823, USA Received 4 September 2003; received in revised form 10 March 2004; accepted 15 March 2004
Abstract Maternal tobacco consumption during pregnancy has been associated with lower birth weight infants, preterm births, intrauterine growth retardation, smaller head circumference and increase in morbidity, yet few studies have examined the role tobacco has on the opiate neonatal abstinence syndrome (NAS). This study examined the effect of prenatal tobacco exposure on NAS for infants born to mothers maintained on methadone during gestation. Twenty-nine pregnant women and their newborn infants participated in this study. Tobacco exposure was based on maternal self-report with 16 women reporting cigarette consumption of 10 or less per day and 13 reporting smoking 20 cigarettes or more a day. The onset, peak, and duration of NAS were examined. Results showed that infants born to mothers who reported smoking 20 or more cigarettes per day had significantly higher NAS peak scores of 9.8 versus 4.8, and took longer to peak (113.0 h versus 37.8 h), than light smokers of 10 or fewer cigarettes per day. We concluded that tobacco use in conjunction with methadone plays an important role in the timing and severity of NAS in prenatally exposed infants. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Perinatal; Methadone; Nicotine; Withdrawal
1. Introduction Opioid dependence during pregnancy is a growing concern in today’s society, especially since the non-medical use of analgesics is rapidly increasing among women in their childbearing years. While methadone remains the recommended treatment for illicit opioid dependence based on its low teratogenic potential and association with improved birth outcome (Kandall et al., 1976; Connaughton et al., 1977; Finnegan, 1991; Kaltenbach and Finnegan, 1986), it is not without disadvantages. Of most concern is the risk that the neonate will undergo neonatal abstinence syndrome (NAS). NAS is characterized by signs and symptoms indicated by dysfunction of the autonomic nervous system, ∗ Corresponding author. Tel.: +1-410-550-7684; fax: +1-410-550-7687. E-mail address: [email protected] (H.E. Jones).
gastrointestinal tract, and respiratory system (Kaltenbach and Finnegan, 1989; Connaughton et al., 1975; Blinick et al., 1969). While the association between methadone dose and NAS has been examined, the literature is inconsistent, with eight studies suggesting a relationship between methadone dose and NAS (Dashe et al., 2002; Malpas et al., 1995; Doberczak et al., 1991; Doberczak et al., 1993; Harper et al., 1977; Madden et al., 1977; Strauss et al., 1976; Ostrea et al., 1976) and eight studies suggesting no relationship (Brown et al., 1998; Hagopian et al., 1996; Mack et al., 1991; Stimmel et al., 1982–83; Newman et al., 1975; Rosen and Pippenger, 1976; Rosen and Pippenger, 1975; Blinick et al., 1973). This inability to establish a clear dose–response relationship between methadone dose and NAS severity may be due to other factors, such as tobacco exposure that may contribute to the severity of NAS. As is true for opiates, abrupt cessation of chronic nicotine administration is associated with a withdrawal syndrome
0376-8716/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.drugalcdep.2004.03.012
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in adults. Symptoms include dysphoria or depressed mood, insomnia, irritability, anxiety, difficulty concentrating, restlessness, and decrease in heart rate (Heishman, 1999). Some of these symptoms are similar to those seen during opiate withdrawal (Martin et al., 1973). Similar to adults, it appears that neonates who undergo abrupt discontinuation of prenatal tobacco exposure also display withdrawal signs. Compared to controls, tobacco-exposed neonates have heightened Moro (startle) reflex, tremors, and impaired neonatal habituation, orientation, consolability, autonomic regulation, orientation to sound, and gastrointestinal and visual disturbances (Picone et al., 1982; Law et al., 2003). These signs are similar to those seen with opiate induced NAS (Finnegan et al., 1975). The withdrawal associated with tobacco exposure also appears to be dose-related, since neonatal abstinence was seen in women who were heavy smokers (i.e., consumed greater than 20 cigarettes/day) (Garcia-Algar et al., 2001). Most recently, the neurobehavioral alterations associated with abrupt cessation of in utero tobacco exposure following delivery have been reported when women smoked as few as 6.7 cigarettes/day (Law et al., 2003). Although prenatal exposure and abrupt cessation of both methadone and tobacco appear to produce withdrawal symptomatology, as yet no study has directly examined the role that the degree of tobacco exposure may have on NAS symptomatology in neonates of methadone-treated mothers. Given that approximately 90% of pregnant women treated with methadone report cigarette smoking during pregnancy (Svikis et al., 1997; Haug et al., 2001; Tuten et al., 2003), it is important to examine the role tobacco exposure plays in NAS associated with methadone. This study examines neonatal withdrawal in infants born to mothers maintained on methadone for their opiate addiction and who also smoked cigarettes during their pregnancy. This study specifically examines the onset, duration, and peak effects of neonatal withdrawal for infants born to mothers who were classified as either light or heavy smokers based on self-reported tobacco use at the time of enrollment into the study and at delivery.
2. Methods 2.1. Participants Thirty-eight pregnant women were recruited from the Center for Addiction and Pregnancy between June 2000 and July 2001. This project, part of a larger clinical trial, was approved by the Johns Hopkins Bayview Medical Center (JHBMC) and the National Institute on Drug Abuse (NIDA) Institutional Review Boards. All participants provided written informed consent and were compensated for their participation. Included in the study were women who (1) had a DSM-IV diagnosis of current opioid dependence and were treated with methadone pharmacotherapy (mean dose 77.0 mg/day ± 19.4) and (2) were less than 28 weeks
pregnant. A total of nine women were excluded from the study for either fetal demise (n = 2), not being methadone maintained (n = 2) or being non-smokers (n = 5). The 29 mother-infant dyads were divided into two groups based on maternal self-reported smoking habits. Light smokers (LS) (n = 16, 55%) were women who reported cigarette consumption of half a pack (i.e., 10 cigarettes/day) or less per day (mean 8.4 cigarettes/day ± 2.3), and had a mean smoking history of 201.6 months ± 72.0, range 36–288 months. Heavy smokers (HS) (n = 13, 45%) were women who reported smoking equal to (i.e., 20 cigarettes/day) or more than a pack a day (mean 21.5 cigarettes/day ± 5.5) and had a mean smoking history of 164.0 months ± 78.5, range 12–288 months. This light versus heavy smoking categorization is based on results of previous research (Kallén, 2001). Since we found the mean number of cigarettes smoked per day for the light group to be 8 and 21 for the heavy smoking group, we adopted similar cutoffs. Smoking histories were not significantly different between the two groups (t(27) = −1.59, P = 0.12). Since no significant differences were observed on baseline characteristics between the LS and HS, those from the overall sample are presented. The total sample mean age was 30 years ± 5.7, with a mean of 11 years of education ± 1.9, 88% were African American, 86% were single and 86% were unemployed. Medical co-morbid conditions included hepatitis C (38%), hepatitis B (14%), syphilis (10%), HIV (6%), and anxiety treatment with fluoxetine (17%). Concurrent drug use at the onset of the study was evident by urine toxicology screens and self-report for cocaine (93%), benzodiazepine (17%), ethanol (10%), and marijuana (10%). Participants enrolled in treatment at a mean estimated gestational age (EGA) of 17.1 ± 5.8 weeks and a mean dose of methadone at delivery of 75.6 mg/day ± 22.9 for LS and 78.8 mg/day ± 14.9 for HS. 2.2. Setting Participants were enrolled at the Center for Addiction and Pregnancy (CAP), a specialized comprehensive drug treatment facility for pregnant and recent post-partum women. Treatment included an initial seven-day residential stay followed by intensive outpatient treatment, observed urine drug screens, and daily methadone dosing. Ancillary services including obstetrical, medical, psychiatric, and pediatric care were provided (Jansson et al., 1996). 2.3. Procedure Participants were recruited for this study during the first days of their CAP residential treatment and were followed throughout pregnancy. Participants were expected to attend daily group sessions and weekly individual counseling. Methadone dosing occurred daily in late afternoon, or in the early morning and late afternoon for those on a split-dosing schedule. Primary care providers and CAP staff recorded participants’ smoking history at the time of enrollment and
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during the post-partum hospital stay. Smoking histories were obtained by questionnaires and interviews. Treatment (e.g., methadone pharmacotherapy and urine toxicology) and delivery outcome data were extracted from maternal and neonatal medical charts. 2.4. Outcome measures 2.4.1. Urine drug testing Observed urine specimens were collected every Monday, Wednesday, and Friday by CAP staff. The number of maternal prenatal urine specimens obtained was 1222 out of a possible 1644 specimens (74%). The number of urine specimens collected per participant depended on the duration of time enrolled in the study. On site urine analysis for opiates and cocaine was performed with the Abuscreen On-Trak Rapid Assays for Drug Abuse (Roche Diagnostic Systems® Indianapolis, Indiana). The cutoff for positive specimens was 300 ng/mL for cocaine (benzoylecogonine) and illicit opiates (morphine). Presumed positive specimens were confirmed by gas chromatography–mass spectrometry at an off-site certified drug laboratory. In addition, weekly random comprehensive drug screens were performed using thin layer chromatography (TLC) or enzyme multiplied immunoassay technique (EMIT). The compounds identified by TLC included: quinine (cutoff 200 ng/mL); ativan/dalmane, benzodiazepines, clonazepam and valium (cutoff 300 ng/mL); morphine (cutoff 500 ng/mL); barbiturates, codeine, dilaudid, meprobamate, PCP, phenmetrazine, phenobarbital (cutoff 1000 ng/mL); and amitriptyline/nortriptyline, demerol, doxepin, glutethimide, hydrocodone, hydroxyzine, imipramine, LAAM, methadone, morphine, and propoxyphene (cutoff 200 ng/mL). Cannabinoids (cutoff 100 ng/mL), cocaine (cutoff 300 ng/mL), and amphetamines (cutoff 1000 ng/mL) were detected using EMIT. The JHBMC laboratory performed maternal and infant drug screens at delivery or shortly thereafter. Specimens were screened using BioRad Liquichek Immunoassay (RioRad Laboratories® Hercules, California) for cannabinoids (cutoff 50 ng/mL), barbiturates and benzodiazepines (cutoffs 200 ng/mL), and cocaine and opiates (cutoffs 300 ng/mL). 2.4.2. Maternal delivery measures All maternal delivery measures were abstracted from the medical records as noted by the midwife/physician and nursing staff. EGA at delivery was based on the first day of the last menstrual cycle and calculated by the primary care provider and adjusted, if needed, after confirmation by ultrasound around the 20th week of gestation. Prematurity was defined as any infant born before 37 weeks of gestation. Type of birth (vaginal or cesarean section), and maternal urine toxicology (tested for opioids, cocaine, barbiturates, and benzodiazepines) were also collected. Maternal hospital stay was calculated from the date of maternal admission to the date of discharge.
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2.4.3. Birth outcome measures The birth weight (g), length (cm), head circumference (cm), and urine toxicology results were obtained at birth. Apgar scores were obtained at 1 and 5 min after birth, rating color, muscle tone, heart rate, respiratory effort, and reflex with a possible score ranging from 0 to 10. The need for specialized care (i.e., any night spent in the Neonatal Intensive Care Unit (NICU)) and length of NICU stay also were obtained from the medical records. Total length of hospital stay was calculated from the date of birth to the date of discharge. 2.4.4. NAS assessment Nursing staff on the post-partum unit assessed neonatal withdrawal every 4–12 h, depending on the intensity of withdrawal, during the first 4 days of life or until discharge from the hospital. Symptoms were recorded using a modified Finnegan neonatal abstinence syndrome scale (Kaltenbach and Finnegan, 1986). The minimum NAS score is zero and indicates no signs of withdrawal. The maximum obtainable score is 42. The NAS score is based on excessive crying, sleep habits, reflex, undisturbed, and disturbed tremors, muscle tone, excoriation, generalized seizure, fever, frequent yawning, sweating, nasal stuffiness, sneezing, tachypnea, poor feeding, vomiting, loose stools, failure to thrive, and excessive irritability. NAS was examined in several ways. First, the frequencies of NAS were tallied for each infant during the observation period. Each sign or symptom was given a score based on its presence and severity, with higher scores given for more severe symptoms. Infants were treated for withdrawal with tincture of opium medication if the infant scored 8 or above at any two consecutive time points. Second, the NAS peak score was based on the highest score recorded by the staff during the infant’s hospital stay. Third, the time to peak withdrawal was calculated from the time of birth to the time of the peak score. Fourth, the duration of NAS was calculated from the time of the first symptoms of withdrawal until the NAS score was 0 or the infant was discharged from the hospital. 2.4.5. Data analysis Participants were divided into light smokers (≤10 cigarettes/day) and heavy smokers (≥20 cigarettes/day). Two-sample t-tests were used to determine whether the following outcome variables were associated with smoking status (light or heavy): NAS peak score, onset time, and duration; gestational age at delivery; methadone dose; and birth weight and head circumference. Analysis of covariance (ANCOVA) was used to assess the relationship between smoking status and each birth outcome after adjusting for possible confounders. The covariates examined were those that could be associated with both smoking status and outcomes and thus confound the relationships: maternal age and ethnicity, maternal drug use, and maternal length of stay. Gestational age was included as a covariate for the outcome variables birth weight and head circumference; both gestational age and neonate opiate-positive at
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birth were included as covariates for the NAS outcome variables. Since premature delivery can affect NAS signs, the analyses using NAS variables as outcome measures were re-run for the subgroup of 19 participants whose babies were born at full term (gestational age at delivery was at least 37 weeks). Two-tailed tests of significance were used with a Type I error rate = 0.05; P-values greater than 0.05 but less than 0.10 are reported as trends. All analyses were conducted using SAS version 8.2.
3. Results 3.1. Urine drug testing results during treatment The average number of weeks enrolled in the study prior to delivery was similar for the groups: 20.1 ± 5.5 weeks and 17.3 ± 6.7 weeks for light and heavy smokers, respectively. The proportions of possible urine specimens obtained during treatment were also similar for both groups. The LS provided 73% of possible specimens with 21% positive for opiates and/or cocaine, compared to 81% of possible specimens with 17% positive for opiates and/or cocaine in the HS. No LS maternal urine samples were positive for barbiturates and/or benzodiazepines; however, HS had 8% positive for barbiturates and/or benzodiazepines. 3.2. Maternal delivery Mean gestational age at delivery was similar for LS (36.8 ± 4.3 weeks) and HS (38.3 ± 3.6 weeks) and not statistically different (t(27) = 1.03, P = 0.31). Two LS participants had a prior history of premature delivery and delivered their infants at 26 and 28 weeks. Four women in each group delivered between 30 and 37 weeks of gestation; therefore, 34% of the total study sample delivered prematurely. Three women (19%) in the LS group underwent cesarean sections while the rest of the women in both groups had vaginal deliveries. Maternal urine samples at the time of delivery were positive for illicit opioids (13 and 25% for LS and HS groups, respectively), for cocaine (20% for LS, 17% for HS), barbiturates (0% for LS, 8% for HS), and benzodiazepines (0% for LS, 8% for HS). There was no significant difference (t(27), P = 0.66) between the two groups regarding delivery toxicology. The average maternal hospital stay was not significantly different (t(27), P = 0.21) between the two groups with a mean stay of 5.2 ± 5.2 and 3.6 ± 1.2 days for light and heavy smokers, respectively. One participant in the LS group had an extended hospital stay of 24 days due to preterm labor. 3.3. Birth outcome The average birth weight for the LS was 2471.9 ± 853.3 g (range 675–4370 g) and 2784.6 ± 760.5 g (range 1505–4025 g) for the HS. Mean head circumference for
the infants in the LS group was 31.5 ± 2.4 cm (range 25.3–36.0 cm) and 32.3 ± 2.7 cm (range 26.0–35.5 cm) for the HS group. Differences in birth weight and head circumference by smoking amount were not statistically significant, both unadjusted and adjusted for gestational age. Neonatal urine drug screens showed the LS and the HS drug-positive rates of 13 and 31% for opioids, 19 and 23% for cocaine, and 0 and 8% for barbiturates, respectively; all urine specimens in both groups were negative for benzodiazepines. The mean Apgar scores at 1 and 5 min were 7.9 ± 1.6 and 8.7 ± 1.0 for light smokers, and 8.5 ± 0.7 and 8.8 ± 0.4 for heavy smokers, respectively. Three infants in the LS and 4 in the HS were treated in the NICU. For the LS group, the average number of days spent in the NICU was 49 ± 39.8 (range 6–83 days). Admission to the NICU for 2 of the 3 LS infants was due to prematurity (born at 28 and 26 weeks, they stayed 58 and 83 days, respectively). The other LS infant was admitted to the NICU due to a chromosomal abnormality (born at 35.2 weeks and stayed 6 days). The average number of days spent in the NICU for the four HS infants was 13.5 days ± 11.6 (range 3–25 days). One infant was admitted to the NICU due to prematurity (born at 30 weeks) and stayed 25 days. Another infant was admitted due to neonatal withdrawal and stayed 22 days. This infant was the only infant treated with phenobarbital and paregoric in addition to tincture of opium. The other two infants were admitted to the NICU due to meconium aspiration and sepsis and stayed 3 and 4 days, respectively. The average total hospital stay for LS infants was 14.8 days ± 22.6 (range 3–83 days) and 8.5 days ± 7.2 (range 4–26 days) for HS infants; the difference between groups was not statistically significant. 3.4. NAS The frequency of neonatal abstinence signs is presented in Table 1. The signs most frequently noted in LS and HS were disturbed tremors, increased muscle tone and hyperactive Moro reflex. Three infants (19%) from the LS displayed no NAS. However, all of these infants were premature (born at 26.0, 28.0, and 36.5 weeks of gestation), and prematurity can reduce NAS signs compared to those typically found in full term infants (Doberczak et al., 1991). In the LS group, 12.5% of the infants were treated for NAS symptoms and 23% were treated in the HS group. For the full sample (N = 29), mean NAS peak scores were 5.6 ± 3.8 (range 0–13) for LS and significantly higher (P = 0.014) for HS, having a peak score of 9.8±4.8 (range 4–19) (Fig. 1, top panel). There was a significant (P = 0.016) difference in time to peak between the LS (37.8 ± 33.8 h) and the HS (113.8 ± 90.0 h) (Fig. 1, middle panel). After adjusting for gestational age and opiate-positive neonatal toxicology, the association between smoking amount and NAS time to peak remained statistically significant (F(3,20) = 5.88, P = 0.025), while the relationship between smoking amount and NAS peak score represented only a trend
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Table 1 Frequency and percentage of neonatal abstinence syndrome (NAS) signs seen in the light smokers (LS) and heavy smokers (HS) NAS signs
LS Frequency
Percentage
Frequency
Percentage
Disturbed tremors Increased muscle tone Hyperactive moro reflex Undisturbed tremors Fever Sleep <3 h post-feed Marked hyperactive moro reflex Sneezing Stuffiness Sleep <2 h post-feed Tachypnea Excoriation Loose stools Excessive irritability Poor feeding Sweating Sleep <1 h post-feed Vomiting Yawning Generalized seizures Failure to thrive
265 257 124 79 59 53 49 42 32 28 18 16 14 14 10 4 4 4 0 0 0
24.5 23.7 11.4 7.3 5.4 4.9 4.5 3.9 3 2.6 1.7 1.5 1.3 1.3 1.0 0.37 0.37 0.37 0 0 0
495 474 300 163 109 115 11 90 38 63 33 152 62 35 88 26 25 12 18 0 0
20.5 19.6 12.4 6.7 4.5 4.8 0.45 3.7 1.6 2.6 1.4 6.3 2.6 1.4 3.6 1.1 1.0 0.5 0.74 0 0
(F(3,24) = 4.22, P = 0.051). The duration of NAS ranged from 0 to 18 days with a mean of 5.1 ± 4.6 for the LS, and from 4 to 24 days with a mean of 9.5 days ± 7.3 for the HS group; this difference showed a trend towards statistical significance (P = 0.054) (Fig. 1, lower panel). The relationship between smoking amount and NAS duration no longer represented a trend (F(3,24) = 2.35, P = 0.14) after adjusting for gestational age and neonatal opiate-positive toxicology. For the subsample who delivered at full term (N = 19), heavier smoking was significantly associated with a higher NAS peak score (6.8 ± 2.9 for LS, 11.0 ± 5.1 for HS, P = 0.039) as well as longer time to peak (42.9 ± 28.4 h for LS, 116.9 ± 89.9 h for HS, P = 0.042); there was no significant relationship between smoking and duration of NAS (5.9±4.3 days for LS, 10.6±8.7 days for HS, P = 0.15). No NAS variable remained significantly associated with smoking amount after adjusting for gestational age and neonatal opiate toxicology in this subsample.
4. Discussion This paper reports maternal and neonatal outcomes for women who received methadone therapy during pregnancy and were either light (n = 16) or heavy smokers (n = 13). This study showed that, relative to light smoker offspring, neonates of heavy smokers had peak NAS scores that were 57% higher, took 33% longer to peak and had 54% longer duration. The relationship between amount of smoking and NAS peak score and time to peak were statistically significant in the full sample, as well as in the sub-
HS
set of women who delivered at full term (n = 19). The relationship between amount of smoking and time to peak NAS score remained significant after adjusting for gestational age and neonatal opiate toxicology in the full sample; however, no NAS variables remained significantly associated with smoking amount after adjusting for these covariates in the subsample who delivered at full term. Although previous studies have separately examined the effects of tobacco (Garcia-Algar et al., 2001; Law et al., 2003) or methadone (Kaltenbach and Finnegan, 1989; Connaughton et al., 1975; Blinick et al., 1969) on neonatal abstinence, this is the first study to directly examine the role that the level of tobacco exposure may play in methadone-associated NAS. It is also noteworthy that after controlling for gestational age, birth weight between the light (2471.9 g) and heavy (2784.6 g) smokers was not statistically different. Although a clear relationship has been shown between number of cigarettes smoked and decreases in birth weight in non-illicit-drug using women smokers (as few as 6–8 cigarettes/day) (England et al., 2001; Law et al., 2003), the present data suggest that this relationship may not generalize to babies of methadone-treated women. It is possible that this lack of difference in birth weight may be due to the fact that infants in both groups were exposed to tobacco at levels high enough to affect infant birth weight. Another possibility may be that methadone effects override or exacerbate tobacco effects. Alternatively, one study has shown that regardless of tobacco use, increases in birth weight in the drug abusing population, who were receiving treatment, were due to improved nutrition and reduced drug use (Dashe et al., 2002). It is also possible that patterns in smoking topography
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NAS Peak Score
20
*
18 16 14 12 10 8 6 4 2 0 LS
300
Time to Peak (hr)
250
HS
*
200 150 100 50 0 LS
25
HS
NAS Duration (days)
20 15 10 5 0 LS
HS
Fig. 1. Neonatal abstinence syndrome (NAS) parameters for neonates of light (LS) and heavy (HS) smokers. The upper panel shows peak scores, the middle panel shows time to peak and the lower panel shows syndrome duration. (*) P ≤ 0.05.
(i.e., inhalation, nicotine yield, etc.) could have differed between the groups resulting in a similar amount of nicotine and cigarette additives, yielding similar birth weights between light and heavy smokers (Peacock et al., 1991). The present results are both timely and important since a large percentage (90%) of methadone-treated women smoke while pregnant (Svikis et al., 1997; Haug et al., 2001; Tuten et al., 2003), as compared to their non-drug-using counterparts (i.e., 20%) (NIDA, 1996). Given that methadone-treated women also are at elevated risk of adverse birth outcomes compared to non-drug using populations, this population is in dire need of smoking interventions. As yet, little is known about their smoking reduction or quitting behavior during pregnancy. Given these data, it may be that methadone-treated women who are able to reduce smoking to less than 10 cigarettes a day could reduce the incidence and severity of NAS, which carries substantial benefits for the neonate and mother, as well as for society.
It is possible that the level of tobacco smoking may ultimately be a useful predictor of NAS severity in methadoneexposed neonates. Although effort has been devoted to examining the relationship between maternal methadone dose and NAS severity, previous research has not been able to consistently show this association (Dashe et al., 2002; Malpas et al., 1995; Doberczak et al., 1991; Doberczak et al., 1993; Harper et al., 1977; Madden et al., 1977; Strauss et al., 1976; Ostrea et al., 1976; Brown et al., 1998; Hagopian et al., 1996; Mack et al., 1991; Stimmel et al., 1982–83; Newman et al., 1975; Rosen and Pippenger, 1976; Rosen and Pippenger, 1975; Blinick et al., 1973). Possible explanations for the discrepancy in results include restricted methadone dose range, bias in sample selection and lack of control of co-occurring drug exposure. In fact, only 3 of the 16 reports mentioned tobacco use in the description of the participants, and no report described controlling for this important potential confounding factor. Given the present results, level of tobacco exposure may be one critical factor obscuring the relationship between methadone dose and NAS severity. Several limitations should be noted when interpreting these results. First, the addition of an objective measure of maternal tobacco use (i.e., plasma or oral fluid cotinine) would improve the reliability of results and offer an opportunity to explore dose–response relations; however, the fact that dramatic differences in NAS were observed based on self-report of tobacco use, strengthen the confidence in the results and further refinement of smoking status should only enhance the differences observed. Second, repeated measurements of cotinine and methadone blood levels in the neonate at the time of NAS measurement would have provided valuable information to correlate the cotinine and methadone level with NAS symptomatology. This could be especially important since the fetus may be exposed to greater nicotine levels than the mother (Lambers and Clark, 1996; Luck et al., 1985) and NAS severity has been shown to correlate with the declining rate of neonatal plasma methadone level during the first 4 days of life (Doberczak et al., 1993). Third, the addition of a non-smoking methadone-treated comparison group would have added information about the effect that methadone alone has on NAS and allowed for a dose response curve to be established. In addition, maternal self-report can be unreliable. Even though the mothers provided detail accounts of their smoking habits at admission into the study and at the time of delivery, no data was collected on the amount, timing and patterns of nicotine use in the interim. Research has shown that the timing, duration and amount of in utero drug exposure can greatly affect neonatal outcome (Lester et al., 2001). Also, it is possible that other maternal factors not examined in this study may have contributed to the differences observed; however, it should be noted that the two groups did not differ significantly with respect to the baseline characteristics examined. Finally, the relatively small sample size could have reduced statistical power to observe differences in outcome measures associated with smoking: this
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limitation would have been most pronounced in the analysis of the subset of full term infants (N = 19). Replication of these findings in larger samples of methadone-exposed infants is warranted before firm conclusions can be drawn. The results from this study demonstrate the importance of the role that tobacco plays in the timing and severity of NAS of neonates of methadone-treated mothers. Future studies of opioid associated NAS should include the level of tobacco exposure as a variable in the analysis, since this may be a better predictor of NAS severity and need for treatment than the methadone dose alone.
Acknowledgements This study was supported by the National Institute on Drug Abuse Extramural Research Grant DA12403-02 and intramural research funds. We would like to acknowledge the staff at the Center for Addiction and Pregnancy, and labor & delivery and post-partum ward at Johns Hopkins Bayview Medical Center for all of their assistance during the course of this study.
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