Abstract
Aim
To determine the effects of in utero exposure to methadone or buprenorphine on infant neurobehavior.
Design
Three sites from the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study, a double-blind, double-dummy, randomized clinical trial participated in this sub-study.
Setting
Medical Centers that provided comprehensive maternal care to opioid-dependent pregnant women in Baltimore, MD, Providence, RI, and Vienna, Austria.
Participants
39 full-term infants.
Measurements
The NICU Network Neurobehavioral Scale (NNNS) was administered to a subgroup of infants on postpartum days 3, 5, 7, 10, 14-15 and 28-30.
Findings
While neurobehavior improved for both medication conditions over time, infants exposed in utero to buprenorphine exhibited fewer Stress-Abstinence signs (P<0.001), were less Excitable (P<0.001) and less Over-Aroused (P<0.01), exhibited less Hypertonia (P<0.007), and had better Self-Regulation (P<0.04) and required less Handling (P<0.001) to maintain a quiet alert state relative to in utero methadone-exposed infants. Infants who were older when they began morphine treatment for withdrawal had higher Self-Regulation scores (P<0.01), and demonstrated the least amount of Excitability (P<0.02) and Hypertonia (P<0.02) on average. Quality of Movement was negatively correlated with peak NAS score (P<0.01), number of days treated with morphine for NAS (P<0.01) and total amount of morphine received (P<0.03). Excitability scores were positively related to total morphine dose (P<0.03).
Conclusion
While neurobehavior improves during the first month of postnatal life for in utero agonist-medication-exposed neonates, buprenorphine exposure results in superior neurobehavioral scores and less severe withdrawal than does methadone exposure.
Keywords: neonatal abstinence syndrome, NICU Network Neurobehavioral Scale (NNNS), neurobehavior
INTRODUCTION
Methadone is considered the standard of care maintenance medication for use in pregnancy. There is growing evidence that buprenorphine may serve as a reasonable alternative medication for select patients [1-5]. Recently, the controlled clinical trial, Maternal Opioid Treatment: Human Experimental Research (MOTHER) demonstrated the maternal efficacy of both methadone and buprenorphine for treating opioid-dependence during pregnancy as well as the neonatal efficacy of buprenorphine in producing a clinically meaningful reduction in neonatal abstinence severity [6].
Infants exposed to opiates inutero have a 50-80% chance of developing neonatal withdrawal [7-9]. Neonatal abstinence syndrome (NAS) is characterized by autonomic and central nervous system hyperactivity, often with associated gastrointestinal tract, and respiratory system dysregulation [10]. In the MOTHER trial, while the proportion of infants who required pharmacologic intervention did not differ between the methadone- and buprenorphine-exposed infants, the buprenorphine-exposed cohort required 89% less morphine to treat withdrawal and the infants spent on average 43% less time in the hospital [6].
While much is known about the pharmacologic intervention for neonatal opiate withdrawal, less has been reported about the impact of opioid-agonist medications on infant neurobehavior. Neurobehavior comprises observable behaviors, responses, and states that reflect the complex integration of the infant’s central and peripheral nervous systems. The NICU Network Neurobehavioral Scale (NNNS) has been used to describe the neurobehavioral effects of fetal exposure to opiates [1, 11-13], cocaine [14] methamphetamines [15] and nicotine [16, 25]. The NNNS was developed for the National Institutes of Health as part of the Maternal Lifestyle Study of the effects of prenatal drug exposure on child outcome [17]. This scale was developed as a sensitive tool for assessing drug-exposed and other high-risk term and preterm infants between 32-44 weeks gestational age.
As part of the MOTHER trial, neurobehavioral assessments were performed on a cohort of neonates exposed prenatally to either methadone or buprenorphine. The purpose of this planned substudy was to examine the clinical course of neurobehavioral symptoms during the first month of life in infants exposed in utero to methadone or buprenorphine. We hypothesized that prenatal buprenorphine exposure would result in improved newborn neurobehavior when compared to prenatal methadoneexposure.
METHODS
Parent Study: Maternal Opioid Therapy: Human Experimental Research: MOTHER
The MOTHER study was a double-blind, double-dummy, randomized clinical trial including eight clinical sites [6, 18]. The primary goal of the MOTHER project was to evaluate the safety and efficacy of buprenorphine and methadone in pregnant opioid-dependent women and their neonates. The main outcomes of this study showed that while the medication groups did not differ on outcomes regarding maternal treatment efficacy, prenatally buprenorphine-exposed neonates needed, on average, significantly less morphine to treat NAS, shorter NAS treatment durations and shorter overall hospitalizations relative to prenatally methadone-exposed neonates [6].
The present study was a substudy of MOTHER for which three sites contributed data: Johns Hopkins University School of Medicine, Baltimore, MD; The Warren Alpert Medical School of Brown University, Providence, RI; and Medical University of Vienna, Vienna, Austria. Following inpatient induction onto double-blind study medication, each of these sites provided comprehensive outpatient care to participants which included obstetrical care, psychiatric treatment, case management and thrice-weekly monitoring for drug use. All sites received local Institutional Review Board approval, and independent data and safety oversight was conducted by a Data and Safety Monitoring Board.
Between May 4, 2005, and October 31, 2008, opioid-dependent women aged 18 to 41 years with a single fetus pregnancy between 6-30 weeks of gestation were screened and recruited. A detailed description of site selection, study coordination, subject selection, and protocol details have been previously published [18].
A total of 57 infants were enrolled in the parent study from the three contributing sites; 9 infants were born before 37 weeks gestational age, 4 infants were not able to be assessed due to other medical conditions and 5 due to unknown reasons. Thirty-nine full-term infants (>37 weeks gestational age) were evaluated with the NNNS (21 methadone-exposed and 18 buprenorphine-exposed).
Neonatal Assessment
All neonates were evaluated for NAS for a minimum of 10 days and were managed in a newborn nursery setting unless their medical condition warranted closer observation. Beginning on day 1 of postnatal life, hospitalized neonates were examined every 4 hours by trained staff blinded to study condition. If a neonate was discharged from the hospital before day 10, it was expected that s/he and the mother would reside in a residential setting, and NAS observations by trained staff blinded to study condition continued until day 10 with NAS scores collected twice daily at least 8 hours apart. To produce reliable and valid clinical observations, staff was trained on administration of the NAS. The interviewer/rater achieved the standard of agreement with the scores provided by the gold-standard experts initially and on periodic evaluations. Inter-rater agreement was excellent with the smallest intraclass correlation coefficient exceeding 0.94 [6].
A neonatal withdrawal score was derived using a modified Finnegan Scale [19] (MOTHER NAS Scale) that has a total of 28 items with 19 items used for scoring and medication decisions. The maximum total withdrawal score was 42. Original item definitions [20] and the morphine medication protocol [2, 21] were refined before data collection. A protocol was established and used by all sites, defining the NAS score above which anti-withdrawal medication was initiated, (i.e.: a neonate scoring 9-12 resulted in a re-score after feeding or within the hour. If the re-score was 9 or above, treatment was started based on the highest score. If a re-score was 0-8, treatment was not initiated. Treatment was immediately started without reassessment if the score exceeded 12), maintained, and weaned. Details of this protocol have been published elsewhere [18]. Because the study involved multiple sites with different nursery surroundings, it was not possible for all infants to be managed in the exact same type of environment. All subjects, however, were afforded standard comfort interventions including swaddling, minimal handling, and low lighting.
NICU Network Neurobehavioral Scale (NNNS)
Neurobehavior was assessed using the NNNS administered by a certified examiner masked to study condition on days 3, 5, 7, 10, 14-15 and 28-30 post birth. The NNNS provides an assessment of behavioral, neurologic and stress/abstinence function. The behavioral items include behavioral state, and sensory and interactive responses derived from the Neonatal Behavioral Assessment Scale [22]. The neurologic items assessed include active and passive tone, primitive reflexes and central nervous system integrity as well as the degree of maturation. The stress/abstinence score, derived from the work of Finnegan [23], and observations of other high risk populations including preterm infants, is a series of “yes” or “no” items organized by system. The NNNS consists of a pre-assessment observation period followed by the neurologic and behavioral assessment. The stress/abstinence component is based on observations during the entire administration of the NNNS. The NNNS items are then scored and summarized into the following scales: Habituation, Attention, Arousal, Regulation, Handling, Quality of Movement, Excitability, Lethargy, Non-Optimal Reflexes, Asymmetric Reflexes, Hypertonicity, Hypotonicity and Stress/Abstinence (scales defined in Table 1). Appropriate psychometric characteristics of the scales have been established and previously described [17]. The examination is administered between feedings in a quiet room with the infant initially asleep.
Table 1.
Summary Scores (excluding Habituation) of the NICU Network Neurobehavioral Scale (NNNS)
| Attention | Indicates an infant’s ability to attend and respond to auditory and visual stimulation; high scores on this scale show good response and sustained alertness. |
| Handling | Indicates the number and type of maneuvers necessary to keep the infant in the appropriate state to administer items; high scores indicate infants who need substantial input from the examiner in order to elicit attention and response to stimuli. |
| Quality Movement | A measure of motor control including smoothness, maturity, modulation of movement of the arms and legs as well as startles and tremors; high scores indicate good quality of movement |
| Self Regulation | Indicates how the infant copes with the demands of the exam, with higher scores indicating better regulation. |
| Non-Optimal Refl. | The number of non-optimal reflex responses |
| Stress/Abstinence | The number of stress/abstinence signs displayed by the infant across five organ systems |
| Arousal | Indicates the infant’s overall level of arousal and associated motor activity during the exam; high scores indicate high arousal, activity, and fussing and crying during the exam. |
| Hypertonia | Indicates increased muscle tone in the arms, legs, and trunk; a high score describes an infant whose overall tone is consistently hypertonic |
| Hypotonia | Indicates decreased muscle tone in the arms, legs, and trunk; a high score on this scale describes an infant who was consistently hypotonic |
| Asymmetrical Refl. | A count of the number of times a reflex on one side of the body is stronger or weaker than on the other side. |
| Excitability | A measure of high levels of motor, state and physiological reactivity; high scores indicate high levels of irritability even with attempts to soothe. |
| Lethargy | A measure of low levels of motor, state and physiological reactivity; high scores indicate extreme under-arousal despite the necessary handling during the exam. |
Statistical Analysis
Maternal and neonatal demographic data were compared using analysis of variance for continuous measures and χ2 tests of independence for categorical measures. A series of 2 (Medication Condition) X 6 (Assessment Day: 3, 5, 7, 10, 14-15, 28-30) linear mixed model analyses (IBM SPSS Statistics, 19.0, Somers, NY) were conducted to examine main effects of Medication Condition and Assessment Day (infant age in days at assessment), as well as Medication by Days interactions on the NNNS outcome measures. Linear as well as curvilinear effects were examined in these mixed models in order to best describe trajectories of change over the assessment period. Habituation was evaluated only in those neonates asleep at the start of the NNNS. As few infants were able to be captured asleep, this variable is excluded from longitudinal analysis. Partial correlations were used to examine relationships between infant neurobehavior on the NNNS, NAS, and morphine treatment, controlling for medication condition. The alpha level for significance was set at 0.05. Missing data was expected in this study both at the variable level due to individual differences in the infants’ ability to tolerate all aspects of the NNNS assessment and to availability of the infants after discharge. Missing data was not significantly different between medication condition: 4 (22.2%) of buprenorphine and 7 (33.3%) of methadone, X2 = 0.591, P = 0.497.
RESULTS
Participant Characteristics
Maternal
There was no difference between Medication Conditions in maternal demographic, substance use, or pregnancy history (Table 2).
Table 2.
Maternal Baseline Characteristics (N=39)
| Total Sample (N=39) f(%) or M (SD) |
Methadone (n=21) f(%) or M (SD) |
Buprenorphine (n=18) f(%) or M (SD) |
|
|---|---|---|---|
| Demographics | |||
| Maternal age | 27.3 (5.9) | 27.8 (5.5) | 26.7 (6.4) |
| Education | 10.7 (1.9) | 10.5 (1.8) | 10.9 (2.0) |
| Gestational age at study entry | 18.3 (6.5) | 18.5 (7.5) | 18.1 (5.4) |
| Married | 7 (17.9%) | 4 (19%) | 3 (16.7%) |
| Race | |||
| White | 34 (87.1%) | 18 (85.7%) | 16 (88.9%) |
| Black | 4 (10.2%) | 3 (14.3%) | 1 (5.6%) |
| Other | 1 (2.5%) | 0 (0%) | 1 (5.6%) |
| Employed | 7 (17.9%) | 3 (14.3%) | 4 (22.2%) |
| Legal status uninvolved | 32 (82%) | 17 (81%) | 15 (83.3%) |
| Substance Use at Enrollment | |||
| Current cigarette smoker | 38 (97.4%) | 21 (100%) | 17 (94.4%) |
| Cocaine use | 12 (30.7%) | 7 (33.3%) | 5 (27.8%) |
| Opioid use (Illicit) | 22 (56.4%) | 12 (57.1%) | 10 (55.6%) |
| Any Psychotropic | 19 (48.7%) | 10 (47.6%) | 9 (50.0%) |
| Any Antidepressant | 15 (38.4%) | 8 (38.1%) | 7 (38.9%) |
| Anxiolytics | 9 (23.0%) | 5 (23.8%) | 4 (22.2%) |
| Current treatment | |||
| Maintenance (methadone or buprenorphine) | 33 (94.2%) | 18 (94.7%) | 15 (93.8%) |
| Detoxification | 0 (0%) | 0 (0%) | 0 (0%) |
| Neither maintenance nor detoxification | 2 (5.7%) | 1 (5.3%) | 1 (6.3%) |
| Pregnancy History | |||
| Previous pregnancies | 2.6 (1.9) | 2.5 (1.5) | 2.8 (2.4) |
| Previous full-term deliveries | 1.6 (1.2) | 1.5 (0.9) | 1.8 (1.5) |
| Previous pre-term deliveries | 0.2 (0.5) | 0.2 (0.7) | 0.1 (0.2) |
| Previous miscarriages/induced abortions | 0.8 (1.2) | 0.8 (1.0) | 0.9 (1.4) |
| Living children | 1.7 (1.3) | 1.8 (1.0) | 1.7 (1.5) |
Note. All ps > .3 for tests comparing the Medication Conditions. The test of independence for Race collapsed the Black and Other groups, given the small number of Other participants. Current treatment at enrollment information not available for 2 methadone and 2 buprenorphine participants.
Neonatal
Likewise, the neonatal birth parameters were similar between Medication Conditions in the cohort completing the NNNS assessments, namely there was no difference in birthweight, gestational age or Apgar scores (Table 3). There was a significant main effect [F (1, 75) = 6.96, P<0.01] of Medication Condition for infant weight over the first 30 days after birth [M = 3006 grams (SE = 47.82) for buprenorphine-exposed infants v. M = 3000.9 grams (SE = 58.1) for methadone-exposed infants]. However, there were no significant differences between Medication Conditions on the simple comparisons on the NNNS assessment days (all Ps>0.05). Among neonates, 13 methadone-exposed and 14 buprenorphine-exposed neonates required medication to treat NAS in this subsample.
Table 3.
Neonatal Characteristics (N=39)
| Total Sample N=39 f(%) or M (SD) |
Methadone n=21 f(%) or M (SD) |
Buprenorphine n=18 f(%) or M (SD) |
|
|---|---|---|---|
| Delivery Variables | |||
| Infant Gender | 16 (41.1%) | 9 (42.9%) | 7 (38.9%) |
| Cesarean section | 16 (41.1%) | 9 (42.9%) | 7 (38.9%) |
| Gestational age at delivery (weeks) | 38.8 (1.2) | 38.6 (0.9) | 39.2 (1.4) |
| Birthweight (gm.) | 3021.5 (393.7) | 2992.9 (326.2) | 3055.0 (468.1) |
| Infant length (cm.) | 49.5 (2.3) | 49.3 (1.8) | 49.7 (2.7) |
| Head circumference (cm.) | 33.8 (1.4) | 33.8 (1.2) | 33.8 (1.6) |
| Apgar score at 1 minute | 8.3 (1.5) | 8.0 (1.9) | 8.5 (0.9) |
| Apgar score at 5 minutes | 9.3 (1.2) | 9.1 (1.5) | 9.4 (0.9) |
| Days of infant hospital stay | 15.5 (12.1) | 18.7 (15.5) | 11.8 (4.0) |
| NAS Scores and Treatment (Morphine) | |||
| Peak NAS Score | 12.7 (3.8) | 13.1 (4.7) | 12.2 (2.3) |
| Treated for NAS w Morphine | 27.0 (69.2) | 13.0 (61.9) | 14.0 (77.8) |
| Days medicated for NAS | 10.7 (13.5) | 13.8 (2.9) | 7.2 (3.1) |
| Total Amount of Morphine (mg) | 12.7 (37.5) | 21.5 (49.9) | 2.5 (3.5) |
Notes. NAS = Neonatal Abstinence Syndrome. Tests of significance of the Medication Condition effect have been previously reported (Jones et al., 2010).
The Relationship of Medication Condition to Infant Opioid Withdrawal
The values for peak NAS score, proportion of infants requiring morphine to treat NAS, the number of days of morphine treatment for NAS, and the total amount of morphine given for the infants in the NNNS study reflect those in the parent study (Table 3). However, when examining the average morphine dose required for infant withdrawal symptoms over days congruent with NNNS assessments (Days 3 through 30 after delivery), there was a significant Medication Condition effect [F(1, 192) = 17.08, P<0.001] and a suggestive non-significant change over Assessment Days [F(1, 72) = 2.08, P<0.08]. The buprenorphine-exposed infants required less morphine to treat withdrawal than infants in the methadone-exposed condition, and both groups had a significant linear [F (1, 73) = 6.8, P<0.02] and curvilinear (cubic) [F (1, 129) = 4.9, P<0.03] trajectory over days of assessment (Figure 1).
Figure 1.
Average daily morphine dose (mg.) in the NNNS cohort measured on days congruent with NNNS assessment.
The Relationship of Medication Condition to Infant Neurobehavior
Due to the significant differences between Medication Condition for the amount of morphine used to treat NAS, the average morphine dose was used as a covariate in the analysis of all of the NNNS scales.
Medication Main Effects
There were significant Medication Condition main effects for six of the NNNS subscales (Table 4). The buprenorphine-exposed infants had lower mean Excitability, Arousal, and Hypertonia scores, and fewer Stress-Abstinence Signs than the methadone-exposed infants (Means and Standard Errors can be found in Table 5). Buprenorphine-exposed infants required less Handling to maintain a quiet alert state throughout the assessments, and this was reflected in higher mean Self-Regulation scores than the methadone-exposed infants.
Table 4.
Results of Linear Mixed Models for Infant Neurobehavior Subscales (NNNS)
| Main Effects | Interaction | Covariate | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Medication | Assessment Day | Medication X Day | Morphine Dose | |||||||||
| df(den) | F | p | df(den) | F | p | df(den) | F | p | df(den) | F | p | |
| Attention | 153.21 | 0.04 | 0.839 | 51.33 | 10.90 | <.001 | 50.24 | 0.50 | 0.77 | 108.88 | 8.83 | 0.004 |
| Quality of Movement | 179.73 | 0.55 | 0.461 | 54.49 | 19.78 | <.001 | 54.11 | 1.17 | 0.34 | 146.25 | 10.02 | 0.002 |
| Self-Regulation | 175.07 | 4.21 | 0.042 | 58.82 | 8.88 | <.001 | 57.96 | 1.06 | 0.39 | 149.37 | 5.24 | 0.023 |
| Non-Optimal Reflexes | 181.40 | 1.72 | 0.191 | 60.66 | 0.92 | 0.476 | 59.51 | 0.81 | 0.55 | 144.56 | 0.14 | 0.711 |
| Asymmetrical Reflexes | 166.58 | 3.08 | 0.081 | 51.13 | 0.71 | 0.618 | 50.60 | 0.56 | 0.73 | 136.15 | 0.34 | 0.558 |
| Stress-Abst Signs TOT. | 168.46 | 12.94 | <.001 | 53.30 | 0.21 | 0.957 | 52.13 | 0.68 | 0.64 | 157.14 | 4.25 | 0.041 |
| Handling | 172.30 | 11.40 | 0.001 | 54.56 | 4.13 | 0.003 | 53.18 | 0.62 | 0.68 | 162.50 | 0.05 | 0.827 |
| Arousal | 177.05 | 7.82 | 0.006 | 57.16 | 5.19 | 0.001 | 55.81 | 1.84 | 0.12 | 166.67 | 0.01 | 0.936 |
| Excitability | 184.57 | 12.70 | <.001 | 64.10 | 8.41 | <.001 | 63.55 | 1.71 | 0.15 | 156.60 | 0.97 | 0.327 |
| Depression | 164.00 | 1.80 | 0.182 | 74.95 | 4.67 | 0.001 | 75.22 | 0.32 | 0.90 | 148.24 | 13.53 | <.001 |
| Hypertonia | 114.99 | 7.50 | 0.007 | 53.99 | 3.75 | 0.006 | 52.22 | 2.31 | 0.06 | 92.16 | 0.03 | 0.873 |
| Hypotonia | 147.99 | 0.16 | 0.689 | 55.52 | 0.50 | 0.777 | 55.52 | 1.09 | 0.38 | 131.64 | 0.22 | 0.639 |
Note: df(num) is 1 for medication condition and covariate, and 5 for Assessment Day and Medication Condition X Assessment Day interaction
TABLE 5.
Estimated Marginal Means Infant Neurobehavior Scores (NNNS)
| Methadone Condition | Buprenorphine Condition | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Total
M(SE) |
Day 3
M(SE) |
Day 5
M(SE) |
Day 7
M(SE) |
Day 10
M(SE) |
Day 15
M(SE) |
Day 30
M(SE) |
Total
M(SE) |
Day 3
M(SE) |
Day 5
M(SE) |
Day 7
M(SE) |
Day 10
M(SE) |
Day 15
M(SE) |
Day 30
M(SE) |
|
| Attention | 5.57 (0.16) | 4.84 (0.34) | 4.75 (0.31) | 5.19 (0.34) | 5.58 (0.27) | 6.36 (0.27) | 6.71 (0.33) | 5.54 (0.14) | 5.14 (0.37) | 4.83 (0.30) | 5.20 (0.28) | 5.66 (0.24) | 5.88 (0.23) | 6.52 (0.32) |
| Quality of Movement | 4.38 (0.07) | 3.67 (0.16) | 4.07 (0.13) | 4.26 (0.13) | 4.53 (0.12) | 4.75 (0.13) | 5.00 (0.12) | 4.44 (0.06) | 3.85 (0.16) | 4.10 (0.13) | 4.52 (0.13) | 4.72 (0.11) | 4.61 (0.12) | 4.82 (0.12) |
| Self-Regulation | 5.28 (0.11) | 4.70 (0.19) | 4.96 (0.23) | 5.05 (0.20) | 5.27 (0.20) | 5.61 (0.25) | 6.09 (0.23) | 5.54 (0.10) | 4.95 (0.20) | 5.04 (0.23) | 5.63 (0.19) | 5.82 (0.19) | 5.92 (0.23) | 5.87 (0.23) |
| Non-Optimal Reflexes | 4.16 (0.24) | 4.97 (0.48) | 4.39 (0.53) | 4.35 (0.45) | 3.65 (0.39) | 3.98 (0.52) | 3.61 (0.40) | 3.81 (0.21) | 3.65 (0.49) | 3.96 (0.53) | 3.90 (0.43) | 3.48 (0.38) | 3.85 (0.48) | 3.98 (0.41) |
| Asymmetrical Reflexes | 0.71 (0.09) | 0.69 (0.21) | 0.63 (0.17) | 0.70 (0.18) | 0.76 (0.17) | 0.64 (0.14) | 0.86 (0.23) | 0.52 (0.08) | 0.91 (0.22) | 0.44 (0.17) | 0.50 (0.18) | 0.55 (0.17) | 0.37 (0.13) | 0.37 (0.24) |
| Stress-Abst Signs TOT. | 0.29 (0.04) | 0.22 (0.06) | 0.32 (0.06) | 0.28 (0.07) | 0.33 (0.07) | 0.29 (0.08) | 0.29 (0.08) | 0.14 (0.03) | 0.21 (0.07) | 0.17 (0.06) | 0.15 (0.06) | 0.12 (0.07) | 0.12 (0.07) | 0.07 (0.09) |
| Handling | 0.69 (0.04) | 0.73 (0.07) | 0.86 (0.08) | 0.66 (0.08) | 0.71 (0.08) | 0.66 (0.08) | 0.54 (0.09) | 0.54 (0.04) | 0.70 (0.06) | 0.63 (0.08) | 0.54 (0.08) | 0.56 (0.07) | 0.52 (0.08) | 0.28 (0.09) |
| Arousal | 4.35 (0.09) | 4.34 (0.17) | 4.54 (0.17) | 4.60 (0.19) | 4.53 (0.23) | 4.17 (0.17) | 3.92 (0.15) | 4.05 (0.08) | 4.53 (0.18) | 4.42 (0.17) | 3.85 (0.18) | 3.91 (0.23) | 3.90 (0.16) | 3.70 (0.15) |
| Excitability | 4.23 (0.32) | 5.30 (0.65) | 5.21 (0.65) | 5.16 (0.59) | 4.11 (0.57) | 3.25 (0.65) | 2.35 (0.53) | 2.98 (0.27) | 4.84 (0.67) | 4.62 (0.65) | 2.14 (0.56) | 2.18 (0.55) | 2.40 (0.60) | 1.72 (0.54) |
| Depression | 3.82 (0.25) | 5.23 (0.57) | 3.94 (0.51) | 4.36 (0.70) | 3.41 (0.47) | 2.93 (0.43) | 3.07 (0.29) | 4.22 (0.22) | 4.86 (0.59) | 4.55 (0.51) | 4.71 (0.70) | 4.00 (0.46) | 3.75 (0.40) | 3.46 (0.29) |
| Hypertonia | 0.38 (0.07) | 0.99 (0.26) | 0.49 (0.20) | 0.44 (0.14) | 0.26 (0.14) | 0.13 (0.07) | −0.01 (0.06) | 0.12 (0.07) | 0.35 (0.28) | 0.23 (0.21) | −0.01 (0.14) | 0.11 (0.14) | −0.01 (0.06) | 0.06 (0.05) |
| Hypotonia | 0.05 (0.03) | 0.11 (0.07) | 0.06 (0.04) | 0.01 (0.05) | 0.06 (0.04) | 0.01 (0.07) | 0.07 (0.08) | 0.07 (0.03) | 0.06 (0.07) | 0.00 (0.04) | 0.06 (0.04) | 0.00 (0.04) | 0.13 (0.06) | 0.14 (0.08) |
The total scores reflect mean values for N=21 methadone and N=18 buprenorphine infants. However, not all participants contributed to every summary score on every day as infants who were not in the proper behavioral state during the assessment were not able to be scored for certain variables. In addition, not all infants were able to be assessed on every scheduled day; the number of cases contributing to each assessment day [Total N (Methadone n/Buprenorphine n); D3=36 (19/17), D5=35 (18/17), D7= 34 (17/17), D10=36 (19/17), D15=31 (15/16), and D30=30 (16/14).
Infant Neurobehavior over Days
Eight of the summary variables showed significant change over Assessment Days (Table 4). All eight had significant linear trends over time: Scores for Attention, Quality of Movement, and Self-Regulation had significant linear increases over days, while scores for Handling, Arousal, Excitability, Depression, and Hypertonia showed significant linear decreases over days (Figure 2). In addition, five of the variables had significant quadratic trends over days: Self-Regulation, Quality of Movement, Hypertonia, Excitability, and Depression. There was not a significant change over time for Stress-Abstinence Signs, Asymmetrical Reflexes, Non-Optimal Reflexes, or Hypotonia. There were no significant Medication Condition X Assessment Days interactions for any of the NNNS variables (Table 4).
Figure 2.
NNNS Summary Scores, trajectories over days of assessment.
The Relationship of Infant Neurobehavior to Infant Opioid Withdrawal and Morphine Dose
Two participants in the methadone-exposed group were outliers for total morphine dose and days treated for NAS and were therefore excluded from correlation analyses. Partial correlations (controlling for Medication Condition) showed that infants who were older when they started receiving morphine treatment for withdrawal (for the 27 infants who were treated for NAS) had higher mean Self-Regulation scores (r = 0.39, df = 22, P<0.01), lower Excitability (r = −0.48,df = 22, P<0.02) and lower Hypertonia (r = −0.51, df = 22, P<0.02) scores overall. For the total sample, Quality of Movement scores were significantly and negatively correlated with peak NAS scores (r = −0.45, df = 34, P<0.01), number of days treated with morphine for NAS (r = −0.50, df = 34, P<0.01), and total amount of morphine received (r = −0.58, df = 34, P<0.001). Excitability scores were positively related total morphine dose (r = 0.37,df = 34, P<0.03).
DISCUSSION
The MOTHER trial demonstrated that prenatally buprenorphine-exposed neonates required significantly less morphine to treat NAS, a significantly shorter duration of NAS treatment, and a significantly shorter hospital stay than prenatally methadone-exposed neonates [6]. This study, composed of a cohort of infants from the MOTHER trial, demonstrated a difference in neurobehavior after controlling for postnatal morphine treatment between methadone and buprenorphine-exposed infants. The buprenorphine-exposed infants exhibited fewer Stress-Abstinence signs, less Excitability, Arousability, and Hypertonia, had better Self-Regulation and required less Handling to maintain a quiet alert state throughout the assessments when compared to the methadone-exposed neonates.
Infants in both medication conditions demonstrated significant changes in neurobehavioral functioning on the NNNS subscales over assessment days that reflect maturation, including increasing scores for Attention, Quality of Movement and Self-Regulation, while other subscales, whose high scores indicate more problematic neurobehavioral functioning, showed decreasing scores including Handling, Arousal, Excitability, Depression and Hypertonia. These trajectories are consistent with typical maturational trends, despite the infants’ prenatal opioid exposure. The significant quadratic trajectories for Self-Regulation, Quality of Movement, Hypertonia, Excitability and Depression, suggest that the change over the first 30 days after birth is more complex than simple linear change. The deviations from linear curves for these variables occur between days 7 and 10, which coincides with the time of the highest average morphine dose. Therefore, it is possible that neurobehavioral functioning measured by the NNNS reflects neurobehavoral maturation relative to previous exposures as well as contemporary challenges.
Evidence for this relationship exists in the curvilinear trajectory of morphine dose over assessment days, with the highest doses given between 10 and 15 days after birth. In addition, infants receiving the highest total morphine doses had the least optimal scores for Quality of Movement and Excitability. Moreover, infants who received morphine treatment at later ages had the most optimal scores for Self-Regulation, Excitability, and Hypertonia. These data suggest that both the severity of and treatment for withdrawal may adversely affect neurobehavioral functioning, at least during the time of the exposure.
Why the buprenorphine-exposed neonates exhibited differences in neurobehavior compared to the methadone cohort is unclear, although this could be related to the partial versus full agonist activity of buprenorphine compared to methadone. Differences in neurobehavior between these two medication conditions have been studied as early as 24 weeks of gestation in the fetus, with greater variability in heart rate, more accelerations and better coupling between fetal movements and heart rate in the buprenorphine-exposed fetuses compared to the methadone cohort, suggesting potential differential effects of these medications early in gestation [24].
Much has been described about varied pharmacologic treatment strategies for NAS. Conversely, little is known about the neurobehavioral effects of fetal exposure to opiates [1, 11-13], and to our knowledge, to date, this is the largest cohort of infants whose neurobehavior has been assessed following fetal buprenorphine exposure [1, 13, 24]. Because the first NNNS administration in this study was conducted on day of life 3, neurobehavioral changes prior to this time are speculative. However, on average, infants in both medication conditions who had NAS severe enough to require morphine had treatment initiated by the third day of life. A correlation between NNNS summary scores and the neonatal abstinence tool (NAS) has been demonstrated by Velez [12] who noted that infants requiring pharmacotherapy for withdrawal were more irritable, hypertonic and had greater difficulty modulating arousal when compared to those infants not requiring treatment. In the current study, significant differences in NNNS summary scores are noted between medication conditions, with both cohorts demonstrating improvement in neurobehavior by one month of age.
Previously, Jones et al. [13] assessed the neurobehavior of infants born to mothers completing a randomized, double-blind study of methadone and buprenorphine to treat opioid dependence. Buprenorphine-exposed infants had greater Arousal and Excitability in the first week of life when compared to the methadone-exposed infants. While the exact reasons for the differences in the results between that study and the present study are unknown, the differing maternal drug use histories may partially explain the findings. When compared to the MOTHER cohort, the previously reported buprenorphine-using Jones et al. cohort had more than 3 times the number of cocaine users, 17% fewer nicotine users in the month before delivery and 25% fewer users of SSRI’s. Moreover, the methadone-using Jones et al. cohort had 57% more cocaine users, 18% fewer nicotine users in the month before delivery and 28% more users of SSRI’s. In addition to opiates, cocaine [14] and nicotine [16, 25] are known to have effects on infant neurobehavior. Exact comparisons between NNNS sub-scores for each study cannot be made as values were reported differently. An additional explanation for the differing results could be a function of sample size. Recovery or convergence of neurobehavioral scores between conditions was not noted for some summary scores until one month of life in the MOTHER cohort. Whether similar findings would have been seen in the Jones et al. study is not known as the patients in that report were only followed until 14 days. It is also not clear if the trajectory or manner in which the opiate-exposed conditions recovered was similar in the two studies as this was not reported in the Jones et al. cohort.
Because methadone, although not FDA approved, is the standard of care for opioid dependence treatment during pregnancy, a majority of infants exhibiting signs of withdrawal from a maintenance opioid medication are methadone-exposed. As such, the short term neurobehavioral findings in this paper have implications for hospital management. There is no environmental standard for the hospitalized opiate-exposed newborn. Some hospitals manage these infants in the neonatal intensive care unit, while others reside in a transitional unit or an area within the newborn nursery. These settings vary with respect to noise and lighting levels as well as developmental intervention opportunities. While the concept of developmental care has been promoted in the preterm population as a means of reducing stresses in the ICU, no such standard exists for the opiate-exposed infant. Reducing noise and light, infant swaddling, minimal handling and giving longer rest periods [26] are all examples of non-pharmacologic interventions that can provide both short-term and long-term benefits in the preterm population. Such standards could have a positive effect on the neurobehavioral differences demonstrated in the early days of withdrawal for opiate-exposed infants.
Without proper intervention, what starts out as a minor finding in the hospital may be exacerbated as the infant transitions home, as many of these children reside in at-risk environments. The fact that methadone-exposed neonates exhibited neurobehavioral differences early in their course may have implications for future behavior. The NNNS has been used as a predictor of long-term behavioral outcomes. Using latent profile analysis on NNNS scores, discrete behavioral profiles have been established in children examined at one month and then again at 4.5 years of age [27]. Infants assigned to the most worrisome profile (profile 5) were more likely to be exposed to tobacco and illicit drugs including opiates when compared to other subjects. Like the methadone cohort in this paper, those infants had a neurobehavioral profile of poor Self-Regulation, high Arousal and Excitability, Hypertonia and a higher number of Stress Abstinence signs. In addition, the profile 5 patients had poor Quality of Movement, and poor Attention.
While it is encouraging that both methadone- and buprenorphine-exposed groups demonstrated similar trajectories over the first 30 days of age that resulted in more optimal neurobehavioral scores at later ages, the results of the MOTHER study and this current report demonstrate that infants prenatally-exposed to buprenorphine have more optimal neurobehavior compared to prenatally-methadone exposed infants. The trajectory by which the buprenorphine-exposed newborn recovers is marked by less withdrawal symptoms, resulting in a less stressful, more rapid recovery.
The many strengths of this study include the double-blind, double-dummy medication procedures, its randomization and uniform protocol for NAS assessment and treatment. There are also limitations. The present study is limited by a small sample size and the inability to control for several potentially confounding variables including site variations in the nursery environments and concomitant medication, smoking exposure and illicit drugexposure. Furthermore, caution should be taken with respect to the generalizability of the results, as this cohort was highly controlled and closely followed, and may not typically represent the general opioid-dependent population.
Throughout normal development the infant’s genetic agenda primes behavior that elicits appropriate responses from caregivers, ensuring that adequate conditions for development are met [28]. An infant’s state behaviors reflect both its own endogenous processes and exogenous influences from the environment [29]. The full-term healthy newborn is able to maintain smooth movements in tone and posture, as well as manage sleep and wakeful periods [30]. Conversely, the stressed newborn unable to self-regulate, requires the intervention of others to alter his/her environment and promote a calm, smooth state. These results demonstrate that the average methadone-exposed newborn, has increased Excitability, Hypertonia and Arousal countered by periods of inability to Self -Regulate and difficulty with Handling when compared to the average buprenorphine-exposed newborn. Efforts to optimize the environment for these infants could help diminish the neurobehavioral differences seen in this population. An essential component of environmental intervention is education of the staff as well as the family/caregivers. It is the obligation of the hospital staff to demonstrate to the family/caregivers what environmental interventions are optimal (i.e.: low lighting, quiet room) and what type of environmental stimuli can be counterproductive. The NNNS could be used by staff, and demonstrated to the family/caregivers, as a tool to identify “subclinical” neurobehaviors, not noted with the traditional NAS tool, that could be optimized through developmental intervention, to improve infant outcomes and optimize the trajectory of recovery over time. With this information, the family/caregivers can acquire the tools needed to improve their interactions with the baby in a positive manner, and continue to apply this knowledge as the infant transitions home.
ACKNOWLEDGEMENTS
This research was supported by the following grants from National Institute on Drug Abuse: Brown University (R01 DA015778); Johns Hopkins University (R01 DA015764); Medical University of Vienna (R01 DA018417). In addition, we would like to thank the following individuals: Brown University: Marissa Cerrone, Kathe Hawes; Johns Hopkins University: Drs. Kevin O’Grady, Lauren Jansson and Martha Velez; Medical University of Vienna: Drs. Katrin Klebermass, Bernadette Winklbaur, Verena Metz, Ingrid Kuegler, and Andrea Prusa, and the study nurses.
H.J. discloses that she has received reimbursement for time and travel from Reckitt Benckiser.
G.F. discloses that she has received financial support and honoraria for presentations from Reckitt Benckiser, as well as financial support and honoraria for presentations from Schering Plough.
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).
Contributor Information
Barry M. Lester, Departments of Psychiatry and Pediatrics, The Warren Alpert Medical School of Brown University
Hendrée E. Jones, Department of Psychiatry and Behavioral Sciences and Department of Obstetrics and Gynecology, Johns Hopkins University School of Medicine and Research Triangle Institute International
Hai Lin, Department of Pediatrics, The Warren Alpert Medical School of Brown University
Klaudia Graf-Rohrmeister, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna
Gabriele Fisher, Addiction Clinic, Department of Psychiatry and Psychotherapy, Medical University of Vienna
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