Investigating the link between early life stress and multiple long-term health conditions

ISRCTN	ISRCTN44060592
DOI	https://doi.org/10.1186/ISRCTN44060592
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	Nil known
Protocol serial number	Earlycause funding 848158
Sponsor	European Commission
Funder	Horizon 2020 Framework Programme

Submission date: 29/06/2020
Registration date: 15/07/2020
Last edited: 26/06/2024

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Other

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
Stress experienced in the early stages of life – from pregnancy to adolescence – is common and pervasive, affecting up to 75% of pregnant women (and the unborn baby) and nearly 50% of children, with long-term consequences for development and health. The aim of this study is to find out whether early life stress, a well-established risk factor for depressive, cardiovascular (heart) and metabolic disorders individually, is a cause of multiple long-term health conditions (multi-morbidity) in these disorders.

Who can participate?
Children and adults participating in the included population studies:
1. Population-based samples of children
2. Adults aged over 55 years
3. Adults aged over 18 years with depression or anxiety

What does the study involve?
Data from a set of human population studies are used to examine the relationship between early life stress and multi-morbidity across the lifespan, identify potential biological markers and quantify the role of modifiable lifestyle factors (e.g. exercise, diet, sleep, smoking, alcohol use).

What are the possible benefits and risks of participating?
In terms of benefits, this study will increase the health literacy of the participants by making them aware of the negative effects of early life stress on health and disease. This is an observational study with no interventions, so there are no risks for the participants.

Where is the study run from?
Rotterdam and Amsterdam (Netherlands), Oulu (Finland) and Bristol (UK)

When is the study starting and how long is it expected to run for?
September 2019 to June 2024

Who is funding the study?
European Commission

Who is the main contact?
1. Karim Lekadir
karim.lekadir@ub.edu
2. Cristian Izquierdo Morcillo
c.izquierdo@ub.edu

Contact information

Dr Karim Lekadir
Scientific

Gran Via de les Corts Catalanes 585
Barcelona
08007
Spain

ORCID ID	0000-0002-9456-1612
Phone	+34 (0)934020852
Email	karim.lekadir@ub.edu

Dr Cristian Izquierdo Morcillo
Public

Gran Via de les Corts Catalanes 585
Barcelona
08007
Spain

Phone	None provided
Email	c.izquierdo@ub.edu

Study information

Primary study design	Observational
Study design	Observational study that will leverage existing data from a large set of population research studies (e.g. Generation R, ALSPAC, NFBC, Rotterdam, NESDA)
Secondary study design	Epidemiological study
Study type	Participant information sheet
Scientific title	EarlyCause - causative mechanisms & integrative models linking early life stress to psycho-cardio-metabolic multi-morbidity
Study acronym	EarlyCause
Study objectives	EarlyCause will investigate the hypothesis that early-life-stress (ELS), as a risk factor for depressive, cardiovascular and metabolic disorders individually, is linked to multi-morbidity between these conditions. From a biological point of view, the main hypothesis is that ELS activates a chain of events leading to cellular, molecular, epigenetic and microbial changes which result in dysregulations of processes across tissues. This causative chain would ultimately trigger specific cellular and tissue phenotypes and comorbid pathological traits in the mental, cardiovascular and metabolic domains.
Ethics approval(s)	Approved 30/11/2019, European Commission (Directorate-General for Research and Innovation, European Commission, Brussels; Tel: not provided; david.canovas-jorda@ec.europa.eu), no ref provided
Health condition(s) or problem(s) studied	Multi-morbidity between unipolar depression, type 2 diabetes, and coronary heart disease
Intervention	The EarlyCause study will leverage harmonised data from a set of human population studies to examine the relationship between ELS and multi-morbidity across the lifespan, identify potential molecular markers and quantify the protective vs. exacerbating role of modifiable lifestyle factors. These datasets together span from pregnancy to old age, including the well-known Avon Longitudinal Study of Parents and Children (ALSPAC), Generation R Study (GenR), Northern Finland Birth Cohorts (NFBC 1966 and NFBC 1986), Rotterdam Study, and the Netherlands Study of Depression and Anxiety (NESDA). The researchers will make use of correlational multivariate analyses as well as novel latent modelling techniques to model the shared versus unique contribution of ELS on multi-morbid outcomes. The researchers will apply Mendelian randomisation to infer causality using population-based human genetic data., and to establish the molecular mediation of biological markers (DNA methylation, cortisol, inflammation, microbiome) linking ELS exposure to later multi-morbidity. The researchers will also quantify the protective or exacerbating role of modifiable lifestyle factors (e.g. exercise, diet, sleep, smoking, alcohol use) in the relationships of ELS with biological markers and multi-morbidity.
Intervention type	Other
Primary outcome measure(s)	Current primary outcome measures as of 28/12/2023: 1. Depression assessed using the DSM-IV scale at each round of data collection (every 2-5 years depending on the dataset) 2. Diabetes type 2 assessed using the glycated hemoglobin test at each round of data collection (every 2-5 years depending on the dataset) 3. Coronary heart disease assessed using standard cardiovascular exams (biomarkers, imaging, ECG) at each round of data collection (every 2-5 years depending on the dataset) 4. In NFBC, depressive symptoms were measured using Youth self report (YSR) scale at 16 years in NFBC1986 and using Hopkins Symptoms checklist (HSCL) at 31 and 46 years in NFBC1966 _____ Previous primary outcome measures: 1. Depression assessed using the DSM-IV scale at each round of data collection (every 2-5 years depending on the dataset) 2. Diabetes type 2 assessed using the glycated hemoglobin test at each round of data collection (every 2-5 years depending on the dataset) 3. Coronary heart disease assessed using standard cardiovascular exams (biomarkers, imaging, ECG) at each round of data collection (every 2-5 years depending on the dataset)
Key secondary outcome measure(s)	Current secondary outcome measures as of 28/12/2023: EarlyCause will re-use the outcomes already measured by the Generation R, ALSPAC, NFBC, Rotterdam and NESDA studies at each round of data collection (every 2-5 years depending on the study): 1. Depressive symptoms assessed using the Centre for Epidemiological Studies Depression Scale (CESD) at each round of data collection (every 2-5 years depending on the dataset) 2. Metabolic health-related measures such as obesity and glycemic traits 3. Hypertension assessed using blood pressure test (mmHg) at each round of data collection (every 2-5 years depending on the dataset) _____ Previous secondary outcome measures:EarlyCause will re-use the outcomes already measured by the Generation R, ALSPAC, NFBC, Rotterdam and NESDA studies at each round of data collection (every 2-5 years depending on the study): 1. Depressive symptoms assessed using the Centre for Epidemiological Studies Depression Scale (CESD) at each round of data collection (every 2-5 years depending on the dataset) 2. Glucose level assessed using glycated hemoglobin test at each round of data collection (every 2-5 years depending on the dataset) 3. Hypertension assessed using blood pressure test (mmHg) at each round of data collection (every 2-5 years depending on the dataset)
Completion date	30/06/2024

Eligibility

Participant type(s)
Age group	Mixed
Sex	All
Target sample size at registration	70000
Key inclusion criteria	Current inclusion criteria as of 28/12/2023: The inclusion criteria are the same as those of the population studies included in EarlyCause: 1. Generation R: Population-based sample of children 2. ALSPAC: Born of a mother resident in former Avon health authority, expected data of delivery between 1st April 1991 and 31st December 1992 3. NFBCs: Pregnant mothers living in the two northernmost province of Finland (Oulu and Lapland). NFBC-1966 included all mothers with expected date of delivery between 1st of January to 31st December 1966 and their offspring with data at birth, 31 and 46 years of age. NFBC-1986 included mothers with expected date of delivery between July 1985 to June 1986 and their offspring with data at birth and 16 years of age. 4. Rotterdam Study: Adults >55 years 5. NESDA: Adults >18 years with DSM-IV diagnosis of depression (minor or major depression, dysthymia) or anxiety _____ Previous inclusion criteria: The inclusion criteria are the same as those of the population studies included in EarlyCause: 1. Generation R, ALSPAC, NFBC: Healthy children at birth 2. Rotterdam: Adults > 55 3. NESDA: Adults > 18 with DSM-IV diagnosis of depression (minor or major depression, dysthymia) or anxiety
Key exclusion criteria	For NESDA, severe mental health (e.g. psychosis, bipolar disorder, obsessive-compulsive disorder, or severe addiction) or disability
Date of first enrolment	01/01/1966
Date of final enrolment	30/05/2020

Locations

Countries of recruitment

United Kingdom
England
Finland
Netherlands

Study participating centres

Erasmus Medical Centre Rotterdam

Doctor Molewaterplein 40
Rotterdam
3015 GD
Netherlands

University of Oulu

Pentti Kaiteran katu 1
Oulu
90570
Finland

VU University Medical Center Amsterdam

De Boelelaan 1117
Amsterdam
1081 HV
Netherlands

University of Bath

Claverton Down
Bath
BA2 7AY
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not expected to be made available
IPD sharing plan	The datasets generated during and/or analysed during the current study are not expected to be made available due to legal issues, consents and data policies of the included population studies.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	Arterial Thickness, Stiffness, and Blood Pressure With Brain Morphology	09/11/2023	26/06/2024	Yes	No
Results article	Depression, cardiometabolic disease, and their co-occurrence after childhood maltreatment	13/03/2023	26/06/2024	Yes	No
Results article	Obesity	21/08/2023	26/06/2024	Yes	No
Results article	anorexia nervosa	01/11/2022	26/06/2024	Yes	No
Results article	depression prediction	03/04/2024	26/06/2024	Yes	No
Results article	early-life stress and adolescent psycho-physical health	01/05/2024	26/06/2024	Yes	No
Results article	maternal glycemic dysregulation during pregnancy and neonatal blood dna methylation	04/03/2022	26/06/2024	Yes	No
Results article	metabolic Syndrome	20/11/2023	26/06/2024	Yes	No
Results article	psycho-cardiometabolic multimorbidity	30/06/2023	26/06/2024	Yes	No
Protocol article		21/01/2021	26/06/2024	Yes	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Protocol file			07/08/2020	No	No
Protocol file			07/08/2020	No	No
Study website	Study website	11/11/2025	11/11/2025	No	Yes

Additional files

ISRCTN44060592_PROTOCOL_text.pdf: uploaded 07/08/2020
ISRCTN44060592_PROTOCOL_figures.pdf: uploaded 07/08/2020

Editorial Notes

26/06/2024: Publication references added.
24/06/2024: The study contacts were updated.
28/12/2023: The following changes have been made:
1. The overall study end date has been changed from 31/12/2023 to 30/06/2024.
2. The intention to publish date has been changed from 31/12/2023 to 30/06/2025.
3. The primary outcome measures have been changed.
4. The secondary outcome measures have been changed.
5. The participant inclusion criteria have been changed.
6. The plain English summary has been updated to reflect the above changes.
06/12/2023: The public contact was changed.
24/11/2020: The following changes were made to the trial record:
To reflect the fact that historical datasets are being used for this study:
1. The recruitment start date was changed from 01/01/2020 to 01/01/1966.
2. The recruitment end date was changed from 31/12/2023 to 30/05/2020.
07/08/2020: Uploaded protocol (not peer reviewed) Version n/a (2 files).
30/06/2020: Trial's existence confirmed by the European Commission.