Tove S. Rosen

Children of methadone-maintained mothers: Follow-up to 18 months of age

Limited information is available on the long-term effects of in utero methadone exposure. This report describes the somatic and neurobehavioral findings of children in the first 18 months of life born to methadone-maintained mothers and to a matched drug-free comparison group of mothers. Findings during the neonatal period were (1) a 75% incidence of moderate-to-severe narcotic abstinence syndrome, (2) a significant incidence of head circumferences below the third percentile, and (3) elevated systolic blood pressure. In follow-up, the methadone children had (1) a significantly higher incidence of otitis media; (2) a significant incidence of head circumferences below the third percentile; (3) neurologic findings of tone discrepancies, developmental delays, and poor fine motor coordination; (4) a high incidence of abnormal eye findings; and (5) significantly lower scores on the Bayley mental and motor developmental indices. These neurobehavioral findings in children of methadone-treated mothers at 18 months of age may be predictors of later learning and behavioral problems.

Pharmacologic observations on the neonatal withdrawal syndrome

The relationship between a maternal dose of methadone and the incidence and severity of neonatal signs of withdrawal, placental transfer of drug, and the relationship between maternal and neonatal plasma levels of methadone were studied in 30 mothers and their infants. Plasma levels of methadone were analyzed using a gas chromatographic method. Our studies demonstrate that the relationship between maternal dose of methadone and the incidence of neonatal withrawal symptoms was closely related to the last maternal dose of methadone. The ratio of neonatal to maternal plasma concentrations of methadone was 2.2:1. Neonatal withdrawal symptoms appear to be related to individual variation in maternal metabolism of the drug, placental transfer of methadone, and most importantly, to the individual variations in the rate of excretion of methadone as reflected in the neonatal plasma t 1/2. At plasma levels of methadone greater than or equal to 0.06 mug/ml, the symptomatic patients appeared to be protected from withdrawal. When the plasma concentration fell below this level, withdrawal symptoms began within 24 hours.

Epicardial border zone overexpression of skeletal muscle sodium channel, SkM1, normalizes activation, preserves conduction and suppresses ventricular arrhythmia: an in silico, in vivo, in vitro study

Background— In depolarized myocardial infarct epicardial border zones, the cardiac sodium channel (SCN5A) is largely inactivated, contributing to low action potential upstroke velocity (&OV0312; max), slow conduction, and reentry. We hypothesized that a fast inward current such as the skeletal muscle sodium channel (SkM1) operating more effectively at depolarized membrane potentials might restore fast conduction in epicardial border zones and be antiarrhythmic. Methods and Results— Computer simulations were done with a modified Hund-Rudy model. Canine myocardial infarcts were created by coronary ligation. Adenovirus expressing SkM1 and green fluorescent protein or green fluorescent protein alone (sham) was injected into epicardial border zones. After 5 to 7 days, dogs were studied with epicardial mapping, programmed premature stimulation in vivo, and cellular electrophysiology in vitro. Infarct size was determined, and tissues were immunostained for SkM1 and green fluorescent protein. In the computational model, modest SkM1 expression preserved fast conduction at potentials as positive as −60 mV; overexpression of SCN5A did not. In vivo epicardial border zone electrograms were broad and fragmented in shams (31.5±2.3 ms) and narrower in SkM1 (22.6±2.8 ms; P=0.03). Premature stimulation induced ventricular tachyarrhythmia/fibrillation >60 seconds in 6 of 8 shams versus 2 of 12 SkM1 (P=0.02). Microelectrode studies of epicardial border zones from SkM1 showed membrane potentials equal to that of shams and &OV0312; max greater than that of shams as membrane potential depolarized (P<0.01). Infarct sizes were similar (sham, 30±2.8%; SkM1, 30±2.6%; P=0.86). SkM1 expression in injected epicardium was confirmed immunohistochemically. Conclusions— SkM1 increases &OV0312; max of depolarized myocardium and reduces the incidence of inducible sustained ventricular tachyarrhythmia/fibrillation in canine infarcts. Gene therapy to normalize activation by increasing &OV0312; max at depolarized potentials may be a promising antiarrhythmic strategy.

Sympathetic neural modulation of cardiac impulse initiation and repolarization in the newborn rat.

We injected neonatal rats with nerve growth factor, the antiserum to nerve growth factor, or placebo for the first 10 days of life. Our goal was to determine the relation between sympathetic innervation of the developing heart, the electrocardiographic expression of cardiac rhythm, and the response of the heart to alpha-adrenergic stimulation with phenylephrine. We were especially interested in the latter area because of the prior demonstration in isolated cell systems of sympathetic neural modulation of a 41-kDa GTP regulatory protein and alpha-adrenergic responsiveness. Ten- to 11-day-old rats treated with nerve growth factor had more complete sympathetic innervation, faster heart rates, and higher levels of the 41-kDa protein than the placebo group. Electrophysiological studies were performed on isolated ventricular septa superfused with Tyrodes solution at 37.0 degrees-37.5 degrees C. The electrophysiological response of septa to 10(-9) and 10(-8) M phenylephrine from the 10-11-day-old nerve growth factor group was comparable with that of 3-week-old control animals. In contrast, 10-11-day-old antiserum-treated rats had an abnormal innervation pattern, lower levels of the 41-kDa protein, and a more immature electrophysiological response to alpha-adrenergic stimulation than the placebo group. In addition, antiserum-treated rats had an abnormally prolonged electrocardiographic QT interval. Our results demonstrate for the first time in intact animals a direct link between sympathetic innervation and alpha-adrenergic receptor-effector coupling as well as the dependence on innervation of the modulation of impulse initiation by alpha-agonists. This sequence of developmental events may be important not only in the regulation of normal cardiac rhythm but also in the expression of certain pathological entities such as the congenital long QT syndrome and the sudden infant death syndrome.

Methadone-Maintained Mothers: 3-Year Follow-Up of Parental Functioning

A group of 57 methadone-maintained mothers and 31 matched drug-free controls were compared on their ability to provide adequate child care, capacity for satisfying interpersonal relationships, and motivation for self-improvement. Results indicate that, as a group, methadone mothers require more assistance in parenting, are more socially isolated, and are less likely to pursue vocational and educational activities. The interpersonal and environmental impact of poor parenting further compounds the effects of in utero exposure to methadone, placing these infants at high risk.

Resilient children: individual differences in developmental outcome of children born to drug abusers

Since 1977, we have been following the neurobehavioral development of two groups of children: a group born to women on methadone maintenance and a drug-free comparison group. This study used the data on the children evaluated at 36 months of age to determine whether distinct patterns of developmental outcome can be identified, and which medical, familial, or environmental characteristics are associated with developmental differences. The children were clustered on four measures at 36 months: head circumference percentile, Merrill-Palmer Scale score, neurological evaluation, and referrals for developmental problems. Three distinct clusters emerged, with methadone children disproportionately frequent in Cluster 3, the group showing the poorest development. Comparisons of the clusters on a wide range of variables revealed consistent differences between Cluster 1 and Cluster 3 children in maternal responsiveness and incidence of neglect and family violence. These findings indicate that distinct developmental patterns do occur within this predominantly lower-class ghetto population; further, that children born to methadone-maintained women are more likely to show poor development. However, when the environment provides nurturance and stability, methadone children can show resilience and develop well.

Drug‐Addicted Mothers, Their Infants, and SIDS

In the past decade we have seen an increasing number of newborns born to substanceabusing mothers. The pattern and incidence of drug abuse has changed in the recent years.’-3 Previously, we saw babies born to mothers taking heroin, alcohol, methadonemaintenance, and “pills.” At present the most used drugs are cocaine, marijuana with or without alcohol, and occasional heroin and PCP. All these drugs cross the placenta and enter the fetus. With this change in the drug abuse pattern, we are seeing an increase in the incidence of obstetrical complications such as abruptio placentae, premature labor, fetal distress, venereal and a higher admission rate of premature and asphyxiated infants in our neonatal intensive care units. There has been a surge of reports in both the medical and lay literature on the effects of cocaine on pregnancy and on the neonate. These reports have described neonates with decreased birth weight and length and head circumferences; central nervous system abnormalities and cerebral infarcts, a syndrome of increased tone, abnormal movements, irritability and increased deep tendon reflexes, abnormal EEGs and evoked visual potentials; and genitourinary abnormalities.’-’* It should be remembered, however, that cocaine was one of several drugs abused by many of these mothers. These same infants have a 5-10 times increased risk of dying of sudden infant death syndrome in comparison to the general p o p ~ 1 a t i o n . l ~ ~ ~ ~ SIDS was the cause of death for 25% of infants who died in the first year of life and had been born to addicted women in New York City compared to 10% of the general p~pula t ion .~ We will report on data collected from three groups of mothers and their infants. The mothers were multidrug abusers, on methadone maintenance, or on no drugs of abuse. The primary drugs used were cocaine and marijuana with/without mild to moderate alcohol intake. Data on the perinatal period and the first 12 months of life will be presented.

24-month neurobehavioral follow-up of children of methadone-maintained mothers*

To determine the effects of maternal methadone maintenance during pregnancy on the young child we have longitudinally followed 2 groups of children: one born to mothers on methadone maintenance and a second group born to drug-free mothers. The following report describes our findings during a follow-up assessment at 24 months of age and compares them with a previous assessment at 12 months of age. The findings in the methadone children include no differences in somatic growth except a higher incidence of head circumferences below the third percentile; neurological signs of nystagmus/strabismus, tone and coordination abnormalities and developmental delays; lower mean scores on the Bayley MDI and PDI at 12 months of age and PDI scores at 24 months of age with a greater number of scores below 85. Thus, maternal methadone maintenance places the infant at high risk for future neurobehavioral problems.

Path analysis of variables affecting 36-month outcome in a population of multi-risk children☆

Abstract Path analysis was employed with data collected during a longitudinal neuro-behavioral follow-up study of multi-risk children. The relative impact of maternal medical history, drug abuse, and day-to-day functioning during pregnancy on the course of labor and delivery and on neonatal outcome was examined. The subsequent impact of each of these sets of variables on the childs developmental status at 36 months was then explored. An additional factor, which incorporated postnatal environmental and family functioning characteristics, was also included in the model. Maternal drug abuse had a significant effect on the course of labor and delivery, due in part to the impact of maternal drug abuse on family functioning. The results indicate that in this multi-risk population, environmental and psychosocial variables are important predictors of the childs developmental prospects.

A Canine Model of Torsades de Pointes

Although quinidine has been reported to induce QT interval prolongation and torsades de pointes clinically, the only experimental model currently available for quinidine‐induced torsades de pointes requires the concurrent use of ischemia, reperfusion and cardiac pacing of the isolated, perfused heart. Our purpose in this study was to determine the circumstances under which quinidine might elicit torsades de pointes consistently in the intact dog. We found that maintenance of therapeutic plasma quinidine concentrations, alone, did not induce the arrhythmia. Rather, arrhythmia induction required the additional application of aconitine, which induces early afterdepolarizations and triggered activity. When aconitine was applied to two epicardial sites in dogs having quinidine‐induced QT interval prolongation > 10%, torsades de pointes occurred in 80% of instances. When QT prolongation was < 10%, aconitine‐induced torsades de pointes was seen in only 21% of animals. Our results suggest that in a previously healthy heart quinidine‐induced QT prolongation is, itself, insufficient to induce torsades de pointes consistently, and two independent sites of ectopic activity are needed as well. The ectopic foci appear to modulate one anothers impulse initiation or activation sequence, thereby giving rise to the classical “twisting of the points” associated with the arrhythmia.