Status: Finalised
First registered on:
15/04/2016
Last updated on:
17/05/2022
1. Study identification
EU PAS Register NumberEUPAS13054
Official titleEPID Multiple Sclerosis Pregnancy study - Pregnancy outcomes in Multiple Sclerosis populations exposed and unexposed to interferon beta - a register-based study in the Nordic countries
Study title acronymEPID Multiple Sclerosis Pregnancy study
Study typeObservational study
Brief description of the studyMS disease is the most common chronic neurologic disability in young adult females in their childbearing ages. It is commonly understood that relapses are fewer during pregnancy, but also that medication taken before conception or in early pregnancy could negatively affect pregnancy outcomes. Experience about exposure to MS disease modifying drugs (MSDMDs) during pregnancy has been mostly collected from IFN-βs and glatiramer acetate with no clear association of adverse outcomes such as low birth weight, congenital anomaly or spontaneous abortion. However, it is contraindicated to initiate treatment with IFN-β products during pregnancy. Furthermore, information on newer MSDMD substances such as fingolimod from previous studies is limited.
Due to limited evidence being available regarding the association between exposure to IFN-β products and adverse pregnancy outcomes the four marketing authorization holders (MAHs) of IFN-β are conducting a European-wide IFN-β pregnancy registry. Additionally, the Committee for the Medicinal Products for Human Use (CHMP) has requested a study to enable identification of pregnancy outcomes in the MS population unexposed to IFN-β products for comparison with the ongoing European IFN-β Pregnancy Registry.
The overall research questions of this study are to determine if exposure to IFN-β before or during pregnancy has an adverse effect on pregnancy outcomes in patients with MS and, as requested by the CHMP, to identify the prevalence of adverse pregnancy outcomes in MS women unexposed to IFN-β products.
Was this study requested by a regulator?Yes: EMA
Is the study required by a Risk Management Plan (RMP)?
EU RMP category 3 (required)
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 belongsIQVIA
Department/Research groupIQVIA Global Database Studies
Organisation/affiliationIQVIA
Details of (Primary) lead investigator
Title Dr
Last name Toussi
First name Massoud
Is this study being carried out with the collaboration of a research network?
No
Other centres where this study is being conducted
Multiple centres
In total how many centres are involved in this Study?3
Haukeland University Hospital, Bergen, Norway
Countries in which this study is being conducted
International study
Finland
Norway
Sweden
3. Study timelines: initial administrative steps, progress reports and final report
PlannedActual
Date when funding contract was signed20/12/2012
Start date of data collection02/05/201602/05/2016
Start date of data analysis31/10/2017
Date of interim report, if expected
Date of final study report31/12/201807/06/2019
4. Sources of funding
Please provide estimates of the percentage of funding by source for this study
Names(s)Approximate % funding
Pharmaceutical companiesBayer Pharma AG, Biogen Idec Ltd, Merck Serono Europe Ltd, Novartis Pharma AG100
Charities
Government body
Research councils
EU funding scheme
5. Contact details for enquiries
Scientific Enquiries
Title Dr
Last name Korhonen
First name Pasi
Address line 1Global Database Studies, IQVIA
Address line 2Spektri, Duo Building, Metsänneidonkuja 6
Address line 3
CityEspoo
Postcode02130
CountryFinland
Phone number (incl. country code)358408643912
Alternative phone number
Fax number (incl. country code)
Public Enquiries
Title Mrs
Last name Juuti
First name Rosa
Address line 1Global Database Studies, IQVIA
Address line 2Spektri, Duo Building, Metsänneidonkuja 6
Address line 3
CityEspoo
Postcode02130
CountryFinland
Phone number (incl. country code)358408643912
Alternative phone number
Fax number (incl. country code)
6. Study drug(s) information
Substance class (ATC Code)L03AB07 (interferon beta-1a)
Substance class (ATC Code)L03AB08 (interferon beta-1b)
Substance class (ATC Code)L03AB13 (peginterferon beta-1a)
7. Medical conditions to be studied
Medical condition(s)Yes
Multiple sclerosis
8. Population under study
Age
Preterm newborns
Term newborns (0-27 days)
Infants and toddlers (28 days - 23 months)
Adolescents (12 - 17 years)
Adults (18 - 44 years)
Adults (45 - 64 years)
Sex
Male
Female
Other population
Pregnant women
9. Number of subjects
Estimated total number of subjects1671
Additional information
The total estimated number of pregnancies available for this study is 1671 across all three countries during the study period.
10. Source of data
Is this study being carried out with an established data source?Yes
Data sources registered with ENCePP
Data sources not registered with ENCePP
Care Register for Health Care, National Prescription Register, National Reimbursement Register, Finland
National Patient Register, Medical Birth Register, Swedish Neuroregister, Sweden
National Patient Register, Medical Birth Register of Norway, Norwegian MS register and Biobank, Norway
Sources of data
Disease/case registry
Administrative database, e.g. claims database
Routine primary care electronic patient registry
Pharmacy dispensing records
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?
The main objectives are to estimate and compare the prevalence of adverse pregnancy outcomes between women with MS exposed to IFN-β only vs. unexposed to any MSDMDs and women with MS exposed to IFN-β only vs. unexposed to IFN-β regardless of exposure to other MSDMDs.
Are there primary outcomes?Yes
The primary outcome variable is a serious adverse pregnancy outcome defined as a composite endpoint including elective termination of pregnancy due to foetal anomaly (TOPFA), major congenital anomaly (MCA), and stillbirth.
Are there secondary outcomes?Yes
Other outcome variables include live births, stillbirths, elective TOPFA or elective termination due to other reasons, MCA, spontaneous abortions, ectopic pregnancies and defect cases. The following perinatal health outcomes are also included: mode of delivery, preterm birth, birth weight and height, sex of the newborn, head circumference and Apgar scores.
13. Study design
What is the design of the study?
Cohort study
14. Follow-up of patients
Will patients be followed up?Yes
Please describe duration of follow up
The cohort entry date (i.e. index date) is the date of last menstrual period (LMP). This date is considered as the beginning of the pregnancy. The pregnancies are followed until induced abortion or birth. The births are followed-up for a maximum of 12 months for registration of malformations.
15. Data analysis plan
Please provide a brief summary of the analysis method
The characteristics of all pregnancies with respect to relevant covariates are described with number of events, mean, median, standard deviation, minimum, maximum and inter-quartile range for continuous variables and with number and percentage for categorical variables. The descriptive statistics (the number of events and prevalence) will be presented for each pregnancy outcome. Descriptive analyses of the pregnancy outcomes will be further stratified by e.g. maternal age at LMP, chronic diseases, exposure to any teratogenic medication, duration of MS treatment and gestational age. The prevalence of the pregnancy outcomes will be compared between the study cohorts using log-binomial regression with adjustments for relevant confounders. The RR estimates with 95% confidence intervals and associated p-values will be reported for these comparisons and for confounders used in the model. In indirect comparison between cohort 6 vs. cohort 3, standardized prevalence ratio will be used.
16. ENCePP seal
Are you requesting the ENCePP seal for this study?
No
17. Full protocol
18. Study Results
Please list the 5 most relevant publications using data from your study
ReferenceLink to web-publication
Hakkarainen KM, Juuti R, Burkill S, Geissbühler Y, Sabidó M, Popescu C, Suzart-Woischnik K, Hillert J, Artama M, Verkkoniemi-Ahola A, Myhr KM. Pregnancy outcomes after exposure to interferon beta: a register-based cohort study among women with MS in Finland and Sweden. Therapeutic advances in neurological disorders. 2020 Oct;13:1756286420951072.https://journals.sagepub.com/doi/10.1177/1756286420951072?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
Korjagina M, Hakkarainen KM, Burkill S, Geissbühler Y, Sabidó M, Everage N, Suzart-Woischnik K, Klement R, Hillert J, Verkkoniemi-Ahola A, Bahmanyar S. Prevalence of adverse pregnancy outcomes after exposure to interferon beta prior to or during pregnancy in women with MS: Stratification by maternal and newborn characteristics in a register-based cohort study in Finland and Sweden. Multiple sclerosis and related disorders. 2021 Feb 1;48:102694.https://www.sciencedirect.com/science/article/pii/S2211034820307689
Burkill S, Vattulainen P, Geissbuehler Y, Sabido Espin M, Popescu C, Suzart-Woischnik K, Hillert J, Artama M, Verkkoniemi-Ahola A, Myhr KM, Cnattingius S. The association between exposure to interferon-beta during pregnancy and birth measurements in offspring of women with multiple sclerosis. PloS one. 2019 Dec 30;14(12):e0227120.https://journals.plos.org/plosone/article/authors?id=10.1371/journal.pone.0227120
19. Other relevant documents
Composition of Steering Group and
ObserversNot submitted
Other documents
DescriptionDocumentLatest version
Signed Code of
Conduct Checklist
Submitted
Signed Code of Conduct Declaration
Submitted
Signed Checklist for Study
Protocols
Submitted
