Maternal use of drug substrates of placental transporters and the effect of transporter-mediated drug interactions on the risk of congenital anomalies

Background A number of transporter proteins are expressed in the placenta, and they facilitate the placental transfer of drugs. The inhibition of P-glycoprotein (P-gp) was previously found to be associated with an increase in the risk of congenital anomalies caused by drug substrates of this transporter. We now explore the role of other placental transporter proteins. Methods A population-based case-referent study was performed using cases with congenital anomalies (N = 5,131) from EUROCAT Northern Netherlands, a registry of congenital anomalies. The referent population (N = 31,055) was selected from the pregnancy IADB. nl, a pharmacy prescription database. Results Ten placental transporters known to have comparable expression levels in the placenta to that of P-gp, were selected in this study. In total, 147 drugs were identified to be substrates, inhibitors or inducers, of these transporters. Fifty-eight of these drugs were used by at least one mother in our cases or referent population, and 28 were used in both. The highest user rate was observed for the substrates of multidrug resistance-associated protein 1, mainly folic acid (6% of cases, 8% of referents), and breast cancer resistance protein, mainly nitrofurantoin (2.3% of cases, 2.9% of referents). In contrast to P-gp, drug interactions involving substrates of these transporters did not have a significant effect on the risk of congenital anomalies. Conclusions Some of the drugs which are substrates or inhibitors of placental transporters were commonly used during pregnancy. No significant effect of transporter inhibition was found on fetal drug exposure, possibly due to a limited number of exposures

The Risk of Congenital Heart Anomalies Following Prenatal Exposure to Serotonin Reuptake Inhibitors-Is Pharmacogenetics the Key?

Serotonin reuptake inhibitors (SRIs) are often prescribed during pregnancy. Previous studies that found an increased risk of congenital anomalies, particularly congenital heart anomalies (CHA), with SRI use during pregnancy have created concern among pregnant women and healthcare professionals about the safety of these drugs. However, subsequent studies have reported conflicting results on the association between CHA and SRI use during pregnancy. These discrepancies in the risk estimates can potentially be explained by genetic differences among exposed individuals. In this review, we explore the potential pharmacogenetic predictors involved in the pharmacokinetics and mechanism of action of SRIs, and their relation to the risk of CHA. In general, the risk is dependent on the maternal concentration of SRIs and the foetal serotonin level/effect, which can be modulated by the alteration in the expression and/or function of the metabolic enzymes, transporter proteins and serotonin receptors involved in the serotonin signalling of the foetal heart development. Pharmacogenetics might be the key to understanding why some children exposed to SRIs develop a congenital heart anomaly and others do not

Pharmacogenetics of drug-induced birth defects: the role of polymorphisms of placental transporter proteins

One of the ongoing issues in perinatal medicine is the risk of birth defects associated with maternal drug use. The teratogenic effect of a drug depends, apart from other factors, on the exposition of the fetus to the drug. Transporter proteins are known to be involved in the pharmacokinetics of drugs and have an effect on drug level and fetal drug exposure. This condition may subsequently alter the risk of teratogenicity, which occurs in a dose-dependent manner. This review focuses on the clinically important polymorphisms of transporter proteins and their effects on the mRNA and protein expression in placental tissue. We also propose a novel approach on how the different genotypes of the polymorphism can be translated into phenotypes to facilitate genetic association studies. The last section looks into the recent studies exploring the association between P-glycoprotein polymorphisms and the risk of fetal birth defects associated with medication use during pregnancy

Maternal use of drug substrates of placental transporters and the effect of transporter-mediated drug interactions on the risk of congenital anomalies

Abstract Background A number of transporter proteins are expressed in the placenta, and they facilitate the placental transfer of drugs. The inhibition of P-glycoprotein (P-gp) was previously found to be associated with an increase in the risk of congenital anomalies caused by drug substrates of this transporter. We now explore the role of other placental transporter proteins. Methods A population-based case-referent study was performed using cases with congenital anomalies (N = 5,131) from EUROCAT Northern Netherlands, a registry of congenital anomalies. The referent population (N = 31,055) was selected from the pregnancy IADB.nl, a pharmacy prescription database. Results Ten placental transporters known to have comparable expression levels in the placenta to that of P-gp, were selected in this study. In total, 147 drugs were identified to be substrates, inhibitors or inducers, of these transporters. Fifty-eight of these drugs were used by at least one mother in our cases or referent population, and 28 were used in both. The highest user rate was observed for the substrates of multidrug resistance-associated protein 1, mainly folic acid (6% of cases, 8% of referents), and breast cancer resistance protein, mainly nitrofurantoin (2.3% of cases, 2.9% of referents). In contrast to P-gp, drug interactions involving substrates of these transporters did not have a significant effect on the risk of congenital anomalies

Knowledge and attitude regarding pharmacogenetics among formerly pregnant women in the Netherlands and their interest in pharmacogenetic research

BACKGROUND: Pharmacogenetics is an emerging field currently being implemented to improve safety when prescribing drugs. While many women who take drugs during pregnancy would likely benefit from such personalized drug therapy, data is lacking on the awareness towards pharmacogenetics among women. We aim to determine the level of knowledge and acceptance of formerly pregnant women in the Netherlands regarding pharmacogenetics and its implementation, and their interest in pharmacogenetic research. METHODS: A population-based survey using postal questionnaires was conducted among formerly pregnant women in the Northern parts of the Netherlands. A total of 986 women were invited to participate. RESULTS: Of the 219 women who returned completed questionnaires (22.2% response rate), only 22.8% had heard of pharmacogenetics, although the majority understood the concept (64.8%). Women who had experience with drug side-effects were more likely to know about pharmacogenetics [OR = 2.06, 95% CI 1.16, 3.65]. Of the respondents, 53.9% were positive towards implementing pharmacogenetics in their future drug therapy, while 46.6% would be willing to participate in pharmacogenetic research. Among those who were either not willing or undecided in this regard, their concerns were about the consequences of the pharmacogenetic test, including the privacy and anonymity of their genetic information. CONCLUSION: The knowledge and attitude regarding the concept of pharmacogenetics among our population of interest is good. Also, their interest in pharmacogenetic research provides opportunities for future research related to drug use during pregnancy and fetal outcome

Prenatal exposure to serotonin reuptake inhibitors and congenital heart anomalies:An exploratory pharmacogenetics study

Aim: To explore the role of pharmacogenetics in determining the risk of congenital heart anomalies (CHA) with prenatal use of serotonin reuptake inhibitors.  Methods: We included 33 case-mother dyads and 2 mother-only (child deceased) cases of CHA in a case-only study. Ten genes important in determining fetal exposure to serotonin reuptake inhibitors were examined: CYP1A2, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC6A4, HTR1A, HTR1B, HTR2A and HTR3B.  Results: Among the exposed cases, polymorphisms that tended to be associated with an increased risk of CHA were SLC6A4 5-HTTLPR and 5-HTTVNTR, HTR1A rs1364043, HTR1B rs6296 and rs6298 and HTR3B rs1176744, but none reached statistical significance due to our limited sample sizes.  Conclusion: We identified several polymorphisms that might potentially affect the risk of CHA among exposed fetuses, which warrants further investigation

Characteristics of children born to case mothers and referent population mothers.

<p>Characteristics of children born to case mothers and referent population mothers.</p

User rates of selected drugs among cases and referent population, according to substrate specificity to each placental transporter.

<p>User rates of selected drugs among cases and referent population, according to substrate specificity to each placental transporter.</p

User rates of drugs associated with placental transporter in the first trimester of pregnancy among cases and referent population.

<p>User rates of drugs associated with placental transporter in the first trimester of pregnancy among cases and referent population.</p