P-Glycoprotein-Mediated Drug Interactions in Pregnancy and Changes in the Risk of Congenital Anomalies: A Case-Reference Study

Abstract

IntroductionDrug 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.MethodsIn 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).ResultsDrugs 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s40264-015-0299-3) contains supplementary material, which is available to authorized users.

Maternal Use of Opioids During Pregnancy and Congenital Malformations: A Systematic Review

“…Yazdy et al 35 reported an increased risk of spina bifida with noncodeine opioid exposures. And Daud et al 43 found an increased risk for respiratory malformations associated with prenatal exposure to morphine. However, in a study that evaluated first-trimester exposure to oxycodone, no increased risk of congenital malformations were reported.…”

“…34,35,39,40,43,69–71,83,89 Studies evaluating opioid exposure in aggregate found that use during early pregnancy was associated with an increased risk of congenital malformations overall, 39 as well as heart malformations overall, 34 inguinal hernia with/without obstruction, 39 ventricular septal defects (VSD)/atrial septal defects, 34,39 oral clefts, 39,70,71 dislocated hip/musculoskeletal defects, 39 spina bifida, 34,35 tetralogy of Fallot, 34 hypoplastic left heart syndrome, 34 right ventricular outflow tract obstruction defects, 34 pulmonary valve stenosis, 34 atrioventricular septal defects, 34 isolated clubfoot, 83 neural tube defects, 35 and other heart and circulatory defects. 39 Bracken and Holford 39 also reported that exposure to opioids for the first time during the second trimester was associated with alimentary tract defects.…”

“…35,39,40,43,69,72,73,89 Of these, 4 studies found codeine to be associated with an increased risk of: congenital malformations overall, 39 heart malformations overall, 40,69,89 VSD, 89 and double-outlet right ventricle defects. 89 In 2 studies by Shaw et al, 72,73 codeine use in pregnancy was not significantly associated with congenital cardiac malformations or neural tube defects.…”

Placental control of drug delivery

“…Nonetheless, P-gp undoubtedly plays a significant role in the placental barrier and fetal protection. Recently, it has been shown that there may be a significant risk of congenital anomalies when mothers are administered multiple drugs that are P-gp substrates or inhibitors [84]. …”

Role of ABC and Solute Carrier Transporters in the Placental Transport of Lamivudine

“…One explanation is that a fetalto-maternal directed transport mechanism is involved that diminishes the transplacental passage of lamivudine from mother to fetus. Such information would be of considerable importance for optimizing the pharmacotherapy of pregnant women because placental drug transporters could be involved in pharmacokinetic drug-drug interactions (DDI) affecting fetal drug exposure to concomitantly administered drugs and leading to impaired treatment outcome or adverse effects (7,38). This issue is of particular importance in anti-HIV therapy, where combination of two or more antiretroviral drugs is recommended (3).…”