Marie J. Hayes

Opioid Dependency in Pregnancy and Length of Stay for Neonatal Abstinence Syndrome

OBJECTIVE To examine opioid replacement therapy in pregnancy and effect on neonatal outcomes, including length of hospital stay for neonatal abstinence syndrome. DESIGN Retrospective descriptive study. SETTING Labor and delivery unit and neonatal intensive care unit (NICU), Eastern Maine Medical Center, Bangor, Maine. PARTICIPANTS One hundred fifty-two opioid-dependent pregnant women on methadone maintenance therapy (MMT) (n = 136) or buprenorphine maintenance therapy (BMT) (n = 16) during pregnancy and their neonates. The neonates were born between January 1, 2005 and December 31, 2007. METHODS A review of the electronic medical record (EMR) was conducted of all opioid-dependent women who were maintained on MMT or BMT at the time of admission for labor and delivery and their neonates. RESULTS Maternal methadone dose and concomitant in-utero exposure to benzodiazepines prolonged the length of hospital stay for neonates. Length of stay was shorter in breastfed neonates than formula-fed neonates or neonates who received formula and breast milk. Neonates with prenatal exposure to MMT spent more days in the hospital (21 vs. 14 days) for treatment of neonatal abstinence syndrome (NAS) than infants with prenatal exposure to BMT. CONCLUSION These findings are consistent with previous research on the simultaneous use of methadone and benzodiazepines during pregnancy and provide further direction for the treatment of opioid dependency during pregnancy. Harm reduction strategies for opioid-dependent pregnant women in substance abuse treatment with MMT may one day include guidance on daily treatment doses and recommendations to avoid the concomitant use of benzodiazepines to lessen NAS. Breastfeeding should be recommended to shorten length of stay. Understanding perinatal and neonatal outcomes of pregnant women on methadone or buprenorphine will help to identify optimal treatment for opioid dependency in pregnancy.

Neonatal Abstinence Syndrome: Treatment and Pediatric Outcomes

Recent rise in rates of opiate replacement therapy among pregnant women have resulted in increasing number of infants requiring treatment for neonatal abstinence syndrome (NAS). Short-term and long-term developmental outcomes associated with prenatal opiate exposure are discussed, including symptoms and severity of NAS, and early cognitive and motor delays. Maternal and infant risk factors are discussed, and include patterns of maternal substance use during pregnancy, genetic risk, polysubstance exposure pharmacological treatment for NAS and breastfeeding. The importance of characterizing corollary environmental risk factors is also considered.

Epidemic of Prescription Opiate Abuse and Neonatal Abstinence

IN THIS ISSUE OF JAMA, PATRICK ET AL 1 DESCRIBE THE EFfects on newborn infants of the widespread availability of prescription opiate medications. These medications provide superior pain control for cancer and chronic pain, but have been overprescribed, diverted, and sold illegally, creating a new opiate addiction pathway and a public health burden for maternal and child health. Overdose mortality and dependence rates are highest among disadvantaged, young adults in rural areas (eg, Maine and Kentucky). Young women are nearly as likely as men to abuse opiate medications, leading to an increase in opiate-dependent newborns treated for withdrawal syndrome or neonatal abstinence syndrome (NAS). The standard of care for opiate addiction during pregnancy is methadone maintenance and psychiatric care. Patrick et al demonstrate that the increase in NAS (from an incidence of 1.20 [95% CI, 1.04-1.37] per 1000 hospital births per year in 2000 to 3.39 [95% CI, 3.12-3.67] per 1000 hospital births per year in 2009) has created a health care encumbrance primarily for state Medicaid budgets. In affected states, methadone treatment programs have expanded rapidly and voluntary prescription monitoring programs identify opiate medication use patterns (ie, opiate prescriptions are tracked and individuals who are “shopping” for physicians to prescribe opiates can be identified). However, the burden of addiction on state Medicaid budgets threatens retrenchment of recently established programs despite increased need. This poses a crisis of care for affected fetuses and newborns. However, without accessible treatment of both maternal opiate addiction and new methods of treating NAS, state and federal systems may pay in the future because many of these infants require special services for developmental and behavioral disorders. Patrick et al also observed that over the last decade, there has been no improvement in NAS treatment efficiency as measured by length of stay (LOS). Furthermore, health care expenditures for NAS have increased during the same period. Even within the context of the status quo of medically managed prenatal methadone treatment, opiate-exposed infants risk adverse effects besides the specter of protracted withdrawal. In their analyses of hospital complications of infants with NAS, Patrick et al confirmed other data demonstrating increased rates of prematurity, respiratory disease, and seizures. Opiate withdrawal is often compounded by comorbid polydrug exposure and maternal psychiatric medications, such as antidepressants and benzodiazepines, which have their own withdrawal syndromes. Although the withdrawal from these agents is milder than opiates, such combinatorial withdrawal complicates neonatal care and often extends LOS. Neonatal abstinence syndrome withdrawal severity affects adaptation to postnatal life in critical regulatory areas of sleep, feeding, and autonomic function. Although 60% to 80% of infants exposed in utero to opiates develop NAS and require prolonged hospitalization, averaging 16 days in the study by Patrick et al, there is still considerable uncertainty regarding optimal detoxification protocols and criteria for opiate withdrawal status typically based on symptoms assessed by the Finnegan score calculated every few hours from birth to day 5. Hospitals and clinicians burdened by the increase in NAS incidence can expend substantial efforts to develop treatment protocols to decrease LOS. As outlined by Patrick et al, most clinicians use oral opiate medication (eg, methadone or morphine) and, in difficult cases, a second-line nonopiate drug with -aminobutyric acid (eg, phenobarbital), benzodiazepine (eg, clonazapam), or anti-adrenergic (eg, clonidine) action. Novel pharmacotherapy research is needed to improve maternal opiate maintenance strategies to protect the fetus from in utero withdrawal, and to reduce the incidence and severity of NAS. These efforts have been frustrated by lack of controlled clinical trials. Methadone maintenance therapy during pregnancy is currently idiosyncratic (eg, lack of standardization in maternal care related todosing)andbasedonmaternalwithdrawal symptoms as gestation progresses. Research aimed at predicting which newborns are most at risk for a difficult withdrawal, or will require prompt treatment, has yielded few leads. In the adult pain management literature, individual genetic differences have been found to predict opiate response and dose

Epigenetic Variation in the Mu-Opioid Receptor Gene in Infants with Neonatal Abstinence Syndrome

OBJECTIVE Neonatal abstinence syndrome (NAS) from in utero opioid exposure is highly variable with genetic factors appearing to play an important role. Epigenetic changes in cytosine:guanine (CpG) dinucleotide methylation can occur after drug exposure and may help to explain NAS variability. We correlated DNA methylation levels in the mu-opioid receptor (OPRM1) promoter in opioid-exposed infants with NAS outcomes. STUDY DESIGN DNA samples from cord blood or saliva were analyzed for 86 infants who were being treated for NAS according to institutional protocol. Methylation levels at 16 OPRM1 CpG sites were determined and correlated with NAS outcome measures, including need for treatment, treatment with ≥ 2 medications, and length of hospital stay. We adjusted for covariates and multiple genetic testing. RESULTS Sixty-five percent of infants required treatment for NAS, and 24% required ≥ 2 medications. Hypermethylation of the OPRM1 promoter was measured at the -10 CpG in treated vs nontreated infants (adjusted difference δ = 3.2% [95% CI, 0.3-6.0%], P = .03; nonsignificant after multiple testing correction). There was hypermethylation at the -14 (δ = 4.9% [95% CI, 1.8%-8.1%], P = .003), -10 (δ = 5.0% [95% CI, 2.3-7.7%], P = .0005), and +84 (δ = 3.5% [95% CI, 0.6-6.4], P = .02) CpG sites in infants requiring ≥ 2 medications, which remained significant for -14 and -10 after multiple testing correction. CONCLUSIONS Increased methylation within the OPRM1 promoter is associated with worse NAS outcomes, consistent with gene silencing.

Sleep-Related Nighttime Crying (Yonaki) in Japan: A Community-Based Study

Objective. To examine factors associated with the phenomenon of yonaki, or sleep-related nighttime crying (SRNC), in Japanese children Methods. A cross-sectional design incorporating parental self-report was used to investigate relationships between developmental, psychologic, and constitutional/physiological factors in the incidence of SRNC. Participants were the parents of 170 infants, 174 toddlers, and 137 children at a well-infant clinic in Tokyo, Japan. Results. The lifetime incidence rates of SRNC were 18.8% (infants), 64.9% (toddlers), and 59.9% (children). At all ages, children were most likely to cosleep with their parents; however, infants with reported SRNC were found to cosleep more frequently, whereas infants without SRNC were more likely to sleep in separate, child-dedicated beds. Toddlers with frequent SRNC were more likely to have irregular bedtimes and to have nonparental day care than were those without SRNC. Preschoolers who typically slept 9.5 to 10.5 hours per night were less likely to report SRNC than were children with longer or shorter nighttime sleep durations. In all groups, children with frequent SRNC were more likely to suffer from chronic eczema, and toddlers and preschoolers with SRNC exhibited bruxism more frequently. Conclusions. The traditional Japanese arrangement of cosleeping represents an environment in which parents are readily accessible to children during waking episodes. Physical proximity to the parents in infancy, but not at other ages, is associated with SRNC. The higher incidence of bruxism, chronic eczema, and day care use among children with frequent SRNC supports the hypothesis that nighttime anxiety may promote SRNC.

Methadone versus morphine for treatment of neonatal abstinence syndrome: A prospective randomized clinical trial

Objective:Compare duration of treatment of neonatal abstinence syndrome between methadone and morphine.Study design:A prospective, double-masked, randomized trial at a single site. Randomization of methadone or morphine was stratified for maternal treatment with methadone or buprenorphine. Inclusion criteria were (i) maternal treatment with prescribed methadone or buprenorphine, (ii) withdrawal treatment criteria, (iii) adjusted gestational age ⩾350/7 weeks and (iv) medically stable. Primary outcome was length of opioid treatment.Result:From January 2011 through October 2012, 78 infants were eligible for the study: 41 methadone-exposed and 37 buprenorphine-exposed. Consent was obtained from 31 mothers, 13/41 (32%) methadone-treated and 18/37 (49%) buprenorphine-treated. Length of opioid treatment was significantly shorter for methadone than morphine treatment, median 14 versus 21 days (P=0.008).Conclusion:Methadone had a shorter length of neonatal withdrawal treatment compared with morphine. Owing to the smaller sample size and single site, a larger randomized study is needed.

Sleep fragmentation and evidence for sleep debt in alcohol-exposed infants

BACKGROUND Infants exposed prenatally to alcohol are at increased risk for poor neurodevelopmental outcome including Sudden Infant Death Syndrome. AIM To examine the relationship between prenatal alcohol exposure, sleep, arousal and sleep-related spontaneous motor movements in early infancy. STUDY DESIGN Low-income women (N=13) were interviewed regarding pre- and pregnancy rates of alcohol, cigarette smoking and other substance use in the perinatal period. Infants were examined in a laboratory nap study using EEG, videography and actigraphy at 6-8 weeks of age. Estimates of maternal pre- and pregnancy alcohol use were used to divide infants into high vs. low maternal alcohol use groups. SUBJECTS Mother-infant dyads recruited from a family practice clinic. OUTCOME MEASURES Sleep-related spontaneous movements, behavioral state, and maternal assessments of infant alertness and irritability. RESULTS Pre-pregnancy rates of alcohol consumption including binge drinking correlated with maternal report of poor infant alertness, and increased irritability. High maternal exposure groups showed increased sleep fragmentation, e.g., frequency and duration of wakefulness following sleep onset and decreased active sleep. Bout analysis of the temporal structure of sleep-related spontaneous movements showed significantly reduced bout duration associated with high maternal alcohol use. CONCLUSION These results present evidence that prenatal alcohol exposure disrupts postnatal sleep organization and suppresses spontaneous movements during sleep, and increased sleep fragmentation promotes sleep deprivation. Results are consistent with the SIDS model of chronic sleep debt and suggest that attenuated sleep-related movements should be examined as an important modulator of cardiorespiratory functions during sleep in high-risk groups.

Apneic preterms and methylxanthines: Arousal deficits, sleep fragmentation and suppressed spontaneous movements

Objective:To determine if apneic preterm infants currently treated with methylxanthines develop evidence of sleep deprivation from cumulative arousal and motor activational effects.Study Design:Sleep, wake, arousal and actigraphic movements were monitored in extubated clinically stable premature infants (N=37). Neonates were free of other medications for >72 h and were grouped based on methylxanthine exposure: >5 days with caffeine (n=14), >5 days theophylline (n=13) or no prior exposure (n=10).Result:Duration of methylxanthine treatment predicted increased arousals, wakefulness and actigraphic movements, and decreased active sleep. Recording from 1200 to 0500 hours, methylxanthine-treated groups showed reductions in all arousal parameters: waking state, number of wake epochs, brief arousals and composite arousal index, and shorter fast-burst, sleep-related motility than untreated controls.Conclusion:In apneic preterms, chronic methylxanthine treatment appears to produce sleep deprivation secondary to the stimulatory action of methylxanthines on arousal and motor systems.

Variations in opioid receptor genes in neonatal abstinence syndrome

BACKGROUND There is significant variability in the severity of neonatal abstinence syndrome (NAS) due to in-utero opioid exposure. We wanted to determine if single nucleotide polymorphisms (SNPs) in key candidate genes contribute to this variability. METHODS Full-term opioid-exposed newborns and their mothers (n=86 pairs) were studied. DNA was genotyped for 80 SNPs from 14 genes utilizing a custom designed microarray. The association of each SNP with NAS outcomes was evaluated. RESULTS SNPs in two opioid receptor genes in the infants were associated with worse NAS severity: (1) The PNOC rs732636 A allele (OR=3.8, p=0.004) for treatment with 2 medications and a longer hospital stay (LOS) of 5.8 days (p=0.01), and (2) The OPRK1 rs702764 C allele (OR=4.1, p=0.003) for treatment with 2 medications. The OPRM1 rs1799971 G allele (β=-6.9 days, p=0.02) and COMT rs740603 A allele (β=-5.3 days, p=0.01) were associated with shorter LOS. The OPRD1 rs204076 A allele in the mothers was associated with a longer LOS by 6.6 days (p=0.008). Results were significant point-wise but did not meet the experiment-wide significance level. CONCLUSIONS These findings suggest that SNPs in opioid receptor and the PNOC genes are associated with NAS severity. However, further testing in a large sample is warranted. This has important implications for prenatal prediction and personalized treatment regimens for infants at highest risk for severe NAS.

Neonatal desipramine treatment alters free-running circadian drinking rhythms in rats

Neonatal treatment with monoamine reuptake inhibitors results in a constellation of neurobehavioral alterations in adult rats that may model human depression. Since alterations in circadian rhythmicity have been reported in both depressed patients and in animal depression models, the present study examined the effects of neonatal desipramine treatment (5.0 mg/kg SC from postnatal day 7 through 22) on free-running circadian drinking rhythms. Rhythmicity was examined in constant darkness (DD), constant light (LL), and during adult desipramine treatment (0.25 mg/ml via the drinking water). Compared with saline-treated controls, neonatal desipramine lengthened free-running period in DD, blunted the period-altering effect of LL, and potentiated the period-altering effect of adult desipramine treatment. Neonatal desipramine treatment also increased circadian amplitude and spectral magnitude, but did not modify the effects of light or adult desipramine on these parameters. These results provide further evidence that behavioral depression is associated with alterations in circadian rhythmicity, and are consistent with the hypothesis that such relationships are mediated by brain monoaminergic systems.