Characterization of neonatal opioid withdrawal syndrome in Arizona from 2010-2017.

In this paper, we describe a population of mothers who are opioid dependent at the time of giving birth and neonates exposed to opioids in utero who experience withdrawal following birth. While there have been studies of national trends in this population, there remains a gap in studies of regional trends. Using data from the Arizona Department of Health Services Hospital Discharge Database, this study aimed to characterize the population of neonates with neonatal opioid withdrawal syndrome (NOWS) and mothers who were opioid dependent at the time of giving birth, in Arizona. We analyzed approximately 1.2 million electronic medical records from the Arizona Department of Health Services Hospital Discharge Database to identify patterns and disparities across socioeconomic, ethnic, racial, and/or geographic groupings. In addition, we identified comorbid conditions that are differentially associated with NOWS in neonates or opioid dependence in mothers. Our analysis was designed to assess whether indicators such as race/ethnicity, insurance payer, marital status, and comorbidities are related to the use of opioids while pregnant. Our findings suggest that women and neonates who are non-Hispanic White and economically disadvantaged, tend be part of our populations of interest more frequently than expected. Additionally, women who are opioid dependent at the time of giving birth are unmarried more often than expected, and we suggest that marital status could be a proxy for support. Finally, we identified comorbidities associated with neonates who have NOWS and mothers who are opioid dependent not previously reported.

Enduring consequences of perinatal fentanyl exposure in mice.

Opioid use by pregnant women is an understudied consequence associated with the opioid epidemic, resulting in a rise in the incidence of neonatal opioid withdrawal syndrome (NOWS) and lifelong neurobehavioral deficits that result from perinatal opioid exposure. There are few preclinical models that accurately recapitulate human perinatal drug exposure and few focus on fentanyl, a potent synthetic opioid that is a leading driver of the opioid epidemic. To investigate the consequences of perinatal opioid exposure, we administered fentanyl to mouse dams in their drinking water throughout gestation and until litters were weaned at postnatal day (PD) 21. Fentanyl-exposed dams delivered smaller litters and had higher litter mortality rates compared with controls. Metrics of maternal care behavior were not affected by the treatment, nor were there differences in dams' weight or liquid consumption throughout gestation and 21 days postpartum. Twenty-four hours after weaning and drug cessation, perinatal fentanyl-exposed mice exhibited signs of spontaneous somatic withdrawal behavior and sex-specific weight fluctuations that normalized in adulthood. At adolescence (PD 35), they displayed elevated anxiety-like behaviors and decreased grooming, assayed in the elevated plus maze and sucrose splash tests. Finally, by adulthood (PD 55), they displayed impaired performance in a two-tone auditory discrimination task. Collectively, our findings suggest that perinatal fentanyl-exposed mice exhibit somatic withdrawal behavior and change into early adulthood reminiscent of humans born with NOWS.

Head circumference in infants with nonopiate-induced neonatal abstinence syndrome.

BACKGROUND: No relationship has been reported between nonopiate neonatal abstinence syndrome (NAS) and anthropometric indices, including head circumference (HC). The purpose of this study was to determine the relationship between maternal nonopioid drug use and HC at birth in neonates with NAS. METHODS: This retrospective observational study included neonates born between January 1, 2010 and March 31, 2019, whose mothers had been taking antipsychotic, antidepressant, sedative, or anticonvulsant medications. The outcome measures were HCs of NAS infants and controls. RESULTS: Of 159 infants, 33 (21%) were diagnosed with NAS. There was no maternal opioid use among mothers during pregnancy. The HCs in the NAS group were significantly smaller than those in the control group. The median z-scores for HC at birth were -0.20 and 0.29 in the NAS group and the control group, respectively (P = .011). The median HCs at birth were 33.0 and 33.5 cm in the NAS group and the control group, respectively. Multivariate analysis revealed that maternal antipsychotic drug use and selective serotonin reuptake inhibitors were independently associated with NAS (P < .001 and P = .004, respectively). Notably, benzodiazepine use and smoking were not independent risk factors. CONCLUSIONS: The results suggest an association between maternal antipsychotic drug use and NAS, which was further associated with decreased HC. Careful monitoring of maternal drug use should be considered to improve fetal outcomes.

Complications in pregnant women with sickle cell disease.

Pregnancy in women with sickle cell disease (SCD) is associated with increased maternal and fetal morbidity and mortality. Outcomes vary widely owing to methodological limitations of clinical studies, but overall, hypertensive disorders of pregnancy, venothromboembolism, poor fetal growth, and maternal and perinatal mortality are increased globally. Few therapeutic interventions have been explored other than prophylactic and selective transfusion therapy. Unfortunately, existing data are limited, and it remains unclear whether prophylactic use of chronic transfusions will improve pregnancy outcomes. Management of pregnant women with SCD is best accomplished with a multidisciplinary team that includes a sickle cell expert and an obstetrician familiar with high-risk pregnancies. Women with SCD should have individualized care plans that outline management of acute pain and guidelines for transfusion therapy. Neonates require close monitoring for neonatal abstinence syndrome and hemolytic disease of the newborn. Ideally all young women with SCD will have a "reproductive life plan" developed as a component of preconception counseling and health promotion. Research leading to improved pregnancy management focused on diminishing adverse maternal and neonatal outcomes is overdue. International collaborations should be considered to improve subject recruitment and foster timely completion of clinical trials. Additional therapeutic interventions outside of transfusion therapy should be explored.

Neonatal abstinence syndrome and the gastrointestinal tract.

Development of a healthy gut microbiome is essential in newborns to establish immunity and protection from pathogens. Recent studies suggest that infants who develop dysbiosis may be at risk for lifelong adverse health consequences. Exposure to opioid drugs during pregnancy is a factor of potential importance for microbiome health that has not yet been investigated. Since these infants are born after an entire gestation exposed to mu opioid receptor agonists and have severe gastrointestinal and neurological symptoms, we hypothesize that these infants are at risk for dysbiosis. We speculate that opioid exposure during gestation and development of NAS at birth may lead to a dysbiotic gut microbiome, which may impair normal microbiome succession and development, and impact future health of these children.

The effect of prenatal alcohol co-exposure on neonatal abstinence syndrome in infants born to mothers in opioid maintenance treatment.

OBJECTIVE: This study examined the effects of prenatal alcohol exposure (PAE) on the incidence and severity of neonatal abstinence syndrome (NAS). STUDY DESIGN: For this pilot study, 70 pregnant women on opioid maintenance therapy (OMT) were recruited from a perinatal substance abuse clinic. Subjects were categorized into three study groups based on the timing of alcohol use during pregnancy as assessed by repeated self-reported measures and a comprehensive panel of ethanol biomarkers. NAS outcomes included: duration of hospital stay, the need for pharmacological treatment of NAS, newborn age at the initiation of NAS treatment, duration of treatment and cumulative methadone dose administered. RESULTS: The study included a large proportion of ethnic minorities (81.4% Hispanic, 5.7% American Indian), women with less than a high school education (52.2%) and unplanned pregnancy (82.9%). In multivariate analysis, PAE was not associated with NAS outcomes; however, one newborn diagnosed with fetal alcohol syndrome (FAS) demonstrated much more severe NAS compared to other PAE infants. Interestingly, 3rd trimester PAE was associated with a higher prevalence of microcephaly (62.5%) compared to the PAE abstaining group (36.8%; p = 0.08). CONCLUSION: In this study, PAE was not associated with NAS severity; however, further examination in a larger study is needed.

Prenatal methadone exposure and neonatal neurobehavioral functioning.

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 was also evaluated. Infants who required pharmacologic treatment for NAS showed more dysregulated behavior and signs of stress and 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 nonpharmacologic care.

Opioid maintenance treatment during pregnancy: occurrence and severity of neonatal abstinence syndrome. A national prospective study.

BACKGROUND: Opioid maintenance treatment (OMT) is widely used to treat pregnant women with a history of opioid dependence. This study investigated whether maternal methadone/buprenorphine dose and nicotine use in pregnancy affects the occurrence and duration of neonatal abstinence syndrome (NAS) in the infant. METHODS: Forty-one pregnant women from OMT programmes in Norway who gave birth between January 2005 and January 2007 were enrolled in a national prospective study. Thirty-eight women (81% of the population) were interviewed in the last trimester of pregnancy and 3 months after delivery. Data from the European Addiction Severity Index and a questionnaire measuring enrolled birth information were compared with medical records and urine analyses. RESULTS: Treatment requiring NAS occurred in 58% of the methadone-exposed and in 67% of the buprenorphine-exposed infants. There was no significant relationship between a maternal dose of methadone or buprenorphine in pregnancy and NAS treatment duration for the infant. The mean number of cigarettes consumed correlated significantly with NAS treatment duration for the methadone group. Birth weight for the methadone group was approximately 200 g above international findings despite high doses during pregnancy. CONCLUSIONS: Maternal methadone/buprenorphine dose predicted neither the occurrence nor the need for NAS treatment for the infant.

Neonatal withdrawal syndrome after chronic maternal drinking of mate.

The premature newborn of a mother who reported drinking mate during pregnancy presented with increased jitteriness and irritability, high-pitched cry, hypertonia in the limbs, and brisk tendon reflexes consistent with neonatal withdrawal syndrome. High concentrations of caffeine and theobromine were detected in various maternal and neonatal biological matrices (placenta, cord serum, neonatal urine, maternal and neonatal hair, meconium, and breast milk), demonstrating both acute and chronic prenatal and postnatal exposure to these methylxanthines, contained in high amounts in homemade mate. Symptoms progressively disappeared at 84 hours of age, although intermittent irritability was still present when the infant was discharged at 24 days of age. Fluctuating caffeine (and theobromine) content in different breast milk feeds likely generated the baby's irritability, due to either the physiological stimulatory effects of the methylxanthines or postnatal withdrawal syndrome as the substances cleared from the body. The mother was strongly advised to initiate a considerable, progressive, constant reduction of mate consumption to a maximum of 2 cups a day for the duration of breastfeeding.

Can venlafaxine in breast milk attenuate the norepinephrine and serotonin reuptake neonatal withdrawal syndrome.

A newborn infant whose mother had used venlafaxine, a selective inhibitor of both norepinephrine and serotonin reuptake, throughout pregnancy exhibited signs consistent with the norepinephrine and serotonin reuptake withdrawal syndrome. Is it possible that mother's milk can help mitigate the effects of norepinephrine and serotonin reuptake withdrawal? Pharmacokinetic analysis and review of the only published case with active treatment of a baby with venlafaxine suggest that breastfeeding may mitigate the neonatal withdrawal syndrome.

Role of noradrenergic hyperactivity in neonatal opiate abstinence.

Despite the existence of a well-defined abstinence syndrome in offspring of opiate-dependent mothers, the mechanisms involved in neonatal abstinence remain unclear. The goal of the present study was to determine the contribution of noradrenergic neurons in the opiate abstinence syndrome in neonatal rats (10 days old). First, the ability of the alpha 2-adrenergic agonist, clonidine to attenuate the symptoms of neonatal opiate abstinence precipitated by naloxone was determined. Secondly, the activity of noradrenergic neurons was determined by measuring postmortem levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) in the hypothalamus, hippocampus and cortex in opiate-abstinent pups. Neonatal opiate abstinence was characterized by an increased incidence of wall climbing, tremors and mouthing. Acute treatment with morphine and naloxone in chronic saline-treated pups also produced the tremor, albeit less severe than in pups treated chronically with morphine. Clonidine (0.2 mg/kg) attenuated the expression of tremor and mouthing in neonates, but increased wall climbing. Clonidine elicited wall climbing in opiate-naive neonates. Treatment with morphine followed by naltrexone increased MHPG levels in all of the brain areas examined, irrespective of the chronic treatment, but naltrexone treatment elicited a larger increase in MHPG levels in pups treated chronically with morphine. Acute morphine treatment increased MHPG levels only in the hypothalamus. The results of the present study provide behavioral and neurochemical data supporting the hypothesis that noradrenergic hyperactivity plays a role in neonatal opiate abstinence.

Congenital renal abnormalities in infants with in utero cocaine exposure.

To determine the incidence of renal abnormalities among infants exposed to cocaine in utero, we performed ultrasound studies of the genitourinary tract in 100 consecutive infants admitted to the full-term nursery whose mothers had a history of cocaine use during pregnancy and/or a maternal toxicology screen was positive for cocaine. Mean gestational age of the newborns was 38.4 +/- 2.1 weeks. Mean birth weight was 2,846 +/- 561 gm.; 26% of the patients were less than 2,500 gm. and 18% were small for gestational age. Symptoms of drug withdrawal were present in 47 patients. Two newborns had murmurs consistent with a ventricular septal defect. On ultrasonography, 1 newborn had a unilateral multicystic/dysplastic kidney and 1 had kidneys that were 2 standard deviations below normal in size. Based on our results routine renal ultrasound studies do not appear to be indicated in full-term newborns exposed in utero to cocaine.

[Diaplacental poisoning with narcotics and alcohol in newborn infants]. / Diaplazentare Intoxikation mit Rauschgift und Alkohol bei Neugeborenen.

In seven neonates, clinical symptoms detected on the first day of life appeared to show that toxicological investigations of the blood and urine were indicated in the mother and baby. In five mothers, there was known drug consumption. The investigations revealed toxic concentrations of morphine or cocaine in all babies; these could also be detected at comparable levels in the mothers. In a further case, a perinatal death must be attributed to acute diaplacental alcohol intoxication. The significance of toxicological investigations in neonates and perinatal deaths is also indicated.