P-Glycoprotein-Mediated Drug Interactions in Pregnancy and Changes in the Risk of Congenital Anomalies: A Case-Reference Study
Open accessAbstract
INTRODUCTION: 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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
During the first trimester, the teratogenic effects of drugs that are targets of P-glycoprotein are greater if they are administered in combination with other P-glycoprotein substrates than by themselves, suggesting competitive interactions at the level of the transporter.
“Thus, during the first trimester the teratogenic effects of drugs that are targets of P-glycoprotein is greater if they are administered in combination with other P-glycoproteins substrates than by themselves, suggesting competitive interactions at the level of the transporter (140).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [140]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview
Schinkel, A. H., & Jonker, J. W. (2003) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(02)00169-2 · Cited by 1,427 · see citing works
Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview
Schinkel, A. H., & Jonker, J. W. (2012) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2012.09.027 · Cited by 1,236 · see citing works
Blencowe, H., Cousens, S., Jassir, F. B., Say, L., Chou, D., Mathers, C., Hogan, D., Shiekh, S., Qureshi, Z. U., You, D., et al. (2016) · The Lancet Global Health · doi:10.1016/s2214-109x(15)00275-2 · Cited by 1,062 · see citing works
Cousens, S., Blencowe, H. K., Stanton, C., Chou, D., Ahmed, S., Steinhardt, L. C., Creanga, A. A., Tunçalp, Ö., Balsara, Z. P., Gupta, S., et al. (2011) · The Lancet · doi:10.1016/s0140-6736(10)62310-0 · Cited by 645 · see citing works
Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition
Zhou, S.-F. (2008) · Xenobiotica · doi:10.1080/00498250701867889 · Cited by 599 · see citing works
Prescription drug use in pregnancy
Andrade, S. E., Gurwitz, J. H., Davis, R. L., Chan, K. A., Finkelstein, J. A., Fortman, K. K., McPhillips, H. A., Raebel, M. A., Roblin, D. W., Smith, D. H., et al. (2004) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2004.04.025 · Cited by 562 · see citing works
Very important pharmacogene summary
Hodges, L. M., Markova, S. M., Chinn, L. W., Gow, J. M., Kroetz, D. L., Klein, T. E., & Altman, R. B. (2010) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0b013e3283385a1c · Cited by 437 · see citing works
Drugs as P-glycoprotein substrates, inhibitors, and inducers
Kim, R. B. (2002) · Drug Metabolism Reviews · doi:10.1081/dmr-120001389 · Cited by 382 · see citing works
Pávek, P., Stejskalová, L., Krausová, L., Bitman, M., Vrzal, R., & Dvořák, Z. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00001 · Cited by 378 · see citing works
Ornoy, A., Reece, E. A., Pavlínková, G., Kappen, C., & Miller, R. K. (2015) · Birth Defects Research Part C Embryo Today Reviews · doi:10.1002/bdrc.21090 · Cited by 317 · see citing works
Prescription drug use during pregnancy in developed countries: a systematic review
Daw, J. R., Hanley, G. E., Greyson, D. L., & Morgan, S. G. (2011) · Pharmacoepidemiology and Drug Safety · doi:10.1002/pds.2184 · Cited by 275 · see citing works
Teratogenic effects of antiepileptic drugs
Tomson, T., & Battino, D. (2012) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70103-5 · Cited by 272 · see citing works
Sun, M., Kingdom, J., Baczyk, D., Lye, S. J., Matthews, S. G., & Gibb, W. (2006) · Placenta · doi:10.1016/j.placenta.2005.05.007 · Cited by 223 · see citing works
Role of transporters in drug interactions
Han, H. (2011) · Archives of Pharmacal Research · doi:10.1007/s12272-011-1107-y · Cited by 220 · see citing works
Prouillac, C., & Lecoeur, S. (2010) · Drug Metabolism and Disposition · doi:10.1124/dmd.110.033571 · Cited by 214 · see citing works
P-glycoprotein in the placenta: Expression, localization, regulation and function
Čečková, M., Pávek, P., & Štaud, F. (2006) · Reproductive Toxicology · doi:10.1016/j.reprotox.2006.01.007 · Cited by 205 · see citing works
Bakker, M. K., Jentink, J., Vroom, F., et al. (2006) · BJOG An International Journal of Obstetrics & Gynaecology · doi:10.1111/j.1471-0528.2006.00927.x · Cited by 187 · see citing works
Self-citationThe role of transporters in drug interactions
Endres, C. J., Hsiao, P., Chung, F. S., & Unadkat, J. D. (2005) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2005.11.002 · Cited by 184 · see citing works
Clinical Relevance of Drug-Drug Interactions
van Roon, E. N., Flikweert, S., le Comte, M., et al. (2005) · Drug Safety · doi:10.2165/00002018-200528120-00007 · Cited by 182 · see citing works
Transporter-Mediated Drug–Drug Interactions
Müller, F., & Fromm, M. F. (2011) · Pharmacogenomics · doi:10.2217/pgs.11.44 · Cited by 172 · see citing works
Does inhibition of P-glycoprotein lead to drug–drug interactions?
Balayssac, D., Authier, N., Cayre, A., et al. (2005) · Toxicology Letters · doi:10.1016/j.toxlet.2004.12.008 · Cited by 171 · see citing works
P-glycoprotein expression of the human placenta during pregnancy
Gil, S., Saura, R., Forestier, F., & Farinotti, R. (2004) · Placenta · doi:10.1016/j.placenta.2004.05.013 · Cited by 144 · see citing works
Functional role of P-glycoprotein in the human blood-placental barrier
Molsa, M., HEIKKINEN, T., Hakkola, J., HAKALA, K., Wallerman, O., Wadelius, M., Wadelius, C., & LAINE, K. (2005) · Clinical Pharmacology & Therapeutics · doi:10.1016/j.clpt.2005.04.014 · Cited by 132 · see citing works
Visser, S. T., Schuiling‐Veninga, C. C. M., Bos, J., den Berg, L. T. D. J.-V., & Postma, M. J. (2013) · Expert Review of Pharmacoeconomics & Outcomes Research · doi:10.1586/erp.13.20 · Cited by 130 · see citing works
Self-citationUnadkat, J. D., Dahlin, A., & Vijay, S. (2004) · Current Drug Metabolism · doi:10.2174/1389200043489171 · Cited by 116 · see citing works
Štaud, F., Červený, L., & Čečková, M. (2012) · Journal of drug targeting · doi:10.3109/1061186x.2012.716847 · Cited by 112 · see citing works
Drug–drug interactions affected by the transporter protein, P-glycoprotein (ABCB1, MDR1)
Aszalós, A. (2007) · Drug Discovery Today · doi:10.1016/j.drudis.2007.07.021 · Cited by 91 · see citing works
Role of P-glycoprotein in transplacental transfer of methadone
Nanovskaya, T. N., Nekhayeva, I. A., Karunaratne, N., Audus, K. L., Hankins, G. D. V., & Ahmed, M. S. (2005) · Biochemical Pharmacology · doi:10.1016/j.bcp.2005.03.030 · Cited by 87 · see citing works
Drug use of children in the community assessed through pharmacy dispensing data
Schirm, E., van den Berg, P., Gebben, H., Sauer, P. J. J., & den Berg, L. D. J. (2000) · British Journal of Clinical Pharmacology · doi:10.1046/j.1365-2125.2000.00275.x · Cited by 85 · see citing works
Drug Interactions at the Human Placenta: What is the Evidence?
Rubinchik‐Stern, M., & Eyal, S. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00126 · Cited by 73 · see citing works
Psychotropic Drug–Drug Interactions Involving P-Glycoprotein
Akamine, Y., Yasui‐Furukori, N., Ieiri, I., & Uno, T. (2012) · CNS Drugs · doi:10.1007/s40263-012-0008-z · Cited by 59 · see citing works
May, K. E., Minaříková, V., Linnemann, K., Zygmunt, M., Kroemer, H. K., Fusch, C., & Siegmund, W. (2008) · Drug Metabolism and Disposition · doi:10.1124/dmd.107.019448 · Cited by 49 · see citing works
Hemauer, S. J., Patrikeeva, S., Nanovskaya, T. N., Hankins, G. D. V., & Ahmed, M. S. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.07.002 · Cited by 43 · see citing works
Schirm, E., Tobi, H., & den Berg, L. T. W. D. J. (2004) · Journal of Clinical Epidemiology · doi:10.1016/j.jclinepi.2002.12.001 · Cited by 42 · see citing works
Ceccaldi, P.-F., Gavard, L., Mandelbrot, L., Rey, E., Farinotti, R., Treluyer, J.-M., & Gil, S. (2009) · Obstetrics and Gynecology International · doi:10.1155/2009/726593 · Cited by 37 · see citing works
Drug–drug interactions affected by the transporter protein, P-glycoprotein (ABCB1, MDR1)
Aszalós, A. (2007) · Drug Discovery Today · doi:10.1016/j.drudis.2007.07.022 · Cited by 32 · see citing works
Maternal–fetal and neonatal pharmacogenomics: a review of current literature
Blumenfeld, Y. J., Reynolds-May, M. F., Altman, R. B., et al. (2009) · Journal of Perinatology · doi:10.1038/jp.2009.183 · Cited by 22 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Placental Origins of Chronic Disease
Burton, G. J., Fowden, A. L., & Thornburg, K. L. (2016) · Physiological Reviews · doi:10.1152/physrev.00029.2015 · Cited by 717 · see citing works
Understanding the Chemical Exposome During Fetal Development and Early Childhood: A Review
Krausová, M., Braun, D., Buerki-Thurnherr, T., Gundacker, C., Schernhammer, E., Wisgrill, L., & Warth, B. (2023) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-051922-113350 · Cited by 61 · see citing works
- Authors
- Daud, A. N. A., Bergman, J. E. H., Bakker, M. K., Wang, H., Kerstjens-Frederikse, W. S., de Walle, H. E. K., Groen, H., Bos, J. H. J., Hak, E., & Wilffert, B.
- Affiliations
- University Medical Center Groningen (NL)
- University of Groningen (NL)
- ORCID
- Venue
- Drug Safety
- Published
- 2015-05-29
- Volume
- 38
- Issue
- 7
- Pages
- 651-659
- ISSN
- 0114-5916 (ISSN-L)
- 1179-1942
- PMC
- PMC4486783
- OpenAlex
- W351118931
- Cited by
- 46
- References
- 37
- Citations by year
- 2026: 3 · 2025: 2 · 2023: 6 · 2022: 7 · 2021: 6 · 2020: 3 · 2019: 4 · 2018: 2 · 2017: 4 · 2016: 8 · 2015: 1
- FWCI
- 5.35
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Drug Safety (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc)
- Funders
- Rijksuniversiteit Groningen
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Pregnancy and Medication Impact
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Keywords
- P-glycoprotein, drug interactions, pregnancy, congenital malformations, teratogenicity, maternal-fetal drug transfer, prenatal drug exposure, P-gp substrates, P-glycoprotein inhibitors, EUROCAT registry
- MeSH terms
- Abnormalities, Drug-Induced, Biological Transport, Drug Interactions, Female, Humans, Male, Netherlands, Placenta, Pregnancy, Registries, Risk Factors, Chi-Square Distribution, Odds Ratio, Case-Control Studies, Risk Assessment, Maternal Exposure, ATP Binding Cassette Transporter, Subfamily B, Member 1, Prescription Drugs, Drug-Related Side Effects and Adverse Reactions
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
