Status: Finalised
First registered on:
13/07/2017
Last updated on:
17/05/2022
1. Study identification
EU PAS Register NumberEUPAS19686
Official titleConsequences for life of children with in utero exposure to metformin in Finland – a register-based cohort study
Study title acronymCLUE
Study typeObservational study
Brief description of the studyMetformin is used during pregnancy to treat hyperglycaemia in gestational diabetes mellitus (GDM) and pre-gestational diabetes (PGDM), and to treat the polycystic ovary syndrome (PCOS). Despite the use of metformin during pregnancy in these three conditions, the long-term effects of metformin exposure in utero have not been widely studied in the children beyond two years of age. Evidence on these effects is of major interest, as metformin crosses the placenta and might therefore have long-term effect on the children. Using population-level data from Finland, this study will provide information on these long-term effects among children of women who used metformin during pregnancy.
The aim of this study is to investigate the long-term and immediate effects of exposure to metformin in utero among the children of all pregnant women treated with metformin, regardless of the purpose of use. The long-term effects include e.g. diagnoses of obesity, hypo- and hyperglycaemia, diabetes mellitus, diagnoses related to challenges in motor-social development, and growth-related outcomes. In addition, immediate effects of exposure to metformin in utero will be investigated, including growth outcomes at birth, preterm birth, perinatal mortality, hypo- and hyperglycaemia at birth, and major congenital anomalies.
The long-term effects described above in the children of women pregnant from 1996 onwards and treated during their pregnancy with metformin only, or with a combination of insulin and metformin, will be compared to the children of pregnant women treated during their pregnancy with insulin only. Additionally, and making use of the availability of GDM diagnosis data from 2004 onwards, a cohort of children born to mothers with GDM and naïve to in utero exposure to pharmacological antidiabetic treatment will be added for comparison.
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 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
Not applicable (single centre)
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 signed08/02/2017
Start date of data collection05/11/201830/11/2018
Start date of data analysis31/12/201830/11/2018
Date of interim report, if expected
Date of final study report31/12/202004/08/2020
4. Sources of funding
Please provide estimates of the percentage of funding by source for this study
Names(s)Approximate % funding
Pharmaceutical companiesMerck KGaA100
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 Ms
Last name Hetemäki
First name Saara
Address line 1Global Database Studies, IQVIA
Address line 2Spektri, Duo Building, Metsänneidonkuja 6
Address line 3
CityEspoo
PostcodeFI-02130
CountryFinland
Phone number (incl. country code)358-40-7241592
Alternative phone number
Fax number (incl. country code)
6. Study drug(s) information
Substance class (ATC Code)A10BA02 (metformin)
Substance class (ATC Code)A10A (INSULINS AND ANALOGUES)
7. Medical conditions to be studied
Medical condition(s)Yes
Gestational diabetes
Type 1 diabetes mellitus
Type 2 diabetes mellitus
Polycystic ovaries
8. Population under study
Age
Preterm newborns
Term newborns (0-27 days)
Infants and toddlers (28 days - 23 months)
Children (2 - 11 years)
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 subjects64300
Additional information
Approximately 21,500 children exposed to the drugs of interest and 42,800 unexposed children (but with mothers with GDM) - in total 64,300 children.
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, Register of Primary Health Care Visits, Population Register Centre, Statistics Finland, regional laboratory databases, Finland
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 objective is to estimate longitudinally the prevalence, incidence and risk of diagnoses (obesity, hypoglycaemia, hyperglycaemia, hypertension, diabetes mellitus, PCOS (girls only), and diagnoses related to challenges in motor-social development) from the age of one week for as long as data are available in the four cohorts of interest.
Are there primary outcomes?Yes
The primary outcomes are the long-term diagnoses collected from the age of one week for as long as data are available (maximum follow-up period 20 years).
Are there secondary outcomes?Yes
The secondary outcomes include the immediate effects at birth, up to one year of age and long-term growth-related effects (maximum follow-up period 16 years).
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 children born to the included women in 1996-2016 will be followed, starting from date of birth of the children. The children will be followed until the end of the study period (2016), death, or migration abroad, whichever occurs first. The maximum follow-up period for the primary outcomes is up to the age of 20 years, and for secondary outcomes up to the age of 16 years.
15. Data analysis plan
Please provide a brief summary of the analysis method
For the primary objectives, the prevalence and incidence of children having a long-term diagnosis of interest will be estimated with 95% confidence interval separately within each study cohort and in the total population. The cumulative risk of permanent outcomes will also be characterised using the Kaplan-Meier estimator. In the analyses, three different Cox proportional hazards models will be used: unadjusted, adjusted, and adjusted using also propensity scores. The same three models will be used in logistic regression models to compare the yearly prevalence of the permanent long-term effects.
For the secondary objectives, similar analyses will be conducted as for the primary objectives, considering the nature of the outcome and whether the outcomes are immediate at birth or long-term. For continuous outcomes, linear regression analyses will be conducted. In all regression analyses, the children with in utero exposure to insulin only will be considered as the reference group.
16. ENCePP seal
Are you requesting the ENCePP seal for this study?
Yes
17. Full protocol
18. Study Results
Please list the 5 most relevant publications using data from your study
ReferenceLink to web-publication
None
19. Other relevant documents
Other documents
DescriptionDocumentLatest version
Signed Code of
Conduct Checklist
Submitted
Signed Code of Conduct Declaration
Submitted
Signed Checklist for Study
Protocols
Submitted
