In developed countries an increase in substance abuse in pregnancy can be observed. Opiates cross the placenta easily and lead to intrauterine growth restriction (IUGR), preterm birth and spontaneous abortion [
1‐
4]. Abstinence cannot be achieved in most of the patients and methadone is the recommended standard of care for pregnant opioid-dependent women [
5]. The positive effects of methadone are an increase in birth weight and the prolongation of gestation [
4,
6]. In addition, women in a maintenance therapy program receive more prenatal care which improves the situation for both, mother and fetus. However, the main disadvantage of this therapy is the neonatal abstinence syndrome (NAS) which occurs in 60–80% of the newborns from mothers who consumed methadone and is more intensive than in babies who were prenatally exposed to heroin [
3,
7]. NAS due to opiate withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss and seizures. It's unclear whether the maternal methadone dose correlates with the intensity and duration of NAS [
5,
8]. Nevertheless, transfer rates of methadone are higher from the fetal to the maternal circuit than vice versa [
9]. This phenomenon is based on the fact that methadone is a substrate of the ATP-dependent efflux transporter protein, the P-glycoprotein (P-gp) which is expressed in the brush-border membranes of the maternal derived syncytiotrophoblast and works against the concentration gradient [
7,
9,
10]. Because co-consumption of methadone with other drugs such as cocaine and heroin is frequent, additional drugs may influence the placental transfer of methadone and other substances by different mechanisms. In case of inhibition of the P-gp function by other drugs, the placental barrier may disrupt, and P-gp substrates may increasingly transfer to fetal circulation [
11,
12]. However, there exist no information whether heroin or cocaine are substrates of P-gp. Another mechanism is that of apoptosis or necrosis of the syncytiotrophoblast caused by some drugs. The syncytiotrophoblast is relatively thick in early pregnancy. At first trimester there is less syncytiotrophoblast and mostly of the trophoblast is cytotrophoblast. With increasing gestational age there is a differentiation of cytotrophoblast to syncytiotrophoblast. The release of microparticles shed from the syncytiotrophoblast into the maternal blood is generated during apoptosis or necrosis. MPs are larger than 100 nm in diameter and originate from blebbing membranes of either activated cells or cells undergoing apoptosis and mainly consist of nuclear proteins as well as nucleic acids [
13]. The efficiency of transfer may be reduced by thickening of the basement membranes of capillary endothelium, obliteration of maternal vessels and the increase of the fibrinoid deposits [
14‐
16]. Both mechanisms may affect the incidence and intensity of NAS. Cocaine as opiates leads to spontaneous abortion, low birth weight, fetal growth restriction and in addition to impaired neurodevelopment [
17,
18]. Because of its vasoactivity, cocaine affects the fetal vasculature and impairs placental permeability [
19]. Heroin may be involved in leptin metabolism. Leptin is produced in the placenta [
20,
21] and regulates fetal growth and angiogenesis. In pregnancies with heroin abuse [
22] as well as with IUGR [
23], umbilical cord blood levels of leptin are reduced. It can therefore be assumed that heroin abuse in pregnancy may reduce placental leptin synthesis and contributes to IUGR by reducing fetal growth. Similar effects of methadone or cocaine on leptin are still unknown.
The aim of this study was therefore to investigate the placental transfer of methadone without and with addition of cocaine or heroin in the ex-vivo placenta perfusion model. Thereby placental functions as well as the response of the placental tissue on methadone were key issues.