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1.  Infant autonomic functioning and neonatal abstinence syndrome 
Drug and alcohol dependence  2010;109(1-3):198-204.
Background
Neonatal abstinence syndrome (NAS) expression is widely variable among affected infants and the reasons for this variability are largely unknown; mechanisms that predispose infants to NAS expression are not understood. It has been postulated that the regulatory problems of prenatally drug exposed infants are manifested in dysfunctional vagal regulation of autonomic processes. The current study examines whether cardiac vagal tone, an indicator of parasympathetic neuroregulation, provides a marker for autonomic dysregulation subsequently expressed as NAS in prenatally opioid-exposed newborns.
Methods
Heart period (HP) and cardiac vagal tone (V) were derived from electrocardiogram data collected from 64 methadone-exposed infants on postnatal days 1 and 3. The postpartum NAS course was assessed serially.
Results
Infants with lower V on day 1 had significantly higher NAS symptomatology on day 3. Boys had more severe NAS symptoms than girls through the first 4 days of life and, among infants receiving pharmacologic treatment for NAS, boys required longer treatment course and hospitalizations. Greater poly-drug exposure, detected through toxicology screening throughout pregnancy, and cocaine use in particular, were associated with lower V and shorter HP (faster heart rate) in newborns. Multiple regression models accounted for 25 to 35% of the variance in NAS symptoms and duration of hospitalization in methadone-exposed infants. Significant predictors included infant sex, SSRI/SNRI use, and cigarette smoking.
Conclusions
Results support the hypothesis of a biologic vulnerability of autonomic regulatory functioning in methadone-exposed infants and greater male infant vulnerability to maternal methadone use.
doi:10.1016/j.drugalcdep.2010.01.004
PMCID: PMC2875284  PMID: 20189732
vagal tone; infant; methadone; neonatal drug exposure; neonatal abstinence syndrome
2.  Prenatal methadone exposure and neonatal neurobehavioral functioning 
Pediatric research  2009;66(6):704-709.
Opioid-exposed infants display a wide and variable range of dysregulated neurobehavioral functioning, but the regulatory difficulties experienced by these infants outside the defined clusters of neonatal abstinence syndrome (NAS) have not been well described, and may have implications for the infant’s developmental course. This study describes the neurobehavioral functioning of neonates prenatally exposed to methadone using the NICU Network Neurobehavioral Scale (NNNS) and explores the relationships between maternal factors and infant functioning. The relationship between NNNS measures, NAS severity and need for pharmacotherapy for NAS were also evaluated. Infants who required pharmacological treatment for NAS showed more dysregulated behavior and signs of stress/abstinence as indicated by NNNS scores, but NNNS scores were not significantly correlated with maternal methadone dose. The determination of the range of the methadone exposed infant’s neurobehavioral repertoire could guide the optimal treatment of all such infants, particularly those requiring only non-pharmacological care.
doi:10.1203/PDR.0b013e3181bc035d
PMCID: PMC2796281  PMID: 19690513
3.  ABM Clinical Protocol #21: Guidelines for Breastfeeding and the Drug-Dependent Woman 
Breastfeeding Medicine  2009;4(4):225-228.
A central goal of The Academy of Breastfeeding Medicine is the development of clinical protocols for managing common medical problems that may impact breastfeeding success. These protocols serve only as guidelines for the care of breastfeeding mothers and infants and do not delineate an exclusive course of treatment or serve as standards of medical care. Variations in treatment may be appropriate according to the needs of an individual patient.
doi:10.1089/bfm.2009.9987
PMCID: PMC2989871  PMID: 19835481
4.  Methadone Maintenance and Long-Term Lactation 
Breastfeeding among methadone-maintained women is frequently challenged because of unclear guidelines regarding this practice. Previous research has confirmed that concentrations of methadone in breastmilk in the neonatal period are low. Currently unknown are the concentrations of methadone in breastmilk among women who breastfeed for longer periods of time. The purpose of this research is to examine concentrations of methadone in the plasma and breastmilk of women who breastfeed their infants beyond the neonatal period. Four methadone-maintained women provided blood and breastmilk samples up to 6 months postpartum. The concentrations of methadone in blood and breastmilk were low, contributing to the recommendation of breastfeeding for some methadone-maintained women.
doi:10.1089/bfm.2007.0032
PMCID: PMC2689552  PMID: 18333767
5.  Cigarette Smoking and Neonatal Outcomes in Depressed and Non-Depressed Opioid-Dependent Agonist-Maintained Pregnant Patients 
Aims
To investigate whether cigarette smoking and/or depression contribute to neonatal abstinence syndrome (NAS) severity.
Design
Cohort study analyzing data from a randomized, controlled trial of methadone versus buprenorphine.
Setting
Seven study sites that randomized patients to study conditions and provided comprehensive addiction treatment to pregnant patients.
Participants
119 of 131 opioid-dependent pregnant patients who completed the MOTHER study.
Measurements
Smoking data and depression status were obtained from the Addiction Severity Index and Mini International Neuropsychiatric Interview, respectively. Neonatal outcomes (birth weight, preterm delivery and NAS pharmacologic treatment) were collected from the medical charts. Study site was a fixed-effect factor in all analyses.
Findings
Cigarette smoking was reported by 94% of participants and depression identified in 35%. Smoking was associated with low birth weight, preterm delivery, and NAS pharmacologic treatment in both depressed and non-depressed participants. The association between smoking and NAS treatment differed significantly between depressed and non-depressed participants. Among non-depressed participants, adjusting for site and illicit drug use, each additional average cigarette per day (CPD) increased the odds of NAS treatment by 12% [95%CI: (1.02-1.23), p=0.02]. Among depressed participants, each additional average CPD did not statistically increase the odds of NAS treatment [OR: 0.94, 95% CI: (0.84-1.04), p=0.23].
Conclusions
These results are consistent with the hypothesis that NAS expression is influenced by many factors. The relationship between CPD and NAS pharmacologic treatment is attenuated among depressed women in this study for reasons currently unknown. Further investigations are needed to clarify the complex relationships among maternal smoking, depression, and NAS.
doi:10.1097/ADT.0b013e31821cadbd
PMCID: PMC3401576  PMID: 22833702
Cigarettes; depression; neonatal; pregnancy; opioids
6.  Exposure to violence among substance-dependent pregnant women and their children 
This study examined the prevalence of exposure to violence among drug-dependent pregnant women attending a multidisciplinary perinatal substance abuse treatment program. Participants (N = 715) completed the Violence Exposure Questionnaire within 7 days after their admission to the program. Their rates of lifetime abuse ranged from 72.7% for physical abuse to 71.3% for emotional abuse to 44.5% for sexual abuse. Their rates of abuse remained high during their current pregnancy, ranging from 40.9% for emotional abuse to 20.0% for physical abuse to 7.1% for sexual abuse. Nearly one third of the women reported having physical fights with their current partner (lifetime), and 25% of these women reported that children were present during those physical fights. A total of 30% of the women perceived a need for counseling regarding exposure to violence for themselves and 15% perceived a need for counseling for their children. Study findings confirm previous reports of high rates of abuse and violence exposure among substance-abusing pregnant women and their strong need for counseling for psychosocial sequelae. This study affirmed the value of routine screening for violence exposure in this at-risk population as well as the need to train therapists in specific strategies for helping such women address this complex array of problems.
doi:10.1016/j.jsat.2005.09.001
PMCID: PMC2651191  PMID: 16377450
Violence; Sexual/physical/emotional abuse; Pregnancy; Women; Drug dependence; Children
7.  Fetal Neurobehavioral Effects of Exposure to Methadone or Buprenorphine 
Neurotoxicology and teratology  2010;33(2):240-243.
As part of a double-blind study of medication treatment for opioid dependence during pregnancy, 17 opioid-dependent pregnant women maintained on either buprenorphine or methadone underwent fetal monitoring at 24, 28, 32, and 36 weeks gestation. Maternal demographic information and infant outcomes did not significantly differ by medication group. Earlier in gestation (24 and 28 weeks), buprenorphine-exposed fetuses had higher levels of fetal heart rate variability, more accelerations in fetal heart rate and greater coupling between fetal heart rate and fetal movement than the methadone-exposed group (all p’s <.05). Later in gestation (32 and 36 weeks), buprenorphine-exposed fetuses displayed less suppression of motor activity and longer duration of movements than the methadone-exposed group (all p’s <.05). These results may have implications for the optimal treatment of the opioid-dependent pregnant woman.
doi:10.1016/j.ntt.2010.09.003
PMCID: PMC3040781  PMID: 20868741
buprenorphine; drug dependency; fetal heart rate; fetus; methadone; opioids; pregnancy
8.  Prenatal Methadone Exposure, Meconium Biomarker Concentrations and Neonatal Abstinence Syndrome 
Addiction (Abingdon, England)  2010;105(12):2151-2159.
Aims
Methadone is standard pharmacotherapy for opioid-dependent pregnant women, yet the relationship between maternal methadone dose and neonatal abstinence syndrome (NAS) severity is still unclear. This research evaluated whether quantification of fetal methadone and drug exposure via meconium would reflect maternal dose and predict neonatal outcomes.
Design
Prospective clinical study
Setting
An urban drug treatment facility treating pregnant and post-partum women and their children
Participants
Forty-nine opioid-dependent pregnant women received 30–110 mg methadone daily.
Measurements
Maternal methadone dose, infant birth parameters and NAS assessments were extracted from medical records. Thrice-weekly urine specimens were screened for opioids and cocaine. Newborn meconium specimens were quantified for methadone, opioid, cocaine and tobacco biomarkers.
Findings
There was no relationship between meconium methadone concentrations, presence of opioids, cocaine and/or tobacco in meconium, maternal methadone dose or NAS severity. Opioid, cocaine and tobacco biomarkers also were found in 36.7, 38.7 and 81.1% of meconium specimens, respectively, and were associated with positive urine specimens in the third trimester. The presence of opioids other than methadone in meconium correlated with increased rates of preterm birth, longer infant hospital stays and decreased maternal time in drug treatment.
Conclusions
Methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) concentrations in meconium did not predict infant birth parameters or NAS severity. Prospective urine testing defined meconium drug detection windows for opiates and cocaine as three months, rather than the currently accepted six months. The presence of opioids in meconium could be used as a biomarker for infants at elevated risk in the newborn period.
doi:10.1111/j.1360-0443.2010.03097.x
PMCID: PMC2975817  PMID: 20854338
9.  Maternal methadone dosing schedule and fetal neurobehavior 
Objective
Daily methadone maintenance is the standard of care for opiate dependency during pregnancy. Previous research has indicated that single-dose maternal methadone administration significantly suppresses fetal neurobehaviors. The purpose of this study was to determine if split-dosing would have less impact on fetal neurobehavior than single-dose administration.
Methods
Forty methadone-maintained women were evaluated at peak and trough maternal methadone levels on single- and split-dosing schedules. Monitoring sessions occurred at 36 and 37 weeks gestation in a counterbalanced study design. Fetal measures included heart rate, variability, accelerations, motor activity and fetal movement-heart rate coupling (FM-FHR). Maternal measures included heart period, variability, skin conductance, respiration and vagal tone. Repeated measure analysis of variance was used to evaluate within-subject changes between split- and single-dosing regimens.
Results
All fetal neurobehavioral parameters were suppressed by maternal methadone administration, regardless of dosing regimen. Fetal parameters at peak were significantly lower during single vs. split methadone administration. FM-FHR coupling was less suppressed from trough to peak during split-dosing vs. single-dosing. Maternal physiologic parameters were generally unaffected by dosing condition.
Conclusion
Split- dosed fetuses displayed less neurobehavioral suppression from trough to peak maternal methadone levels as compared to single-dosed fetuses. Split-dosing may be beneficial for methadone-maintained pregnant women.
doi:10.1080/14767050802452291
PMCID: PMC2716036  PMID: 19085624
methadone; methadone dosing; pregnancy; fetus; fetal neurobehavior
10.  A Validated Liquid Chromatography–Atmospheric Pressure Chemical Ionization-Tandem Mass Spectrometric Method for the Quantification of Methadone, 2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), and 2-Ethyl-5-methyl-3,3-diphenylpyroline (EMDP) in Human Breast Milk 
Journal of analytical toxicology  2007;31(5):265-269.
This manuscript details a validated liquid chromatography–atmospheric pressure chemical ionization-tandem mass spectrometry (LC–APCI-MS–MS) method for the quantification of methadone and its metabolites 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyroline (EMDP) in 0.5 mL human breast milk. Limits of detection were 5 ng/mL for methadone and EDDP, and 10 ng/mL for EMDP. Linearity ranged from 10 to 500 ng/mL for all analytes. Breast milk is a complex biological fluid, necessitating several specimen preparation steps to separate methadone and metabolites from the lipophilic matrix. Recoveries were 66–97% following protein precipitation and solid-phase extraction with minimal matrix effect. Acceptable accuracy (89–101%) and precision (15–20% RSD) were achieved for all analytes. This is the first LC–APCI-MS–MS method for the sensitive and specific detection of methadone, EDDP, and EMDP in human breast milk. The method proved suitable for quantification of methadone and metabolites in breast milk of methadone-maintained opiate-dependent women.
PMCID: PMC2745308  PMID: 17579970
11.  The Opioid dependent mother and newborn dyad: non-pharmacologic care 
Journal of addiction medicine  2008;2(3):113-120.
Opioid dependent pregnant and post-partum women and their infants are a complex and vulnerable population requiring individualized, comprehensive and multidisciplinary treatment. Though methadone maintenance in the setting of comprehensive service provision during pregnancy significantly improves pregnancy outcomes for opioid dependent women, its use has implications for the infant, most notably the Neonatal Abstinence Syndrome (NAS). NAS is comprised of physiologic signs and behaviors that indicate a dysfunctional regulation of the central and autonomic nervous systems, and is variable in its expression in affected infants. The disorganized rather than adaptive behaviors displayed by each infant undergoing the effects of in-utero opioid exposure may impair basic functions such as feeding, sleeping, and the ability to be alert and communicate clear cues to caregivers. Understanding and responding to neurobehavioral dysfunction of the newborn may help to promote the infant’s self-organization and self-regulating abilities. However, the substance abusing mother’s physical and psychological wellbeing may be debilitated in the perinatal period, and her ability to recognize and respond to the newborn’s cues may be limited. A multi-tiered comprehensive assessment and intervention of the methadone-maintained mother, her child, and the mother/infant dyad can improve early maternal nurturing interactions, a crucial component of early infant development, particularly in this vulnerable population. The purpose of this article is to review the contribution of maternal opioid dependency to the difficulties experienced by the mother-infant dyad and their treatment providers in the postnatal period, and the non-pharmacological treatment of the infants with suggestions for practical measures with emphasis on the treatment of the mother and baby as an interactional dyad.
doi:10.1097/ADM.0b013e31817e6105
PMCID: PMC2729936  PMID: 19727440
Neonatal Abstinence Syndrome; methadone; substance abuse; opioid; infant
12.  The Opioid Exposed Newborn: Assessment and Pharmacologic Management 
Journal of opioid management  2009;5(1):47-55.
The infant exposed to opioids in utero frequently presents a challenge to the neonatal care provider in the assessment and treatment of symptoms of Neonatal Abstinence Syndrome (NAS) after birth. This review is intended to provide the health care professional with a brief review of current evidence and practical guidelines for optimal evaluation and pharmacologic management of the opioid exposed newborn.
PMCID: PMC2729086  PMID: 19344048
13.  Concentrations of Methadone in Breast Milk and Plasma in the Immediate Perinatal Period 
This study evaluates concentrations of methadone in breast milk and plasma among a sample of methadone-maintained women in the immediate perinatal period. Twelve methadone-maintained, lactating women provided blood and breast milk specimens 1, 2, 3, and 4 days after delivery. Specimens were collected at the time of trough (just before methadone dose) and peak (3 hours after dosing) maternal methadone levels. Paired specimens of foremilk (prefeed) and hindmilk (postfeed) were obtained at each sampling time. Although there was a significant increase in methadone concentration in breast milk over time for the peak postfeed sampling time, t(22) = 2.40, P = .0255, methadone concentrations in breast milk were small, ranging from 21 to 314 ng/mL, and were unrelated to maternal methadone dose. Results obtained from this study contribute to the recommendation of breastfeeding for methadone-maintained women regardless of methadone dose.
doi:10.1177/0890334407300336
PMCID: PMC2718050  PMID: 17478871
methadone; breastfeeding; lactation; breast milk
14.  A Comparison of Cigarette Smoking Profiles in Opioid-Dependent Pregnant Patients Receiving Methadone or Buprenorphine 
Nicotine & Tobacco Research  2013;15(7):1297-1304.
Introduction:
Little is known about the relationship between cigarette smoking and agonist treatment in opioid-dependent pregnant patients. The objective of this study is to examine the extent to which cigarette smoking profiles differentially changed during the course of pregnancy in opioid-dependent patients receiving either double-blind methadone or buprenorphine. Patients were participants in the international, randomized controlled Maternal Opioid Treatment: Human Experimental Research (MOTHER) study.
Methods:
A sample of opioid-maintained pregnant patients (18–41 years old) with available smoking data who completed a multisite, double-blind, double-dummy, randomized controlled trial of methadone (n = 67) and buprenorphine (n = 57) between 2005 and 2008. Participants were compared on smoking variables based on opioid agonist treatment condition.
Results:
Overall, 95% of the sample reported cigarette smoking at treatment entry. Participants in the two medication conditions were similar on pretreatment characteristics including smoking rates and daily cigarette amounts. Over the course of the pregnancy, no meaningful changes in cigarette smoking were observed for either medication condition. The fitted difference in change in adjusted cigarettes per day between the two conditions was small and nonsignificant (β = −0.08, SE = 0.05, p = .132).
Conclusions:
Results support high rates of smoking with little change during pregnancy among opioid-dependent patients, regardless of the type of agonist medication received. These findings are consistent with evidence that suggests nicotine effects, and interactions may be similar for buprenorphine compared with methadone. The outcomes further highlight that aggressive efforts are needed to reduce/eliminate smoking in opioid-dependent pregnant women.
doi:10.1093/ntr/nts274
PMCID: PMC3682847  PMID: 23288871

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