LAUSR

The situation of opioid abuse has deteriorated in recent years. In 2019, 49,860 people died from opioid overdoses in the USA alone, a 6-fold increase since 2000 (Ko et al., 2020). Of particular concern is opioid abuse (e.g., morphine, fentanyl) by pregnant women. It was found that 6.6% of women self-reported opioid use during pregnancy in the USA, and 21.2% of them disclosed opioid misuse (Ko et al., 2020). Infants born to drug-abusing mothers are at risk of preterm delivery, poor intrauterine growth, and neonatal abstinence syndrome (NAS). Currently, Methadone Maintenance Treatment (MMT) is the recommended therapy for opioid addicts, including pregnant women (World Health Organization, 2014). However, the pharmacokinetics of methadone is greatly affected by pregnancy. Physiological changes during pregnancy (e.g., increases in total body fluid, blood volume, and body fat) and metabolic enzyme activities (CYP2B6, CYP3A4) lead to faster clearances of methadone in pregnant women (Badhan and Gittins, 2021). Consequently, a higher dosage may be required during pregnancy. Some researchers suggest a staged escalation approach, i.e., starting from the lowest pre-natal dose (30 mg once daily) to the maximum 120, 140, and 180 mg daily dose for trimester 1, 2 and 3, respectively (Badhan and Gittins, 2021). This is significantly higher than a standard dosage (15–60 mg/day) and may expose fetuses and neonates to higher risks of NAS. Indeed, of all infants born to mothers receiving MMT, 40%–90% show signs of NAS. For example, in a retrospective study of 67 women (40 received MMT at 10–20 mg/day), it was found that 43% of the infants of mothers receiving MMT required treatment for NAS (Malpas et al., 1995). Similar results were also reported in (Dryden et al., 2009). However, it was also found that there was no strong correlation between the dosage of methadone use and the severity of NAS (Malpas et al., 1995; Berghella et al., 2003). In a recent pregnant rat model, it was shown that the methadone concentrations in the blood and brain of fetuses were 1.6 and 2.8 times higher than in dams, respectively (Kongstorp et al., 2019) (Figure 1A). The finding highlights the susceptibility of fetuses tomaternal methadone exposure. Being lipophilic and with a lowmolecular weight (309 Da), methadone readily crosses the placenta barrier via passive diffusion. However, the return of methadone from the fetal side to the maternal side (f→m) also requires active transport by the efflux transporter P-glycoprotein (P-gp) (Nanovskaya et al., 2005). P-gp is expressed at the apical membrane of cotyledons, i.e., the maternal side (Gil et al., 2005; Nanovskaya et al., 2005). Therefore, the placenta acts as barrier that retards the backflow of methadone f→m, which causes a higher plasma concentration of methadone at the fetal side than the maternal side (Figure 1A). To assist the clearance of methadone from the fetal side, P-gp acts as the OPEN ACCESS