Condition category
Pregnancy and Childbirth
Date applied
13/02/2013
Date assigned
15/05/2013
Last edited
10/10/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
It is well established that folic acid supplementation in the early stages of pregnancy can reduce the risk of neural tube defects and some other birth defects. Observational research also suggests that maternal folic acid (folate) intake may have a long-term effect on the central nervous system development of the offspring; however, the evidence so far is inconclusive. The aim of this study is to investigate the effect of folic acid supplementation during pregnancy, on growth, nervous system development and behaviour of the offspring aged 6 and 10.

Who can participate?
Mother-child pairs will be recruited from a previously conducted randomized controlled trial which investigated the effect of folic acid supplementation (400µg/d) in the second and third trimester of pregnancy (FASSTT) study (REC reference number: 05/Q2008/21).

What does the study involve?
Current as of 10/10/2017:
In the FASSTT trial in pregnancy, participants were randomised to receive either folic acid supplement (400µg/d) or placebo in the second and third trimesters of pregnancy. A nonfasting blood sample was collected from each mother participant at the time of recruitment (14th gestational week) and again at the end of pregnancy (36th gestational week) and a cord blood sample was collected at birth. In all cases, the blood samples collected were analysed for B-vitamin concentrations, DNA methylation of targeted genes and genome-wide analysis; the results were compared for the two intervention groups. The children of these women were followed up at ages 6-7y and 10-11y for data on their growth and cognitive function. They also provided DNA samples via cheek swab and blood sample. The DNA samples from the children were collected for DNA methylation of targeted genes and genome-wide analysis to see if maternal folate status during pregnancy influenced DNA methylation in early life. In addition, blood samples collected at follow-up were analysed for B-vitamin concentrations.

Current as of 27/07/2017:
In the FASSTT trial in pregnancy, participants were randomised to receive either folic acid supplement (400µg/d) or placebo in the second and third trimesters of pregnancy. A nonfasting blood sample was collected from each mother participant at the time of recruitment (14th gestational week) and again at the end of pregnancy (36th gestational week) and a cord blood sample was collected at birth. The children of these women were followed up at ages 6-7y and 10-11y for data on their growth and cognitive function. They also provide DNA samples via cheek swab and blood sample. The DNA samples from the children are analysed to see if maternal folate status during pregnancy influenced DNA methylation in early life.

Previous:
For the purpose of this investigation mother-child pairs will be asked to attend a one-off appointment at the Human Intervention Studies Unit (HISU) at Ulster University, Coleraine. The study will be explained to the participants and any queries answered. Informed consent will be obtained from both the mother and the child. The child will be asked to complete a cognitive assessment at approximately 6 years of age using the Wechsler Preschool and Primary Scale of Intelligence test, 3d UK edition (WPPSI) and at the age of 10 years by the Wechsler Intelligence Scale for Children, 4th UK edition (WISC-IV). The psychological tests: Trait Emotional Intelligence Questionnaire (TEIque), Attachment Style Questionnaire and Resilience Questionnaire (RASP) will be used at age 10. The mother will be asked to complete the following; Health & Lifestyle Questionnaire and Parenting Style. Anthropometric measurements of the child will be taken by using standard equipment; weight (digital weighing scales), height (stadiometer), waist circumference (non-stretchable tape) and body fat (portable bioelectrical impedance scales). In addition, a buccal swab and blood sample (age 10 years only) of each child will be taken for DNA methylation and B-vitamin analysis. In a random selection of children, brain activity assessments are carried out using a technique called magnetoencephalography (MEG). This involves using a MEG machine to assess brain function by passively measuring the magnetic fields produced by neurons (nerve cells) in the brain. The current study is the first of its kind to report the use of MEG neuro-imaging in a nutritional investigation of children. Ulster University, Magee has one of the few MEG machines in the UK (and the only one on the Island of Ireland) and the expertise to apply this safe and unintimidating procedure in children.

What are the possible benefits and risks of participating?
There is no direct proven benefit; this study will lead to a greater understanding of the impact of folate in pregnancy on child development. By taking part in the study the mother will find out how their child performs on the cognitive assessment. The results of this study will help to generate specific recommendations for folate intake and supplement usage in pregnancy for better health of the mother and the child. In the unlikely event that the child shows results outside the normal range, the mother’s permission will be asked to refer the child to the consultant paediatrician involved in this study.

Where is the study run from?
The study will be run from Ulster University, Coleraine.

When is the study starting and how long is it expected to run for?
Current as of 27/07/2017:
Original FASSTT trial: June 2005 to October 2007.
Follow-up study: January 2013 to March 2019.
The recruitment of 6 year old children started in January 2013 and concluded in February 2014. The follow-up of the children at age 10 has already begun in February 2016 and is expected to run until March 2019.

Previous:
The study has already begun: recruitment of study participants started in January 2013. Recruitment is expected to finish in February 2014.

Who is funding the study?
Current as of 27/07/2017:
1. Biotechnology and Biological Sciences Research Council (BBSRC) (UK)
2. Economic and Social Research Council (ESRC) (UK)
3. HSC Research and Development Division of the Public Health Agency, Northern Ireland (Enabling Research Award).

Previous:
1. Biotechnology and Biological Sciences Research Council (BBSRC) (UK)
2. Economic and Social Research Council (ESRC) (UK)
3. Northern Ireland Centre for Food and Health (NICHE) (UK)
4. Department of Education and Learning (DEL) (UK)

Who is the main contact?
Ms Aoife Caffrey
caffrey-a@email.ulster.ac.uk
Added 27/07/2017:
Dr Kristina Pentieva
k.pentieva@ulster.ac.uk

Trial website

http://www.bristol.ac.uk/integrative-epidemiology/epigenetics-social-science-network/research-projects-and-networks/epifasstt/

Contact information

Type

Scientific

Primary contact

Dr Kristina Pentieva

ORCID ID

Contact details

School of Biomedical Sciences
University of Ulster
Cromore Road
Coleraine
Coleraine
BT52 1SA
United Kingdom
-
k.pentieva@ulster.ac.uk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

N/A

Study information

Scientific title

The effect of folic acid supplementation during pregnancy on the growth, cognitive development and behaviour of 6 and 10 year old children: a follow-up investigation of children of FASSTT study participants

Acronym

EpiFASSTT

Study hypothesis

It is hypothesised that folic acid supplementation during the second and third trimesters of pregnancy may have significant effects on the cognitive development, behaviour and growth.
This is a follow up study on the participants of a previous randomised controlled trial and their offspring. This previous trial took place in 2005-2007 as part of an on-going collaborative research project between the University of Ulster and the Causeway Hospital, Northern Health and Social Services Trust. It investigated the effect of 'Folic Acid Supplementation in the Second and Third Trimester' and the health outcomes of the mother and new-born (FASSTT study: REC reference number: 05/Q2008/21). A total of 125 women completed the FASSTT study.

Ethics approval

Current ethical approvals as of 27/07/2017:
1. Salisbury & South Wiltshire NHS Research Ethics Committee, 20/06/2005, Ref: 05/Q2008/21
2. Office of Research Ethics Committees in Northern Ireland (ORECNI), 16/08/2012, Ref: 12/NI/0077
3. Northern Health and Social Care Trust, 28/12/2012, Ref: NRP12-0305-05


Previous ethical approvals:
1. Office of Research Ethics Committees in Northern Ireland (ORECNI), 02/09/2016
2. Northern Health and Social Care Trust, 05/09/2016

Study design

Follow-up study on the participants of a previous randomised controlled trial and their offspring

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Other

Trial type

Other

Patient information sheet

Not available in web format, please contact Caffrey-A@ulster.ac.uk or K.Pentieva@ulster.ac.uk to request a patient information sheet

Condition

Folic acid supplementation in pregnancy

Intervention

Current interventions as of 10/10/2017:
In 2005/2007 a randomised controlled trial investigating the effect of Folic Acid Supplementation during the Second and Third Trimester (FASSTT) and the health outcomes of the mother and newborn was conducted. Healthy pregnant women aged 18-35 years, who have taken folic acid supplementation during their first trimester of pregnancy, were recruited from antenatal clinics of the Causeway Hospital, Coleraine. At the end of the first trimester, women willing to take part were randomly assigned to take placebo or 400ug/d of folic acid until the end of the pregnancy. Blood samples were collected from the mother participant before the start of the intervention (14th gestational week), at the 36th gestational week (representative of post-intervention) and a cord blood sample was collected at birth. In all cases, the blood samples collected were analysed for B-vitamin concentrations, DNA methylation of targeted genes and genome-wide analysis; the results were compared for the two intervention groups.
For the purpose of the follow-up investigation, children who were born to mothers who took part in the FASSTT trial will be asked to take part in the FASSTT Offspring study where they will attend an appointment at the Human Intervention Studies Unit (HISU) at Ulster University, Coleraine. The study will be explained to the participants and any queries answered. Informed consent will be obtained from both the mother and assent will be obtained from the child. The child will be asked to complete a cognitive assessment at approximately 6 years of age using the Wechsler Preschool and Primary Scale of Intelligence test, 3d UK edition (WPPSI) and at the age of 10 years by the Wechsler Intelligence Scale for Children, 4th UK edition (WISC-IV). The psychological tests: Trait Emotional Intelligence Questionnaire (TEIque), Attachment Style Questionnaire and Resilience Questionnaire (RASP) will be used at age 10. The mother will be asked to complete a Health & Lifestyle and Parenting Style Questionnaire. Anthropometric measurements of the child will be taken using standard equipment; weight (digital weighing scales), height (stadiometer), waist circumference (non-stretchable tape) and body fat (portable bioelectrical impedance scales). In addition, a buccal swab (obtained by gently rubbing the mucosa inside the cheek) and whole venous blood sample (collected by venepuncture) will be collected for B-vitamin concentrations, DNA methylation of targeted genes and genome-wide analysis; the results were compared for the two intervention groups.
In a random selection of children, brain activity assessments will be carried out using magnetoencephalography (MEG). The MEG machine will be used to assess brain function by passively measuring the magnetic fields produced by neurons in the brain. The current study will be the first of its kind to report the use of MEG neuro-imaging in a nutritional investigation of children. Ulster University, Magee has one of the few MEG machines in the UK (and the only one on the Island of Ireland) and the expertise to apply this safe and unintimidating procedure in children.

Current interventions as of 27/07/2017:
In 2005/2007 a randomised controlled trial investigating the effect of Folic Acid Supplementation during the Second and Third Trimester (FASSTT) and the health outcomes of the mother and newborn was conducted. Healthy pregnant women aged 18-35 years, who have taken folic acid supplementation during their first trimester of pregnancy, were recruited from antenatal clinics of the Causeway Hospital, Coleraine. At the end of the first trimester, women willing to take part were randomly assigned to take placebo or 400ug/d of folic acid until the end of the pregnancy. Blood samples were collected before the intervention and at the 36th gestational week.

For the purpose of the follow-up investigation, children who were born to mothers who took part in the FASSTT trial, will be asked to take part in the FASSTT Offspring study where they will attend an appointment at the Human Intervention Studies Unit (HISU) at Ulster University, Coleraine. The study will be explained to the participants and any queries answered. Informed consent will be obtained from both the mother and assent will be obtained from the child. The child will be asked to complete a cognitive assessment at approximately 6 years of age using the Wechsler Preschool and Primary Scale of Intelligence test, 3d UK edition (WPPSI) and at the age of 10 years by the Wechsler Intelligence Scale for Children, 4th UK edition (WISC-IV). The psychological tests: Trait Emotional Intelligence Questionnaire (TEIque), Attachment Style Questionnaire and Resilience Questionnaire (RASP) will be used at age 10. The mother will be asked to complete a Health & Lifestyle and Parenting Style Questionnaire. Anthropometric measurements of the child will be taken using standard equipment; weight (digital weighing scales), height (stadiometer), waist circumference (non-stretchable tape) and body fat (portable bioelectrical impedance scales). In addition, a buccal swab (obtained by gently rubbing the mucosa inside the cheek) and whole venous blood sample (collected by venepuncture) will be collected for DNA methylation and B-vitamin concentration analysis.

In a random selection of children, brain activity assessments will be carried out using magnetoencephalography (MEG). The MEG machine will be used to assess brain function by passively measuring the magnetic fields produced by neurons in the brain. The current study will be the first of its kind to report the use of MEG neuro-imaging in a nutritional investigation of children. Ulster University, Magee has one of the few MEG machines in the UK (and the only one on the Island of Ireland) and the expertise to apply this safe and unintimidating procedure in children.

Previous interventions:
In 2005/2007 a randomised controlled trial investigating the effect of Folic Acid Supplementation during the Second and Third Trimester (FASSTT) and the health outcomes of the mother and newborn was conducted. Healthy pregnant women aged 18-35 years, who have taken folic acid supplementation during their first trimester of pregnancy, were recruited from antenatal clinics of the Causeway Hospital, Coleraine. At the end of the first trimester, women willing to take part were randomly assigned to take placebo or 400ug/d of folic acid until the end of the pregnancy. Blood samples were collected before the intervention and at the 36th gestational week.

Intervention type

Supplement

Phase

Drug names

Primary outcome measures

To determine the effect of folic acid supplementation during pregnancy on cognitive development of the offspring aged 6 and 10 years. Each child will undergo a cognitive assessment at approximately 6 years of age using the Wechsler Preschool and Primary Scale of Intelligence test, 3rd edition (WPPSI) and at the age of 10 years using the Wechsler Intelligence Scale for Children, 4th UK edition (WISC-IV). The cognitive assessments are composed of a battery of subtests, sampling a broad spectrum of behaviour.

Secondary outcome measures

To investigate the effect of folic acid supplementation during pregnancy on the offspring’s growth, behaviour, brain activity and DNA methylation.
Anthropometric measurements of the child will be taken by using standard equipment; weight (digital weighing scales), height (stadiometer), waist circumference (non-stretchable tape) and body fat (portable bioelectrical impedance scales). In addition, a buccal swab and blood sample (age 10 years only) of each child will be taken for DNA methylation and B-vitamin analysis.
In a random selection of FASSTT children age 10 years old, brain activity assessments will be carried out by magnetoencephalography (MEG). The MEG machine will be used to assess brain function by passively measuring the magnetic fields produced by neurons in the brain. The current study will be the first of its kind to report the use of MEG neuro-imaging in a nutritional investigation of children. Ulster University, Magee has one of the few MEG machines in the UK (and the only one on the Island of Ireland) and the expertise to apply this safe and unintimidating procedure in children.

Overall trial start date

01/06/2012

Overall trial end date

01/03/2019

Reason abandoned

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 27/07/2017:
1. The FASSTT trial involved healthy women in the first trimester of pregnancy with singleton pregnancies, without current pregnancy complications, and aged between 18 and 35y.
2. Women who participated in a previous randomized controlled trial (FASSTT study, REC ref: 05/Q2008/21) and their healthy children aged 6-7y and 10-11y who were born as singleton live births to mothers who completed the trial in the 2nd and 3rd trimesters of pregnancy.
3. Parents who consented and children who assented to their participation in follow-up studies in which cognitive development and growth were measured.

Previous inclusion criteria:
Woman who participanted in a previous randomised controlled trial (FASSTT study, REC reference: 05/Q2008/21) and their children

Participant type

Patient

Age group

Mixed

Gender

Both

Target number of participants

125

Participant exclusion criteria

Current exclusion criteria as of 27/07/2017:
1. The FASSTT trial excluded women from participation if during the first trimester of pregnancy they had taken folic acid supplements at a dose above 400µg/d, if they had gastrointestinal, hepatic, renal, or vascular disease, hematologic disorders, epilepsy, a previous pregnancy with an NTD or were the first degree relative of a woman who had a pregnancy with an NTD, or were themselves a sufferer of an NTD. Participants who were taking a medication known to interfere with B vitamin metabolism or those who had undergone in vitro fertilization treatment were also excluded.
2. Any child who has a severe current health problem or disability with impact on cognitive development (primary outcome measure)
3. Any child whose informed written consent cannot be obtained from the parent/guardian
4. Any child who refuses to have the measurements taken

Previous exclusion criteria:
1. Any child who has a severe current health problem or disability with impact on cognitive development (primary outcome measure)
2. Any child whose informed written consent cannot be obtained from the parent/guardian
3. Any child who refuses to have the measurements taken

Recruitment start date

01/11/2016

Recruitment end date

01/12/2017

Locations

Countries of recruitment

United Kingdom

Trial participating centre

University of Ulster
Coleraine
BT52 1SA
United Kingdom

Sponsor information

Organisation

University of Ulster (UK)

Sponsor details

c/o Nick Curry
Shore Road
Newtonabbey
Co.Antrim
Belfast
BT37 0QB
United Kingdom
+44 (0)28 9036 6234
n.curry@ulster.ac.uk

Sponsor type

University/education

Website

http://www.ulster.ac.uk

Funders

Funder type

Government

Funder name

Northern Ireland Centre for Food and Health (NICHE) (UK)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Department of Education and Learning (DEL) (UK) - PhD studentship

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Biotechnology and Biological Sciences Research Council (BBSRC)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Economic and Social Research Council (ESRC)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Publication and dissemination plan
The results of the original trial have been published (http://ajcn.nutrition.org/content/early/2013/05/29/ajcn.112.057489.full.pdf) and results relating to unmetabolised folic acid (https://www.ncbi.nlm.nih.gov/pubmed/26817717). The results of the FASSTT and EpiFASSTT analyses (relating to maternal folate and offspring cognitive development, growth and DNA methylation in the offspring) are expected to be presented at conferences and published in a series of papers in peer-reviewed journals in 2017 to 2019.

IPD sharing statement:
The data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

31/12/2019

Participant level data

To be made available at a later date

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

10/10/2017: Plain English summary has been updated. All references to mcgarel-c@email.ulster.ac.uk have been removed. Interventions have been updated. 27/07/2017: Added publication and dissemination plan as well as participant level data sharing plan. The age group has been updated from Adult to Mixed. Gender has been updated from female to both genders. Inclusion and exclusion criteria have been updated. Acronym has been added. Ethical approvals and interventions have been updated. The Plain English summary has been updated. The trial website has been added. Please note that this study is a follow up of a randomised controlled trial. 19/07/2017: The public title has been changed from “To determine whether taking folic acid during the later stage has any beneficial effects of the cognitive development and growth of the offspring” to "To determine whether taking folic acid during the later stages of pregnancy has any beneficial effects of the cognitive development and growth of the offspring”. 20/12/2016: The study record has been updated to reflect a follow up when the children are 10 years old. In addition, the overall trial end date has been updated from 31/12/2017 to 01/03/2019. The recruitment dates have also been updated from 01/01/2013 - 01/02/2014 for 6 year old children to 01/11/2016 - 01/12/2017 (for 10 year old children). Finally, BBSRC and ESRC have been added as funders.