Assessing the feasibility of testing for M2 haplotype in predicting adverse pregnancy outcomes: A feasibility study

ISRCTN	ISRCTN17353836
DOI	https://doi.org/10.1186/ISRCTN17353836
IRAS number	340830
Secondary identifying numbers	CPMS 66451

Submission date: 28/11/2024
Registration date: 19/12/2024
Last edited: 20/01/2025

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Pregnancy and Childbirth

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
Recent scientific research has shown that couples who are positive for the M2 haplotype gene may be at a higher risk of implantation failure/preclinical miscarriage if undergoing IVF; miscarriage in the first trimester and pregnancy complications such as high blood pressure in pregnancy (pre-eclampsia), preterm birth (baby delivering before 34 weeks of pregnancy) and fetal growth restriction (baby not growing as expected). Currently, there is no treatment for this condition. The first phase of this study, which will run until March 2025, will be testing couples to see whether they are positive for the M2 haplotype. The study aims to determine the proportion of screened individuals who test positive for the M2 haplotype gene in both males and females; assess the willingness of the source population to undergo screening; and, pilot procedures for obtaining informed consent. The study will involve test biosampling methods and laboratory analysis processes.

Who can take part?
Couples who meet one of the following conditions may be eligible to take part:
• Primary infertility ( never been pregnant) or secondary infertility ( been pregnant before but have been unable to conceive again)
• One or more failed embryo transfers during IVF
• One or more miscarriages including biochemical pregnancy loss (a very early pregnancy loss)
• Problems with the placenta during pregnancy, such as preeclampsia, a low birth weight baby or a spontaneous pre-term birth (less than 34 weeks gestation)

What does the study involve?
Both partners in the couple will need to undergo testing to confirm whether either (or both) of them are positive for the M2 haplotype gene. They will both need to give a blood sample which will be sent to a lab for M2 haplotype testing. They may also choose to give an optional saliva sample. Test results will be sent to the research teams at sites approximately one week after the sample is sent to the lab.

What are the possible risks and benefits of taking part?
Participants will not gain any personal benefit. It is hoped that their participation in this initial phase will help refine study procedures and gather preliminary data to inform future research. The main benefit of the LAMP study will be that information gained from the study will help improve the options available for women and couples in similar circumstances in the future.

Minimal risks are expected from involvement in LAMP. Participants may feel dizzy or faint during the blood test. Staff taking the blood sample will be trained to deal with this. After the test, there may be a small bruise where the needle went in. This should fade over the next few days.

Where is the study run from?
The University of Birmingham is the study sponsor and coordinating organisation.

When is the study starting and how long is it expected to run for?
April 2022 to March 2025

Who is funding the study?
Innovate UK (part of UK Research and Innovation), UK

Who is the main contact?
Please contact the trial mailbox: LAMP@trials.bham.ac.uk

Contact information

Miss Laura Butler
Public

University of Birmingham
Birmingham
B15 2TT
United Kingdom

Phone	+44 (0)7500007709
Email	LAMP@trials.bham.ac.uk

Prof Shakila Thangaratinham
Principal Investigator

University of Liverpool
Liverpool
L69 7ZX
United Kingdom

ORCID ID	0000-0002-4254-460X
Phone	+44 (0)7887775891
Email	S.Thangaratinam@liverpool.ac.uk

Mr Lee Middleton
Scientific

University of Birmingham
Birmingham
B15 2TT
United Kingdom

Phone	+44 (0)121 415 9108
Email	l.j.middleton@bham.ac.uk

Study information

Study design	Multicentre feasibility study and an exploratory prognostic study
Primary study design	Observational
Secondary study design	Cross sectional study
Study setting(s)	Hospital
Study type	Diagnostic, Screening
Participant information sheet	Not available in web format, please use contact details to request a participant information sheet
Scientific title	Level of Adverse pregnancy outcomes in M2 haPlotype (LAMP)
Study acronym	LAMP
Study objectives	Feasibility 1. Determine the feasibility of testing eligible women and men for M2 gene haplotype using the gold standard of Sanger sequencing DNA from blood and saliva samples 2. Determine the proportion of women and men with M2 heterozygous and homozygous status 3. Obtain preliminary estimates to compare the performance of the test for DNA from Blood samples vs Saliva samples by Sanger sequencing in detecting the M2 gene haplotype Prognostic 4. Explore factors which determine the risk of adverse pregnancy outcomes in women and men who test positive for M2 gene haplotype
Ethics approval(s)	Pending submission
Health condition(s) or problem(s) studied	Couples trying to get pregnant who meet at least one of the following conditions: - Primary or secondary infertility (primary infertility is when a pregnancy has never been achieved (when tried for), and secondary infertility is when at least one prior pregnancy has been achieved) - One or more failed implantation post-embryo transfer - One or more miscarriages including biochemical pregnancy loss - Previous placenta-mediated pregnancy complications defined as pre-eclampsia, small for gestational age foetus (<10th centile), spontaneous preterm birth (<34 weeks) or a combination of these.
Intervention	Both partners in the couple will give a blood sample (+/- optional saliva sample) for M2 haplotype testing. The M2 haplotype, a genomic variant with four consecutive nucleotide substitutions in the ANXA5 promoter gene, reduces ANXA5 protein production and is linked to implantation failure, early pregnancy loss, and obstetric complications like pre-eclampsia and small for gestational age fetuses.
Intervention type	Other
Primary outcome measure	Feasibility outcome: The proportion of eligible couples (men and women) who consent to be tested measured using data recorded in study records at one timepoint
Secondary outcome measures	Preliminary estimates of sensitivity (Sn), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV) from the proportions of false positive, false negative, true positive, and true negative rates will be calculated using binomial exact methods. This will be undertaken for salivary versus blood samples for M2 gene haplotype status measured using Sanger sequencing at one timepoint
Overall study start date	01/04/2022
Completion date	31/03/2025

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Upper age limit	40 Years
Sex	Both
Target number of participants	450
Key inclusion criteria	1. Women planning a pregnancy or currently pregnant 2. Women aged 18-40 years old 3. Maternal BMI (body mass index) 18.5-34.9 kg/m2 AND 4. At least one of the following: 5. Primary or secondary infertility (primary infertility is when a pregnancy has never been achieved (when tried for), and secondary infertility is when at least one prior pregnancy has been achieved) 6. One or more failed implantation post-embryo transfer 7. One or more miscarriages including biochemical pregnancy loss 8. Previous placenta-mediated pregnancy complications defined as pre-eclampsia, small for gestational age foetus (<10th centile), spontaneous preterm birth (<34 weeks) or a combination of these. 9. Male partners of eligible women* *The male partner needs to be the same partner as in previous pregnancies where a fertility/pregnancy complication occurred which deemed the woman eligible i.e. primary or secondary infertility, failed implantation post embryo transfer, previous miscarriage, previous placenta mediated pregnancy complication.
Key exclusion criteria	1. Anti-phospholipid syndrome (APS) 2. Participation in a clinical Study of an investigational medicinal product in the last 90 days 3. Participation in any other open or blinded, placebo‐controlled trials of investigational medicinal products (if currently pregnant) 4. Women found to have multiple pregnancies or who have had multiple embryos transferred in IVF (if currently pregnant) 5. Current pregnancy conceived using donor egg or sperm 6. Women who are known to be taking heroin, cocaine or other illegal substances 7. Paternity status not known for male partner 8. Female and/or male participants unwilling to give consent
Date of first enrolment	06/01/2025
Date of final enrolment	31/03/2025

Locations

Countries of recruitment

England
United Kingdom

Study participating centres

University College London Hospitals NHS Foundation Trust

250 Euston Road
London
NW1 2PG
United Kingdom

Liverpool Women's NHS Foundation Trust

Liverpool Womens Hospital
Crown Street
Liverpool
L8 7SS
United Kingdom

Birmingham Women's NHS Foundation Trust

Birmingham Womens Hospital
Metchley Park Road
Birmingham
B15 2TG
United Kingdom

Sponsor information

University of Birmingham
University/education

Edgbaston
Birmingham
B15 2TT
England
United Kingdom

Phone	+44 (0)7814 650 003
Email	researchgovernance@contacts.bham.ac.uk
Website	https://www.birmingham.ac.uk/
"ROR"	https://ror.org/03angcq70

Funders

Funder type

Government

Innovate UK
Government organisation / National government

Alternative name(s): innovateuk
Location: United Kingdom

Results and Publications

Intention to publish date	01/04/2026
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Data sharing statement to be made available at a later date
Publication and dissemination plan	On completion of the study, the data will be analysed, and a Final Study Report prepared. Outputs from this study will be submitted for publication in peer reviewed journals and the findings of the study will be made public within 12 months of the end of the study. Manuscripts will be prepared by the writing group as defined in the study publication plan. Manuscripts should be submitted to the TMG in a timely fashion and in advance of being submitted for publication to allow time for review.
IPD sharing plan	The data-sharing plans for the current study are unknown and will be made available at a later date

Editorial Notes

20/01/2025: Internal review.
29/11/2024: Study's existence confirmed by Innovate UK.