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

doi:10.1016/S0163-6383(84)80027-2

Infant Behavior and Development

Volume 7, Issue 1, January–March 1984, Pages 115-123

https://doi.org/10.1016/S0163-6383(84)80027-2 Get rights and content

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.

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Cited by (45)

A 12-month follow-up of infant neurodevelopmental outcomes of prenatal opioid exposure and polysubstance use
2023, Neurotoxicology and Teratology
Prenatal opioid exposure has been associated with developmental deficits during infancy, but the literature is limited by simple group comparisons and lack of appropriate controls. Previously published research with the current sample documented unique associations between prenatal opioid exposure and developmental outcomes at three and six months, but less is known about associations later in infancy.
The current study examined pre- and postnatal opioid and polysubstance exposure as predictors of parent-reported developmental status at 12 months of age. Participants were 85 mother-child dyads, oversampled for mothers taking opioid treatment medications during pregnancy. Maternal opioid and polysubstance use were reported using the Timeline Follow-Back Interview during the third trimester of pregnancy or up to one month postpartum and updated through the child's first year of life. Seventy-eight dyads participated in a 12-month assessment, including 68 with parent-reported developmental status on Ages and Stages Questionnaire.
At 12 months, average developmental scores fell within normal ranges and prenatal opioid exposure was not significantly related to any developmental outcomes. However, more prenatal alcohol exposure was significantly related to worse problem-solving scores, and this relationship remained after controlling for adjusted age and other substance exposure.
Although findings await replication with larger samples and more comprehensive measures, results suggest that unique developmental risks of prenatal opioid exposure may not persist through the first year of life. Effects of prenatal exposure to co-occurring teratogens, such as alcohol, may become apparent as children exposed to opioids develop.
Prenatal methadone exposure impairs adolescent cognition and GABAergic neurodevelopment in a novel rat model of maternal methadone treatment
2021, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Methadone maintenance treatment (MMT) is the most common treatment for opioid-dependent pregnant women worldwide. Despite its widespread use, MMT is associated with a variety of adverse neurodevelopmental outcomes in exposed offspring, particularly cognitive impairments. The neurobiological abnormalities underlying these cognitive impairments are, however, poorly understood. This is, in part, due to a lack of animal models that represents the standard of care that methadone is administered in the clinic, with inconsistencies in the timing, doses and durations of treatment. Here we describe the characterisation of a clinically relevant rat model of MMT in which the long-term behavioural and neurobiological effects of prenatal methadone exposure can be assessed in adolescent offspring. Female Sprague-Dawley rats were treated orally with an ascending methadone dosage schedule (5, 10, 15, 20, 25 and 30 mg/kg/day), self-administered in drinking water prior to conception, throughout gestation and lactation. Pregnancy success, maternal gestational weight gain, litter survival and size were not significantly altered in methadone-exposed animals. Methadone-exposed offspring body and brain weights were significantly lower at birth. Novel object recognition tests performed at adolescence revealed methadone-exposed offspring had impaired recognition memory. Furthermore, the rewarded T-maze alternation task demonstrated that methadone-exposed female, but not male, offspring also exhibit working memory and learning deficits. Immunoblots of the adolescent prefrontal cortex and hippocampus showed methadone-exposed offspring displayed reduced levels of mature BDNF, in addition to the GABAergic proteins, GAD67 and parvalbumin, in a sex- and brain region-specific fashion. This rat model closely emulates the clinical scenario in which methadone is administered to opioid-dependent pregnant woman and provides evidence MMT can cause cognitive impairments in adolescent offspring that may be underlined by perturbed neurodevelopment of the GABAergic system.
Early inhibitory control and working memory abilities of children prenatally exposed to methadone
2018, Early Human Development
Citation Excerpt :
Existing studies were primarily conducted in the 1980s and 1990s. Results indicate that methadone-exposed children perform less well than non-exposed children on global measures of cognition [11] and intelligence [12,13]. However, scores often fall in the normal range [11,14].
Methadone maintenance is the most common method of treating opioid-dependent pregnant women. However, little is known about the impact of prenatal methadone exposure on child neurocognitive development.
To examine the early executive functioning of children born to methadone-maintained mothers, and to assess relations between executive functioning and later emotional and behavioral adjustment.
Prospective longitudinal study.
The sample consisted of 68 methadone-exposed children and 88 non-methadone-exposed children.
At age 2 years, children's inhibitory control and working memory were assessed using the Snack Delay and Three Boxes tasks. At 2 and 4.5 years, their emotional and behavioral adjustment was assessed using the caregiver-completed Strengths and Difficulties Questionnaire.
Methadone-exposed children had poorer inhibitory control than non-exposed children (p < 0.0001). These differences were explained by maternal education and prenatal benzodiazepine use. With respect to working memory, although both groups performed similarly on the first trial set, non-exposed children significantly improved their performance on the second trial set (p = 0.002), while methadone-exposed children did not (p = 0.92). Inhibitory control at age 2 years was predictive of higher conduct (p = 0.001), hyperactivity (p = 0.0001), peer relationship (p = 0.02), and total (p < 0.0001) problems at 4.5 years even after adjustment for behavioral problems at 2 years.
Methadone-exposed children demonstrate difficulties with inhibitory control and possibly sustained attention/learning. These difficulties were explained by factors correlated with maternal prenatal methadone use. Longer-term follow-up of these children is needed to understand the effects of prenatal methadone exposure and related maternal factors on executive functioning and behavioral adjustment.
PCBs and measures of attention and impulsivity on a continuous performance task of young adults
2017, Neurotoxicology and Teratology
The present study examines the relationship between current body burden of persistent PCBs and attention and impulsivity in 140 Akwesasne Mohawk young adults aged 17 to 21 whose environment has been contaminated by industrial effluent. Attention and impulsivity were measured by errors of omission, errors of commission, and patterns of reaction time responses on the Conners Continuous Performance Test. The PCB measure was the sum of those persistent PCB congeners detected in 50% of the participants. After adjusting for multiple covariates, regression analyses showed a significant positive relationship between PCB levels and omission scores, but only for males.
The gestational foundation of sex differences in development and vulnerability
2017, Neuroscience
Citation Excerpt :
Although this is a less frequently explored topic, two early studies reported that methadone exposure is associated with poorer performance on developmental assessments in the first 2 years of life in exposed boys as compared to exposed girls. It is unclear from the analyses whether these reflect main effects for sex or differential vulnerability (Johnson et al., 1984; Suffet and Brotman, 1984). The most prominent effects of antenatal cigarette smoking are restrictions to fetal growth.
Despite long-standing interest in the role of sex on human development, the functional consequences of fetal sex on early development are not well-understood. Here we explore the gestational origins of sex as a moderator of development. In accordance with the focus of this special issue, we examine evidence for a sex differential in vulnerability to prenatal and perinatal risks. Exposures evaluated include those present in the external environment (e.g., lead, pesticides), those introduced by maternal behaviors (e.g., alcohol, opioid use), and those resulting from an adverse intrauterine environment (e.g., preterm birth). We also provide current knowledge on the degree to which sex differences in fetal neurobehavioral development (i.e., cardiac and motor patterns) are present prior to birth. Also considered are contemporaneous and persistent sex of fetus effects on the pregnant woman. Converging evidence confirms that infant and early childhood developmental outcomes of male fetuses exposed to prenatal and perinatal adversities are more highly impaired than those of female fetuses. In certain circumstances, male fetuses are both more frequently exposed to early adversities and more affected by them when exposed than are female fetuses. The mechanisms through which biological sex imparts vulnerability or protection on the developing nervous system are largely unknown. We consider models that implicate variation in maturation, placental functioning, and the neuroendocrine milieu as potential contributors. Many studies use sex as a control variable, some analyze and report main effects for sex, but those that report interaction terms for sex are scarce. As a result, the true scope of sex differences in vulnerability is unknown.
Subsequent anxiety-related behavior in rats exposed to low-dose methadone during gestation, lactation or both periods consecutively
2012, Pharmacology Biochemistry and Behavior
Citation Excerpt :
In these respects, the only significant outcomes pertained to the sex of the animals namely, a faster increase in body weight and a higher incidence of physical abnormalities in males than in females. The lack of any significant effects of perinatal exposure to methadone on the development of post weaning body weight is similar to some earlier findings involving both humans (Johnson et al., 1984) and animals (Hutchings et al., 1992). This result suggests that, at least when methadone dose levels are relatively low, the direct effects of prenatal opioid exposure on physical growth may be minimal after other factors (e.g., impaired drug-related parental behavior, Wilens et al., 1995) are taken into account.
In order to assess the long-term behavioral consequences of exposing rats to methadone during gestation, lactation or both periods consecutively, pregnant Wistar dams were provided with drinking water containing approximately 2.39 mg/kg/day methadone. Soon after birth, litters of offspring were assigned to methadone-naïve foster mothers. Half of these foster mothers were then provided with drinking water containing methadone (approximately 2.86 mg/kg/day), while the other half received unadulterated water. Maternal weight gain, pregnancy duration, litter sizes, sex ratios and average pup weights were recorded. Following weaning on postnatal day (PND) 28, individual rats were weighed and inspected for physical abnormalities and stress reactions at PND20, 60 and 120. At these same ages, observations were also made of the rats' behavior in an emergence apparatus, and an open field. Apart from a smaller number of full-term pregnancies, there were no effects of any type of methadone treatment on physical measurements recorded at any age. Nor were there any behavioral effects of gestational methadone experienced on its own. However, methadone experienced during lactation (without gestational exposure) decreased emergence speed at PND30, and for all testing ages combined, increased open-field ambulation (males only), walking, rearing and occupancy of the center of the apparatus. Exposure to methadone during both gestation and lactation decreased emergence latencies at PND30 and, for all ages combined, decreased ambulation (males only), center occupancy and defecation. The subsequent behavioral effects of methadone were largely confined to lactational exposure and, when combined with gestational exposure, suggested increased anxiety.

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^*: Research supported by NIDA grant RO1-DA01663.

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

Journal of Pediatrics

American Journal of Obstetrics and Gynecology

American Journal of Obstetrics and Gynecology

Journal of Pediatrics

Journal of Pediatrics

Journal of Pediatrics

Journal of Pediatrics

Journal of Pediatrics

Pharmacology, Biochemistry and Behavior

Effects of maternal methadone addiction on offspring in rats

Archives of International Pharmacodynamics

Pathophysiological and behavioral effects of the transplacental transfer of narcotic drug to the fetuses and neonates of narcotic-dependent mothers

Bulletin on Narcotics

Prenatal methadone exposure: Effects on behavior in early infancy

Pediatric Pharmacology