Children exposed to maternal methadone treatment prenatally are at risk of abnormal neurodevelopment

Abstract

Illicit opiate use among females of reproductive age has been steadily increasing in recent decades. Today, opioid maintenance treatment (OMT) is the recommended treatment for opioid-addicted pregnant females. Based on animal studies, there is evidence of the adverse effects of opiate use upon fetal brain development, putting the infant at a potential risk for abnormal neurodevelopment including motor and cognitive impairments, inattention, and hyperactivity. Even so, health authorities (including the World Health Organization [WHO]) state that the confounding factors associated with a drug-addicted lifestyle (i.e. malnutrition, criminality, and increased risk of infections and lack of prenatal health care services) are probably the main risk factors to fetal health and development, and to a lesser extent any direct adverse drug effect, and hence recommend OMT during pregnancy. At the same time the WHO admits that their OMT recommendation is based on ‘very low quality of evidence’ and that long-term follow-up studies of children exposed to OMT in utero is lacking. An increase has been observed in the prevalence of neonatal abstinence syndrome (NAS), commonly due to prenatal opioid use, which indicates negative influence on neonatal central nervous functioning. Little is known about whether NAS is a biomarker for persistent disturbances of normal early brain development, leading to different types of neurodevelopmental impairments in childhood (similarly to fetal alcohol spectrum disorder). The systematic review and meta-analysis by Monnelly et al. is of interest since it summarizes neurodevelopmental and visual outcome in children whose mothers were prescribed maintenance methadone for opioid-dependency in pregnancy. The review includes 41 identified papers with meta-analysis performed for eight studies. In the meta-analysis the authors report reduced behavioral scores in six of seven studies while four out of five studies reported abnormal visual scores. However, the authors clearly emphasize that there is still limited evidence concerning any causal relationship between prescribed methadone in pregnancy and later abnormal outcome in offspring, and that the observed relationship may be biased, i.e. that several other potentially harmful factors appear together with the opioid exposure. However, even if the causal relationship is difficult to prove, the authors point to the important message that these children are at risk for abnormal development and should therefore be thoroughly followed up in childhood. The authors also correctly state that longitudinal studies should be performed to reveal the full clinical picture that may emerge when these children develop. Even though there has been a marked increase in the number of children prenatally exposed to opioid medications during the last two decades, the optimal treatment is still debatable (i.e. how these females should be treated to minimize the potential harm to the fetus). Another factor that complicates the picture is the risk of polydrug use, both illicit and prescribed, among pregnant females prescribed OMT. In a Scottish study including 56 infants born to mothers on OMT during pregnancy, 91% of infants had been exposed to illicit drugs in utero and almost one-half was also exposed to alcohol. Determining the additional risk resulting from polydrug use combined with alcohol during pregnancy is an exceptionally challenging task, and more research is required on the interactive effects of simultaneous drug use on later child development. More animal studies are still needed where one can control for several of the confounding factors seen in clinical human studies on prenatal drug exposure. In addition, there is a lack of quantitative imaging studies (i.e. multimodal magnetic resonance imaging) looking at brain structure-function relationships longitudinally in prenatally opioid-exposed children.