title: P-Glycoprotein-Mediated Drug Interactions in Pregnancy and Changes in the Risk of Congenital Anomalies: A Case-Reference Study.
abstract: BACKGROUND
  Drug use in pregnancy is very common but may cause harm to the fetus. The teratogenic effect of a drug is partly dependent on the drug level in the fetal circulation, which is associated with the transport across the placenta. Many drugs are substrates of P-glycoprotein (P-gp), an efflux transporter that acts as a protective barrier for the fetus. We aim to identify whether drug interactions associated with P-gp promote any changes in fetal drug exposure, as measured by the risk of having children with congenital anomalies.
  
  
  METHODS
  In this study, cases (N = 4634) were mothers of children with congenital anomalies registered in the EUROCAT Northern Netherlands registry, and the reference population were mothers of children (N = 25,126) from a drug prescription database (IADB.nl).
  
  
  RESULTS
  Drugs that are associated with P-gp transport were commonly used in pregnancy in cases (10 %) and population (12 %). Several drug classes, which are substrates for P-gp, were shown to have a higher user rate in mothers of cases with specific anomalies. The use of this subset of drugs in combination with other P-gp substrates increased the risk for specific anomalies (odds ratio [OR] 4.17, 95 % CI 1.75-9.91), and the addition of inhibitors further increased the risk (OR 13.03, 95 % CI 3.37-50.42). The same pattern of risk increment was observed when the drugs were analyzed separately according to substrate specificity.
  
  
  CONCLUSIONS
  The use of drugs associated with P-gp transport was common during pregnancy. For several drug classes associated with specific anomalies, P-gp-mediated drug interactions are associated with an increased risk for those specific anomalies.
authors.affiliation: Unit of Pharmacotherapy and Pharmaceutical Care, Department of Pharmacy, University of Groningen, Groningen, The Netherlands, n.a.a.daud@rug.nl.
authors.forename: Aizati N A
authors.initials: AN
authors.lastname: Daud
authors.forename: Jorieke E H
authors.initials: JE
authors.lastname: Bergman
authors.forename: Marian K
authors.initials: MK
authors.lastname: Bakker
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Wilhelmina S
authors.initials: WS
authors.lastname: Kerstjens-Frederikse
authors.forename: Hermien E K
authors.initials: HE
authors.lastname: de Walle
authors.forename: Henk
authors.initials: H
authors.lastname: Groen
authors.forename: Jens H J
authors.initials: JH
authors.lastname: Bos
authors.forename: Eelko
authors.initials: E
authors.lastname: Hak
authors.forename: Bob
authors.initials: B
authors.lastname: Wilffert
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000014:Abnormalities, Drug-Induced / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism; D001692:Biological Transport; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D009426:Netherlands; D016017:Odds Ratio; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D055553:Prescription Drugs / Q000009:adverse effects* / Q000145:classification; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D055553:Prescription Drugs