Opioids and the developing brain: time to rethink perinatal care for infants of opioid-dependent mothers.

Illicit use of opioids is a global health crisis with major implications for women and children. Strategies for managing opioid use disorder (OUD) in pregnancy have been tested over the past 40 years, but studies have focused on maternal and pregnancy outcomes, with less attention given to long-term follow-up of exposed children. Here, we provide a narrative review of recent advances in the assessment and management of neonatal opioid withdrawal syndrome (NOWS), and we summarise evidence from multiple domains-neuroimaging, electrophysiology, visual development and function, neurodevelopment, behaviour, cognition and education-which suggests that prenatal opioid exposure modifies child development. Further studies are required to determine the optimal management of pregnant women with OUD and babies with NOWS. We identify knowledge gaps and suggest that future study designs should evaluate childhood outcomes, including infant brain development and long-term neurocognitive and visual function.

Maternal Exposure and Neonatal Effects of Drugs of Abuse.

The public health crisis of pregnant women being exposed to drugs of abuse and of its impact on their unborn children continues to grow at an alarming rate globally. The state of pregnancy is unique, with physiological changes that can lead to changes in the way drugs are handled by the body in both pharmacokinetics and response. These changes place the pregnant woman, fetus, and newborn infant at risk, as many of these drugs can cross the placenta and into breast milk. The substances most commonly linked to harmful effects include alcohol, tobacco, cannabis, stimulants, and opioids. The pharmacological and toxicological changes caused by in utero exposure or breastfeeding exposure are difficult to study, and the full extent of the mechanisms involved are not fully understood. However, these changes can significantly affect the risks of substance abuse and influence optimal treatment of pregnant women with a substance use disorder. In addition, newborns who were exposed to drugs of abuse in utero can experience withdrawal syndromes. Pharmacological management in infants is used to guide and treat withdrawal symptoms, with the goal being to improve the infant's sleep, eating, and comfort. Several barriers may prevent pregnant women from seeking help for substance use, including stigma and interactions with the legal system. Understanding changes in pharmacology, including pharmacokinetic changes that happen during pregnancy, is essential for anticipating the extent of maternal exposure and neonatal adverse effects.

Prenatal opioid exposure - Increasing evidence of harm.

Prenatal opioid exposure adversely impacts upon fetal growth and places the newborn at risk of neonatal opioid withdrawal. The severity and duration of opioid withdrawal cannot be predicted in the individual baby and may be contributed to by other drugs including benzodiazepines and alcohol as well as cigarette smoking. Mitigating factors include breastfeeding, rooming in and absence of maternal polypharmacy. Less well recognised are a variety of other complications associated with prenatal opioid exposure including epigenetic changes, effects on neurophysiological function and structural alterations to the developing brain. The visual system is significantly affected, with changes to both clinical and electrophysiological function persisting at least to mid-childhood. Longer term neurodevelopmental and behavioural outcomes are confounded by multiple factors including poverty, parent-child interaction and small study numbers, but systematic reviews consistently demonstrate poorer outcomes for those children and young people prenatally exposed to opioids. Crucially, manifestation of neonatal withdrawal is not a prerequisite for important long term problems including behavioural, emotional or motor function disorder, sensory or speech disorder, strabismus and nystagmus. A body of evidence supports an independent adverse effect of prenatal opioid exposure upon fetal brain development, mediated via a systemic neuro-inflammatory process. Children prenatally exposed to opioids should remain under appropriate follow up, at least until school entry, as difficulties may only become apparent in mid-childhood. Future studies of the management of opioid use disorder in pregnancy, including maintenance methadone, must include longer term outcomes for the baby.

Prenatal tobacco, marijuana, stimulant, and opiate exposure: outcomes and practice implications.

Abuse of drugs by pregnant women both in the United States and worldwide has raised many questions regarding the effects of prenatal drug exposure on the developing fetus and subsequent child outcomes. Studies using the neurobehavioral teratology model have been undertaken to determine specific prenatal drug effects on cognitive and behavioral development. Here we summarize the findings of studies that have investigated the developmental effects of prenatal exposure to tobacco, marijuana, stimulants, and opiates. These studies consider the timing and amount of prenatal exposure; other drug exposures; maternal characteristics; and other health, nutritional, and environmental factors. We review treatment options for pregnant, substance-dependent women and therapeutic interventions for exposed children.

Tolerance and addiction; the patient, the parent or the clinician?

Tolerance has been recognized for some time where chronic exposure to certain drugs, particularly benzodiazepines and opioids, is associated with apparent tachyphylaxis. When these drugs are stopped or progressively reduced as in 'tapering', withdrawal symptoms may result. Tolerance and the flip side of the coin, withdrawal, are the determinants of addiction. It is increasingly apparent that tolerance can occur acutely, even within the time span of a single anesthetic for a surgical procedure. Addiction is caused by agents, foreign to the body, that provoke adaptation by homeostatic biological processes. When these agents are withdrawn, the adaptive mechanisms, devoid of substrate, take time to diminish and produce symptoms recognizable under the term of 'withdrawal'. Children may be exposed to these agents in different ways; in utero, as a result of substances that the mother ingests by enteral, parenteral or inhalational means that are transmitted to the infant via the placenta; as a result of an anesthetic for surgery; or as a result of sedation and analgesia administered to offset the stresses and trauma inherent from intensive care treatment in the neonatal intensive care unit or pediatric intensive care unit. Additionally, anesthetic and intensive care staff are exposed to powerful and addictive drugs as part of everyday practice, not simply by overt access, but also by subliminal environmental exposure.

Infant autonomic functioning and neonatal abstinence syndrome.

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 25-35% 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.

Vagus nerve stimulation (VNS) is effective in treating catastrophic 1 epilepsy in very young children.

The objective of this study is to evaluate the safety and efficacy of vagus nerve stimulation (VNS) in very young children suffering from catastrophic epilepsy and status epilepticus. We reviewed files of 60 VNS-implanted children at our institution and we selected six very young patients, less than 3 years old (mean age at implant 1.6 years). All patients suffered from severe cognitive impairment and catastrophic epilepsy with underlying diagnosis of hemimegalencephaly (1), hypoxic-ischemic encephalopathy (1), tuberous sclerosis complex (1), and malignant migrating partial epilepsy of infancy (3). Three patients were VNS-implanted during admission at intensive care unit (ICU) after developing life-threatening status epilepticus. The mean follow-up time was 41.6 months. The VNS was implanted using a single cervical incision. No surgery-related complications were observed. Four of six children have shown a significant, persistent improvement in seizure control (range, 60-90%). In patients with status, insertion of the vagal nerve stimulator allowed early cessation of status and discharge from ICU. Quality of life and parental satisfaction improved and for three children there was some milestone evolution. Catastrophic epilepsy in infancy can be devastating and difficult to treat with drugs and surgery. If resective surgery is inappropriate or refused, VNS can be considered as a well-tolerated and effective procedure even in toddlers affected by severe epilepsy and multiple developmental disabilities.

Prospective randomised comparative study of the effect of buprenorphine, methadone and heroin on the course of pregnancy, birthweight of newborns, early postpartum adaptation and course of the neonatal abstinence syndrome (NAS) in women followed up in the outpatient department.

OBJECTIVE: The aim of the study was to evaluate the effect of substitution therapy in heroin addicted pregnant women on the course of pregnancy, perinatal outcomes and course of the neonatal abstinence syndrome. DESIGN OF THE STUDY: A five-year randomised prospective comparative study METHODS: The study was carried out in the period of 2002-2007. The group of patients included 147 i.v. heroin-addicted pregnant women. All of them were outpatients of our Perinatal Care Unit. Their daily dose of heroin was approximately lg. Later, 30 women were disqualified from the study for breaking the randomised criteria engagement. The substitution therapy in women who agreed to undergo it, started during the I. trimester of pregnancy. Finally, 47 heroin, 32 methadone and 38 buprenorphine addicted women were enrolled in the study. Birthweight of newborns was compared with the national birthweight tables. Severity and duration of neonatal abstinence syndrome (NAS) were evaluated by Finnegan s score scale. RESULTS: None of the women delivered before the end of 34th gestational week. We did not encounter any perinatal death or developmental defect. The lowest birthweight, the highest number of newborns with IUGR and the most numerous placental changes were found in the group of heroin-addicted women. The differences compared to the two groups receiving substitution therapy were statistically significant (p < 0.05). The severity and course of NAS were the most severe (p < 0.001) in newborns of women from the methadone group. CONCLUSION: Comparison of the groups of outpatients is in many ways questionable because of the restricted possibility of the patients' control. The lifestyle of addicted women has the same impact as the drug use alone. This is probably the main reason for differences in some of the monitored parameters between individual groups. Based on our results we can state that substitution therapy provides pregnant women with the possibility of social stabilization and adequate prenatal care. substitution therapy decreases the street heroin consumption. Methadone notably protracts the newborn's abstinence syndrome. With regard to this fact, attention has been recently focused on substitution with buprenorphine that seems to be from this viewpoint a more considerate option.

Prenatal methamphetamine use and neonatal neurobehavioral outcome.

BACKGROUND: Methamphetamine (MA) use among pregnant women is an increasing problem in the United States. How prenatal MA exposure affects neonatal neurobehavior is unknown. OBJECTIVE: To examine the neurobehavioral effects of prenatal MA exposure. DESIGN: The Infant Development, Environment and Lifestyle (IDEAL) study screened 13,808 subjects and 1632 were eligible and consented. 166 (n=74 exposed) were enrolled in a longitudinal follow-up. Exposure was determined by meconium assay and self-report with alcohol, marijuana, and tobacco present in both groups. The NICU Network Neurobehavioral Scale (NNNS) was administered within the first 5 days of life. Analyses conducted on NNNS summary scores included exposure group effects, heavy MA use effects, association with frequency of use by trimester, and dose-response relationships with amphetamine metabolites. RESULTS: After adjusting for covariates, exposure to MA was associated with increased physiological stress. Heavy MA use was related to lower arousal, more lethargy, and increased physiological stress. First trimester MA use was related to elevated stress abstinence. Third trimester use was related to poorer quality of movement. Higher level of amphetamine metabolites in meconium was associated with increased CNS stress. CONCLUSIONS: Prenatal MA exposure was associated with neurobehavioral patterns of decreased arousal, increased stress, and poor quality of movement. The dose-response relationships may represent neurotoxic effects from MA.

Illicit drug use and neonatal outcomes: a critical review.

Although the neonatal consequences of tobacco and alcohol exposure are well established, the evidence related to prenatal illicit drug use is less consistent despite prevalent views to the contrary. The many social, psychosocial, behavioral, and biomedical risk factors for adverse birth outcomes associated with illicit drug use complicate the evaluation of neonatal effects. Placing emphasis on recent research, this review summarizes the epidemiologic literature on the neonatal impact of marijuana, opiate, and cocaine use. Of these drugs, cocaine use is most consistently related to fetal growth decrements and dose-response effects have been observed. However, studies to date have largely failed to control for associated social, psychosocial, and contextual factors. Additional recommendations for future research are provided. It is likely that interventions will need to address the factors surrounding drug use to greatly improve neonatal outcomes (e.g., social circumstances, poor nutrition, stress, infections).

TDM grand rounds: neonatal nicotine withdrawal syndrome in an infant prenatally and postnatally exposed to heavy cigarette smoke.

A heavy smoking, lactating mother delivered a baby that exhibited spontaneous tremors, fluctuations of muscular rigidity, and opisthotonus at 48 hours of life. Although the symptoms did not disappear within the following days, they could be controlled by swaddling or wrapping the baby in a blanket. The absence of any other etiology generated a suspicion of prenatal exposure to heavy tobacco smoke and potential neonatal nicotine withdrawal syndrome. This diagnosis was supported by extremely high concentration of hair nicotine and cotinine in the infant's hair and in different segments of maternal hair. The presence of non-negligible amounts of nicotine and cotinine in breast milk confirmed that the mother did not quit smoking after delivery, despite her reports. The breast-fed newborn continued to have 3 to 4 crises of spontaneous tremors and alternant muscular rigidity per day for a month. More studies are needed to establish neonatal nicotine withdrawal.

Neonatal abstinence syndrome in methadone-exposed infants is altered by level of prenatal tobacco exposure.

Maternal tobacco consumption during pregnancy has been associated with lower birth weight infants, preterm births, intrauterine growth retardation, smaller head circumference and increase in morbidity, yet few studies have examined the role tobacco has on the opiate neonatal abstinence syndrome (NAS). This study examined the effect of prenatal tobacco exposure on NAS for infants born to mothers maintained on methadone during gestation. Twenty-nine pregnant women and their newborn infants participated in this study. Tobacco exposure was based on maternal self-report with 16 women reporting cigarette consumption of 10 or less per day and 13 reporting smoking 20 cigarettes or more a day. The onset, peak, and duration of NAS were examined. Results showed that infants born to mothers who reported smoking 20 or more cigarettes per day had significantly higher NAS peak scores of 9.8 versus 4.8, and took longer to peak (113.0 h versus 37.8 h), than light smokers of 10 or fewer cigarettes per day. We concluded that tobacco use in conjunction with methadone plays an important role in the timing and severity of NAS in prenatally exposed infants.

Maternal methadone dose and neonatal withdrawal.

OBJECTIVE: The purpose of this study was to determine whether maternal methadone dosage correlates with neonatal withdrawal in a large heroin-addicted pregnant population. STUDY DESIGN: A retrospective review of all maternal/neonatal records of pregnancies that were maintained on methadone therapy in our institution was conducted. After in-hospital stabilization, women were given daily methadone therapy under direct surveillance, with liberal dosage increases according to maternal withdrawal symptoms. Neonatal withdrawal was assessed objectively by the neonatal abstinence score. The average methadone dose in the last 12 weeks of pregnancy and the last methadone dose before delivery (cutoffs of 40, 60, or 80 mg) were correlated to various objective measures of neonatal withdrawal. RESULTS: One hundred mother/neonate pairs on methadone therapy were identified. Women who received an average methadone dose of <80 mg (n=50 women) had a trend toward a higher incidence of illicit drug abuse before delivery than women who received doses of >/=80 mg (n=50 women; 48% vs 32%; P=.1). Women who received an average methadone dose of <80 mg had similar highest neonatal abstinence score, need for neonatal treatment for withdrawal, and duration of withdrawal compared with women whose condition was maintained with dosages of >/=80 mg (score, 11.1 vs 11.5; 68% vs 66%; and 13.3 vs 13.6 days, respectively; all P>.5). For all cutoffs that were used for high versus low dose and for both the average and last methadone dosage analyses, neonatal withdrawal was similar. CONCLUSION: The maternal methadone dosage does not correlate with neonatal withdrawal; therefore, maternal benefits of effective methadone dosing are not offset by neonatal harm.

Sleep in babies born to chronically heroin addicted mothers. A follow up study.

The effects of chronic addiction to, and withdrawal from, opiates on sleep have been described in experimental animals, in human adults and infants born to addicted mothers. These sleep alterations are seen through the first weeks of life. Thirteen maternally addicted babies were studied. Sleep samples were recorded and scored within a few days following birth and repeated 4 or 5 weeks later after recovery from the abstinence syndrome. A significant decrease in quiet sleep and increase of active sleep were found. The same alterations, although less marked, were observed in a follow up recording performed during the second month of life. Sleep alterations in addicted newborns could be related to central nervous system (CNS) distress caused by withdrawal. The authors however propose a perturbation of endogenous opiates subsequent to fetal addiction as a cause of sleep alterations.

Perinatal cocaine and methamphetamine exposure: maternal and neonatal correlates.

Maternal and neonatal growth, behavior, and physiologic organization were evaluated in 104 mother-infant pairs with positive results of urine toxicology screens. ANOVA comparison of cocaine, methamphetamine, and cocaine plus methamphetamine groups revealed no significant differences in perinatal variables. The Finnegan withdrawal scoring scheme demonstrated that all three groups of infants had altered neonatal behavioral patterns, characterized by abnormal sleep patterns, poor feeding, tremors, and hypertonia. Infants exposed to cocaine or methamphetamine or both were combined and compared with both narcotic-exposed and drug-free mother-infant pairs matched for known maternal risk factors. All drug-exposed groups had significantly higher rates of prematurity and intrauterine growth retardation and smaller head circumferences than did the drug-free comparison group. A significantly higher rate of placental hemorrhage occurred in the cocaine plus methamphetamine group. Stepwise multiple regression analysis assessed the independent contribution of maternal factors; cocaine or methamphetamine was adversely, negatively associated with gestational age, birth weight, length, and occipitofrontal circumference. The increased rate of prematurity, intrauterine growth retardation, and perinatal complications associated with perinatal exposure to cocaine or methamphetamine was greater than that predicted by coexisting risk factors and was consistent with the pharmacologic properties of these drugs.