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Status: Finalised

First registered on: 06/04/2016

Last updated on: 31/01/2020

1. Study identification

EU PAS Register NumberEUPAS13051

Official titleDrug transporter protein -mediated drug interactions during pregnancy and offspring outcome

Study title acronymPgP and BCRP interactions and pregnancy

Study typeObservational study

Brief description of the studyBackground. Drug transporter proteins play an important role in the bioavailability and toxicity of drugs. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are the two important efflux transporter proteins in the human placenta. It is not known if drug transporter protein -mediated drug interactions account for the possible teratogenicity of drugs or if such interactions can also predispose to neonatal drug toxicity. Objectives. To investigate if concomitant use of two or more drug transporter substrates or a substrate and an inhibitor during first trimester is associated with an increased risk of offspring major congenital malformations. Specifically, we will assess the risk of overall malformations in offspring of women using SGAs, and the risk of cardiac malformations in offspring of women using SSRIs or bupropion, and the risk of severe or prolonged neonatal adaptation problems. Methods. This is a population-based cohort study based on the Drugs and Pregnancy project database in Finland. Data are derived from national health registers: the Medical Birth Register, the Register on Induced Abortions, the Malformation Register and the Prescription Register and Special Refund Entitlement Register. Data in these registers have been collected during Jan 1st 1996 - Dec 31st 2011 and include all births (live and still births), pregnancy terminations due to major congenital malformation, and information on drug purchases during pregnancy and 3 months before pregnancy. To this database we will further link data on individual drugs and their relation (substrate, inhibitor) to P-gp and BCRP from the University of Washington Metabolism and Transport Drug Interaction Database (DIDB). Offspring of women with concomitant use of two or more drug transporter substrates, or a combination of a substrate and an inhibitor, are compared to offspring of women using only one drug transporter specific substrate, and to unexposed.

Was this study requested by a regulator?No

Is the study required by a Risk Management Plan (RMP)? Not applicable

Regulatory procedure number (RMP Category 1 and 2 studies only)

Other study registration identification numbers and URLs as applicable

2. Research centres and Investigator details

Coordinating study entity

Centre to which the investigator belongsDrugs and Pregnancy

Department/Research groupDrugs and Pregnancy -research

Organisation/affiliationNational Institute for Health and Welfare, THL

Website/Homepagehttp://www.thl.fi/drugsandpregnancy

Details of (Primary) lead investigator

Title Dr

Last name Malm

First name Heli

Is this study being carried out with the collaboration of a research network?

Other centres where this study is being conducted

Multiple centres

In total how many centres are involved in this Study?3

TIS Helsinki

Department of Clinical Pharmacology, Helsinki University and Helsinki University Hospital

Countries in which this study is being conducted

National study

Finland

3. Study timelines: initial administrative steps, progress reports and final report

PlannedActual

Date when funding contract was signed02/01/2015

Start date of data collection31/08/201619/11/2018

Start date of data analysis30/11/2016

Date of interim report, if expected31/05/2017

Date of final study report30/05/201810/12/2019

4. Sources of funding

Please provide estimates of the percentage of funding by source for this study

Names(s)Approximate % funding

Pharmaceutical companies

Charities

Government bodyFinnish Medical Agency, National Institute of Health and Welfare, Social Insurance Institution100

Research councils

EU funding scheme

5. Contact details for enquiries

Scientific Enquiries

Title Dr

Last name Malm

First name Heli

Address line 1P.O. BOX 790

Address line 2

Address line 3

CityHelsinki

Postcode00029

CountryFinland

Phone number (incl. country code)358947176589

Alternative phone number

Fax number (incl. country code)

Email address heli.malm@hus.fi

Public Enquiries

Title Dr

Last name Malm

First name Heli

Address line 1P.O. BOX 790

Address line 2

Address line 3

CityHelsinki

Postcode00029

CountryFinland

Phone number (incl. country code)358947176589

Alternative phone number

Fax number (incl. country code)

Email address heli.malm@hus.fi

11. Scope of the study

What is the scope of the study?

Risk assessment

Primary scope : Risk assessment

12. Main objective(s)

What is the main objective of the study?

To investigate if concomitant use of two or more drug transporter substrates or a substrate and an inhibitor during first trimester is associated with an increased risk of offspring major congenital malformations. Specifically, we will assess the risk of overall malformations in offspring of women using SGAs, and the risk of cardiac malformations in offspring of women using SSRIs or bupropion.

Are there primary outcomes?Yes

Major congenital malformations and major cardiac malformations, according to EUROCAT coding (www.eurocat-network.eu ). Neonatal outcomes: Apgar score <7; need for respirator treatment; need for treatment in neonatal (intensive) care unit; need for care outside home at the age of one week

Are there secondary outcomes?No

13. Study design

What is the design of the study?

Cohort study

14. Follow-up of patients

Will patients be followed up?Not applicable/no follow-up

15. Data analysis plan

Please provide a brief summary of the analysis method

All data are anonymized and coded prior to statistical analysis. The prevalence of specific outcomes is compared between the different exposure groups of pregnant women and their offspring. Crude and adjusted odds ratios (cOR and aOR) and 95% confidence intervals (CI) were calculated. Statistical significance was set at a P value of less than 0.05. Univariate analyses are used to study demographic differences between the study cohorts. Univariate and logistic regression are used to calculate crude and adjusted odds ratios (cOR and aOR), and 95% confidence intervals (CI) and to assess the association between exposures during pregnancy and major congenital malformations and other perinatal outcomes. Covariates will be tested using a P -value of < 0.1 to detect associations with exposure and outcome. If associated with both exposure and outcome, the covariate will be included as a true confounder in the analysis.