title: 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.
  
  
  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.
authors.affiliation: University of Groningen, Groningen Research Institute of Pharmacy, PharmacoTherapy, -Epidemiology & -Economics, Groningen, the Netherlands.|Universiti Sains Malaysia, School of Pharmaceutical Sciences, Discipline of Clinical Pharmacy, Penang, Malaysia.
authors.forename: Aizati N A
authors.identifier: http://orcid.org/0000-0003-4336-9468
authors.initials: AN
authors.lastname: Daud
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors.forename: Jorieke E H
authors.initials: JE
authors.lastname: Bergman
authors.affiliation: University of Groningen, Groningen Research Institute of Pharmacy, PharmacoTherapy, -Epidemiology & -Economics, Groningen, the Netherlands.
authors.forename: Monika P
authors.initials: MP
authors.lastname: Oktora
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors.forename: Wilhelmina S
authors.initials: WS
authors.lastname: Kerstjens-Frederikse
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Epidemiology, Groningen, the Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: Groen
authors.affiliation: University of Groningen, Groningen Research Institute of Pharmacy, PharmacoTherapy, -Epidemiology & -Economics, Groningen, the Netherlands.
authors.forename: Jens H
authors.initials: JH
authors.lastname: Bos
authors.affiliation: University of Groningen, Groningen Research Institute of Pharmacy, PharmacoTherapy, -Epidemiology & -Economics, Groningen, the Netherlands.
authors.forename: Eelko
authors.initials: E
authors.lastname: Hak
authors.affiliation: University of Groningen, Groningen Research Institute of Pharmacy, PharmacoTherapy, -Epidemiology & -Economics, Groningen, the Netherlands.|University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, the Netherlands.
authors.forename: Bob
authors.initials: B
authors.lastname: Wilffert
mesh_terms: D000013:Congenital Abnormalities / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy
chemical_list: D026901:Membrane Transport Proteins