Abstract
Aim
To identify factors that predict the expression of neonatal abstinence syndrome (NAS) in infants exposed to methadone or buprenorphine in utero.
Design and Setting
Multi-site randomized clinical trial in which infants were observed for a minimum of 10 days following birth, and assessed for NAS symptoms by trained raters.
Participants
n = 131 infants born to opioid dependent mothers, 129 of which were available for NAS assessment.
Measurements
Generalized linear modeling was performed using maternal and infant characteristics to predict: peak NAS score prior to treatment, whether an infant required NAS treatment, length of NAS treatment, and total dose of morphine required for treatment of NAS symptoms.
Findings
53% of the sample (68 infants) required treatment for NAS. Lower maternal weight at delivery, later estimated gestational age (EGA), maternal use of selective serotonin reuptake inhibitors (SSRIs), vaginal delivery, and higher infant birth weight predicted higher peak NAS scores. Higher infant birth weight and greater maternal nicotine use at delivery predicted receipt of NAS treatment for infants. Maternal use of SSRIs, higher nicotine use, and fewer days of study medication received also predicted total dose of medication required to treat NAS symptoms. No variables predicted length of treatment for NAS.
Conclusions
Maternal weight at delivery, estimated gestational age, infant birth weight, delivery type, maternal nicotine use, and days of maternal study medication received, and the use of psychotropic medications in pregnancy may play a role in the expression of neonatal abstinence syndrome severity in infants exposed to either methadone or buprenorphine.
Keywords: tbc
Introduction
Since the 1970s, methadone has been the standard of care for treatment of opioid dependence during pregnancy [1]. Methadone maintenance reduces illicit drug use and its concomitant risks, increases compliance with prenatal care, and improves obstetrical and neonatal outcomes [2–3]. By stabilizing opioid agonist concentrations in maternal blood plasma, methadone maintenance protects the fetus from the adverse effects of repeated opioid withdrawal [4]. However, intrauterine exposure to opioids, including those used in maintenance treatment, may produce a treatable constellation of signs and symptoms known as neonatal abstinence syndrome (NAS). NAS is characterized by central nervous system hyperirritability; gastrointestinal dysfunction; respiratory distress; and vague autonomic symptoms. High pitched cry, hyperactive Moro reflex, increased muscle tone, sleep disturbances, tremors and seizures are signs of CNS excitation due to NAS. Areas of GI dysfunction include poor feeding, excessive sucking, regurgitation and diarrhea. Autonomic disturbances include sweating, fever, yawning, sneezing and mottling, while respiratory dysregulation is indicated by nasal stuffiness and rapid respiration [5]. Reports of the incidence of NAS range from 13–94% in methadone-exposed infants [6–8]. While clinical consensus has established that assessment and treatment of NAS are critical elements of the standard of care for prenatally opioid-exposed neonates, there has been continuous controversy as to whether there is a positive relationship between maternal methadone dose and severity of NAS [8]. Accordingly, there is an extensive literature examining this relationship albeit with inconsistent results. A number of studies have found a significant correlation between maternal dose and NAS symptoms [9–10], and others have found no relationship [6, 11–15]. Additionally, few studies have accounted for the effects of nicotine, prescribed medications (selective serotonin reuptake inhibitors and anxiolytics such as benzodiazepines) and non-prescribed and illicit drug use on the development of NAS. These substances are important to include in any examination of NAS as they have been associated with symptoms similar to NAS in the infant shortly after birth [14, 16–21].
Buprenorphine has been utilized in Europe since 1996 as a maintenance medication for opioid dependence and in 2002 was approved for use in the US [22]. Although not approved in either Europe or the US for use in pregnant women, European case reports and prospective studies suggest infants born to buprenorphine-maintained mothers have less severe NAS than infants born to methadone-maintained women [23, 24]. However, with both methadone and buprenorphine, there is broad variability in the expression of NAS and the factors that influence whether one infant requires treatment for NAS while another does not are still largely unknown. The Maternal Opioid Treatment; Human Experimental Research (MOTHER) study, a multi-site, double-blind, double-dummy randomized controlled trial investigating the efficacy of methadone and buprenorphine in pregnant opioid-dependent women has found that infants exposed to buprenorphine required significantly less morphine to treat NAS, had a significantly shorter hospital stay, and a significantly shorter duration of treatment [25]. It did not, however, find a difference in the number of infants requiring NAS treatment according to medication condition. This study is a secondary analysis of MOTHER data to further delineate factors, in addition to the agonist medications of buprenorphine or methadone, which predict the expression of NAS severity in infants.
Methods
Participants
Participants in this study were 131 infants born to mothers enrolled in a multi-site double-blind, double-dummy, flexible-dosing, randomized clinical trial to compare the relative effectiveness of methadone versus buprenorphine for treatment of opioid dependency during pregnancy. One infant died following birth, and one infant was too premature (29 weeks estimated gestational age) to allow for NAS assessment, leaving a remaining sample of 129. Mothers were opioid-dependent women between the ages of 18 to 41 with a single-fetus pregnancy enrolled in the trial between May 4, 2005 and October 31, 2008 [25]. Participants were recruited from among pregnant women seeking treatment for opioid dependence. Average EGA week at study entry was 17.2 (SD = 6.1). All participants received comprehensive substance abuse treatment and prenatal care (see Jones et al., in this Supplement for a detailed description).
Procedures
Infants were observed for a minimum of 10 days for NAS symptoms, and scored every four hours by trained staff using a modified Finnegan scale while in the hospital. Infants discharged from the hospital prior to the tenth day of observation were scored twice daily by a trained rater. An expert-rater trained a gold standard scorer at each study site. Inter-rater reliability was maintained through the use of training videos recording NAS assessment of three infants. Gold standard scorers at each site were required to view new training videos created every six months, and score infants within two points of the expert-rater. Intra-class correlation estimate of the degree of agreement between the expert rater and gold standard scorers suggested excellent inter-rater agreement [25]. Infants requiring treatment for NAS were medicated with morphine according to a standard symptom-based protocol, where dose was increased until control of symptoms was achieved [25]. Weaning began following stability of symptoms for 48 hours, and dose was decreased by 0.02 mg every 24 hours. Phenobarbital was administered if symptoms were not controlled by morphine, and judged necessary by the treating physician.
Data Analysis
Predictor variables selected for examination included maternal maintenance dose at delivery in mg; number of days mother received study medication; mother’s use of anxiolytics or hypnosedative medications; mother’s use of psychiatric medications including antidepressants, serotonin reuptake inhibitors (SSRIs), and/or antipsychotic medications during pregnancy; number of cigarettes smoked 24 hours prior to delivery; maternal weight (in pounds) at delivery; delivery type (vaginal or cesarean); estimated gestational age (EGA) at delivery; and infant birth weight (in grams). Maternal use of antidepressants, serotonin reuptake inhibitors (SSRIs), and/or antipsychotic medications were coded as a single variable in the MOTHER database and this variable was used in the initial analyses. SSRIs were later recoded and examined separately from antidepressant and antipsychotic medications in subsequent analyses. As relatively few participants were positive for abused drugs (opiates, cocaine, benzodiazepines) during the two weeks prior to delivery (less than 10% for each drug), these variables were not included in the analysis. Maternal buprenorphine doses (range 2–32 mg) were converted to their methadone equivalent (20–140 mg) for all analyses using the standard equivalent table for double-blind dosing in the MOTHER trial [25]. Maternal medication condition (buprenorphine or methadone) was included as a control variable in all analyses and site was included in all models to adjust for possible differences between the study sites.
There were missing data on two variables for approximately 16% of the sample: number of cigarettes smoked in the 24 hours prior to delivery and maternal weight at delivery. Missing values for these two variables were estimated utilizing monthly data on number of cigarettes smoked, screening data on smoking dependence, and data from the two obstetrical visits prior to delivery. Ad hoc power analysis showed power at 0.80 to detect a medium to large effect size (0.15) with alpha set at 0.05 for 9 predictors and 2 control variables.
Models were constructed for four outcome variables: the binary variable of 1) infant’s receipt of treatment for NAS, and the continuous variables of 2) infant’s peak NAS score prior to treatment, 3) number of days the infant required NAS treatment, and 4) the total dose of morphine required for NAS treatment. Generalized linear multivariate modeling was conducted using maximum likelihood estimation (Newton-Raphson), assuming a binomial distribution, (logit link function) for the binary outcome variable and a Poisson distribution (log link function) for continuous outcome variables.
Results
Maternal and infant characteristics are presented in Table 1.
Table 1.
Maternal and infant characteristics
| Methadone | Buprenorphine | |
|---|---|---|
|
| ||
| n = 129 | Mean/Percent (SD) | Mean/Percent (SD) |
| MATERNAL | ||
| Maternal weight at delivery (lbs) | 171.5 (4.6) | 165.4 (4.4) |
| Vaginal delivery | 63.0% | 70.7% |
| Maternal maintenance dose at delivery (mg) | 85.0 (4.2) | 16.6 (1.0) |
| Days of study medication | 158.7 (6.6) | 168.8 (5.7) |
| UDS two weeks prior to delivery | ||
| Benzodiazepines | 1.4% | 5.6% |
| Cocaine | 5.6% | 9.3% |
| Opiates | 5.6% | 11.1% |
| Cigarettes (N) 24 hours prior to delivery | 12.2 (0.9) | 8.7 (0.9) |
| SSRIs | 21.9% | 27.8% |
| Anxiolytics | 27.8 % | 40.4% |
| INFANT | ||
| EGA at delivery (weeks) | 37.9 (0.3) | 39.1 (0.3) |
| Birth weight (gm) | 2878.5 (66.3) | 3093.7 (72.6) |
| Peak NAS score prior to treatment | 12.8 (0.6) | 11.0 (0.7) |
| Treated for NAS | 56.9% | 47.4% |
| Length of treatment (days) | 9.9 (1.6) | 4.1 (1.0) |
| Total amount of morphine (mg) | 10.4 (2.6) | 1.1 (0.7) |
Note: UDS: urine drug screen; SSRIs: selective serotonin reuptake inhibitors; Days of study medication: maternal maintenance medication; EGA: estimated gestational age; NAS: neonatal abstinence syndrome
Infant’s receipt of treatment for NAS
Approximately 53% of the sample (68 infants) required treatment for NAS (Table 1). Whether or not an infant required medication for NAS symptoms was predicted by infant birth weight and number of cigarettes smoked 24 hrs prior to delivery, with both higher infant birth weight (P = 0.009) and greater number of cigarettes smoked (P = 0.03) increasing the likelihood of the infant’s requiring NAS treatment (Table 2). EGA week at delivery approached, but did not reach, significance at the 0.05 level (P = 0.07). In-utero exposure to psychotropic medications, delivery type, maternal weight, maternal medication dose and number of days the mother received double-blind study medication did not affect the likelihood of the infant’s receipt of NAS treatment.
Table 2.
Correlates of infant’s receipt of NAS treatment
| n = 129 | |||
|---|---|---|---|
| Predictor | b | z | P |
| Birth weight | 0.001 | 2.61 | 0.009* |
| Cigarettes | 0.07 | 2.25 | 0.03+ |
| EGA at delivery | −0.26 | −1.84 | 0.07 |
| Anxiolytics | −0.51 | −1.21 | 0.23 |
| SSRIs | 0.04 | 0.08 | 0.94 |
| Delivery type | −0.06 | −0.13 | 0.90 |
| Maternal weight | −0.01 | −1.36 | 0.18 |
| Maternal maintenance dose | 0.001 | 0.20 | 0.84 |
| Days of study medication | 0.003 | 0.77 | 0.44 |
P < 0.05.
P < 0.01.
P < 0.001.
Note: Days of study medication: maternal maintenance medication
Infant’s peak NAS score prior to treatment
Infants with higher birth weights had higher peak NAS scores prior to treatment (b = 0.0003; SE = 0.0001; P = 0.0002), as did infants born to mothers with a lower maternal weight at delivery (b = −0.002; SE = 0.0009; P = 0.03) (Table 3). Neither EGA week (b = −0.46; SE = 0.27; P = 0.09) nor SSRIs (b = −0.01; SE = 0.87; P = 0.99) reached significance in the model where SSRIs were analyzed as a combined variable with antidepressants and antipsychotic medications. However, when mother’s use of SSRI medications during pregnancy was separated out from other psychotropic medications it produced a statistically significant effect on infant NAS scores in bivariate regression (b = 2.72; SE = 0.94; P = 0.004). When included in the generalized linear model, SSRI use remained significant at the 0.01 level (b = 0.22; SE = 0.07; P = 0.002) and EGA at delivery reached statistical significance (b = −0.05; SE = 0.02; P = 0.04) with maternal exposure to SSRIs and EGA at delivery both predicting higher NAS scores. Infants delivered via cesarean section had lower peak NAS scores prior to treatment than those delivered vaginally (b = −0.14; SE = 0.07; P = 0.05).
Table 3.
Correlates of peak NAS score
| n = 129 | |||
|---|---|---|---|
| Predictor | b | Wald χ2 | P |
| Birth weight | 0.0003 | 13.90 | 0.0002** |
| Maternal weight | −0.002 | 4.72 | 0.03+ |
| EGA at delivery | −0.05 | 4.39 | 0.04+ |
| SSRIs | 0.22 | 9.28 | 0.002* |
| Anxiolytics | −0.02 | 0.12 | 0.72 |
| Cigarettes | 0.006 | 1.82 | 0.18 |
| Delivery type | −0.14 | 3.76 | 0.05 |
| Maternal maintenance dose | 0.002 | 2.10 | 0.15 |
| Days of study medication | 0.000 | 0.00 | 0.96 |
P < 0.05.
P < 0.01.
P < 0.001.
Note: SSRIs: selective serotonin reuptake inhibitor;; days of study medication: maternal maintenance medication
Number of days infants required treatment
Maternal use of SSRI’s, antidepressants, or antipsychotics during pregnancy correlated with infants requiring longer treatment for NAS (b = 9.43; SE = 3.67; P = 0.01). However, when use of SSRIs was analyzed apart from other medications it was non-significant in both bivariate regression (b = 5.83; SE = 4.13; P = 0.16) and in the generalized linear model (b = 0.19; P = 0.34) (Table 4). There was also a trend toward an inverse relationship between number of days the mother received study medication and length of treatment for the infant (b = −0.004; SE = 0.002; P = 0.09). However, no other variables predicted the length of infant NAS treatment.
Table 4.
Correlates of length of treatment and total dose of morphine
| n = 68 | Length of treatment | Total dose of morphine | ||||
|---|---|---|---|---|---|---|
| Predictor | b | Wald χ2 | P | b | Wald χ2 | P |
| Birth weight | 0.0003 | 1.92 | 0.17 | 0.0007 | 2.11 | 0.15 |
| EGA at delivery | 0.06 | 0.92 | 0.34 | 0.16 | 1.60 | 0.21 |
| Delivery type | −0.29 | −1.40 | 0.24 | −0.83 | 3.26 | 0.07 |
| Maternal maintenance dose | 0.003 | 1.52 | 0.22 | 0.003 | 0.20 | 0.65 |
| Maternal weight | −0.002 | 0.49 | 0.48 | −0.006 | 0.95 | 0.33 |
| Days of study medication | −0.004 | 2.93 | 0.09 | −0.01 | 6.95 | 0.008* |
| Anxiolytics | 0.006 | 0.00 | 0.97 | −0.09 | −0.04 | 0.89 |
| SSRIs | 0.19 | 0.90 | 0.34 | 0.89 | 5.77 | 0.02+ |
| Cigarettes | 0.02 | 3.18 | 0.07 | 0.05 | 3.86 | 0.05+ |
P < 0.05.
P < 0.01.
P < 0.001.
Note: SSRIs: selective serotonin reuptake inhibitor; days of study medication: maternal maintenance medication
Total dose of morphine required for NAS treatment
Maternal use of anti-depressants, SSRIs, or antipsychotic medication during pregnancy also correlated with higher total dose of medication for infants (b = 33.47; SE = 13.94; P = 0.02). Looking specifically at maternal use of SSRI medication during pregnancy, those infants exposed to SSRIs in utero required greater doses of morphine to treat NAS symptoms (b = 0.89; SE = 0.37; P = 0.02). Higher number of days of maternal receipt of study medication predicted lower total infant doses of morphine (b = −0.01; SE = 0.004; P = 0.008). Greater number of cigarettes smoked 24 hour prior to delivery correlated with higher total dose of morphine (b = 0.05; SE = 0.02; P = 0.05).
Discussion
This study examines factors that affect the severity of NAS and the trajectory of its treatment in a sample of infants born to opioid-dependent pregnant women receiving agonist maintenance during pregnancy.
Maternal maintenance dose at delivery and maternal use of anxiolytics were not related to any of the four outcome variables.
Higher infant birth weight increased the likelihood of requiring treatment for NAS and both higher infant birth weight and EGA predicted higher peak NAS scores prior to treatment. This is consistent with previous findings that both higher infant birth weight and EGA at delivery increase the likelihood of requiring NAS treatment [12, 26]. The lower peak NAS scores prior to treatment for those infants delivered by cesarean section as opposed to vaginal delivery may be a function of the analgesics used for surgery. Lower maternal weight at delivery correlated with higher peak NAS score prior to treatment. The mechanism for this association is not clear, however, lower maternal body mass index has been correlated with other adverse neonatal outcomes, such as intrauterine growth restriction [27]. A woman’s body mass index reflects her nutritional status and may affect placental function with consequences for fetal development and neonatal adaptation [28]. Moreover, for prenatally opioid-exposed neonates, a significant relationship has been found between the severity of placenta alteration and NAS [29].
Fewer days of maternal receipt of study medication was also associated with total dose of morphine required to treat NAS and a trend towards association with greater length of NAS treatment. While such findings are counter-intuitive, many of the patients entered substance abuse treatment concurrent with beginning participation in the study, therefore days of maternal medication may in fact reflect the length of time the mother received comprehensive substance abuse treatment, prenatal care, and reduced her concomitant illicit drug use. It is also consistent with previous findings that babies conceived on methadone do not exhibit more severe neonatal abstinence than infants exposed to methadone for only part of the gestational period [30] and that longer maternal methadone treatment correlates with better birth outcomes [31, 33].
Nicotine exposure, as measured by the number of cigarettes smoked during the 24 hours prior to delivery, predicted infant’s receipt of NAS treatment and total dose of medication required to treat NAS symptoms but did not affect peak NAS score or treatment length. This finding is not consistent with previous reports that heavy tobacco exposure in utero was correlated with higher NAS scores and greater duration of treatment [14, 17–18]. However, two of these studies compared the effects of heavy versus light cigarette smoking (defined as 20 versus 10 cigarettes per day) on NAS severity [14,18] and Bakstad et al. (2009) found a relationship between mean number of cigarettes per day to duration of NAS treatment for methadone-exposed infants but not for buprenorphine-exposed infants [17]. However, the relationship of nicotine exposure to the need for NAS treatment and the amount of medication required for treatment support previous findings that nicotine exacerbates the expression of opioid NAS [14, 17–18].
Maternal use of SSRIs predicted higher peak NAS scores prior to treatment as well as the total dose of medication required for those infants who required treatment, but did not increase the likelihood of the infant’s receipt of treatment. These findings are consistent with previous work showing that neonates prenatally exposed to both methadone and SSRI/SNRI medications were not more likely to be treated for NAS, but when infants were treated for NAS, they required significantly greater amounts of morphine [20].
Limitations
In this study, we are unable to examine the role of illicit drug use in the expression of NAS requiring medication treatment. The MOTHER study utilized a contingency management component which was very effective in reducing illicit drug use during the trial. The result was a very low incidence of concomitant drug abuse, with use of specific drugs too infrequent to include in the analyses. The minimal exposure to benzodiazepines is especially relevant as benzodiazepines have been identified in the literature as having a potential role in NAS severity [6, 9, 12]. We also were unable to examine the role of breastfeeding on NAS. Although we had a number of participants who chose to breastfeed, we did not have data specific to the length of time and/or daily consistency with which they breastfed. As such meaningful comparisons were limited.
While these data provide an initial look at the potential role of prescribed psychotropic medication in the development of NAS symptom severity, condensing of drug classes in the data limits our ability to draw conclusions regarding specific medications. The multiplicity of drugs prescribed in each drug category also did not allow for examination of individual medications separately.
Further research on maternal use of SSRIs and other antidepressants is needed to delineate the effects of different classes of medications on the incidence and trajectory of NAS symptoms related to prenatal opioid exposure. The neonatal behavioral syndrome associated with SSRIs is usually mild and self-limited and the association with specific SSRI agents has not been well established [32]. Moreover, to our knowledge there are only two studies to date that have examined the role of SSRI in relation to NAS associated with prenatal opioid exposure [20, 33].
While the occurrence of NAS is a consequence of prenatal opioid exposure, results from the MOTHER study indicate differences in NAS severity related to methadone and buprenorphine. Specifically, buprenorphine-exposed infants required less morphine to treat NAS, a shorter duration of treatment, and a shorter hospital stay than methadone exposed infants [25]. The results of the present study further indicate that infant birth weight, EGA at delivery, maternal weight at delivery, the use of SSRI’s and nicotine are additional factors that influence both the expression of NAS severity and its trajectory during treatment. Continued research is needed to better understand the dynamics of inter-relationships for these factors as well as to define additional factors that may affect the expression of NAS.
Acknowledgments
This research was supported by the following grants from National Institute on Drug Abuse: Brown University (R01DA015778); Johns Hopkins University (R01 DA015764); Thomas Jefferson University (R01DA015738); University of Toronto (R01DA015741); University of Vermont (R01DA018410 and M01RR109); University of Vienna (R01DA018417); Vanderbilt University (R01DA 017513 and M01RR00095 from the General Clinical Research Center); and Wayne State University (R01DA15832).
Footnotes
Declaration of interest
This study was funded by the National Institute on Drug Abuse. No contractual constraints on publishing were imposed by the funding body.
The clinical trial was registered with ClinicalTrials.gov (Identifier: NCT00271219; Title: RCT Comparing Methadone and Buprenorphine in Pregnant Women)
H.J. discloses that she has received reimbursement for time and travel from Reckitt Benckiser.
Contributor Information
Karol Kaltenbach, Department of Pediatrics, Jefferson Medical College, Thomas Jefferson University
Amber Holbrook, Department of Pediatrics, Jefferson Medical College, Thomas Jefferson University
Mara G. Coyle, Department of Pediatrics, The Warren Alpert Medical School of Brown University
Sarah H. Heil, Departments of Psychiatry and Psychology, University of Vermont
Amy Salisbury, Department of Pediatrics, Women and Infant Hospital and The Warren Alpert Medical School of Brown University
Susan Stine, Department of Psychiatry and Behavior Neurosciences, Wayne State University
Peter Martin, Department of Psychiatry and Pharmacology, Vanderbilt University
Hendrée Jones, Department of Psychiatry, Johns Hopkins University School of Medicine
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