Folate trial for recurrent miscarriage

INTERVENTION: 5‐methyltetrahydrofolate (5‐MTHF) based prenatal multivitamin (intervention ‐ Arm 1) Dose: 5‐MTHF 2,500mcg per day 5‐methyltetrahydrofolate (5‐MTHF) is the biologically active form of folate. It does not build up like folic acid and can be utilised without being converted to the form required to support DNA integrity. Participants will be required to take one dose (3 capsules) of their allocated prenatal multivitamin per day. They will also be provided to avoid folic acid fortified foods. They will be asked to receive regular blood testing including: Methylenetetrahydrofolate reductase (MTHFR) polymorphism, Vitamin B12, methylmalonic acid (MMA), red cell folate, serum folate, homocysteine. The initial baseline blood test will be completed immediately upon recruitment ie: first 2 weeks, another blood test will be taken following 2 reproductive cycles. Participants who fall pregnant will receive a blood test each trimester of pregnancy for the duration of the trial. Provider ‐ the PhD candidate is a naturopath with 12 years experience and therefore within her scope of practice to dispense the prenatal multivitamins. Delivery ‐ Intervention will be sent every 3 months via mail with internet based meetings every 6 weeks Participants will be recruited Australia wide There will be a rolling recruitment period from January 16, 2023 to March 30, 2023. Participants recruited into the study will immediately commence on the prenatal multivitamin and continue until the trial period is completed, December 30, 2023. Participants will be therefore be participating in the trial for a minimum of 9 months, maximum 12 months, depending on their recruitment date. An internet based meeting will be conducted with the PhD Candidate who is a naturopath, every 6 weeks CONDITION: Recurrent Miscarriage; ; Recurrent Miscarriage Reproductive Health and Childbirth ‐ Abortion Reproductive Health and Childbirth ‐ Fertility including in vitro fertilisation Reproductive Health and Childbirth ‐ Fetal medicine and complications of pregnancy Reproductive Health and Childbirth ‐ Other reproductive health and childbirth disorders PRIMARY OUTCOME: Feasibility determined by an audit of participant adherence to their allocated treatment, which will be assessed using participant self‐report.; ; ; ; ; ; ; ; ; ; [At 9 months after randomisation] SECONDARY OUTCOME: Acceptability ‐ Conversion rate of participants who enquire about the study assessed assessed by audit of participants that enquire vs those that are recruited. ; [After completion of rolling recruitment phase (end March 2023)] Acceptability ‐ Proportion of participants who accept randomisation assessed by audit of study database. ; [9 months post randomisation] Acceptability ‐ Proportion of participants who complete the study assessed by audit of study database. ; [9 months post randomisation] Acceptability ‐ Proportion of participants who withdraw from the study assessed by audit of study database. ; [9 months post randomisation] Acceptability of the proposed study protocol to participants and potential participants determined by assessing the number of eligible individuals who enquire about study involvement according to study recruitment logs. ; ; [At 9 months after randomisation] Confirmation of recurrent pregnancy loss assessed via researcher/participant meetings. ; [Assessed at 4, 6, 8 and every 6 weeks thereafter until conclusion of study (December 30, 2023)] Confirmation of viable pregnancy scan at 18‐22 weeks gestation assessed via Dr confirmation of a 'viable pregnancy' scan. ; [Assessed between 18‐22 weeks of gestation] Effectiveness and practicality of the participant and researcher blinding process. Participants self‐reported perception of whether they had been allocated the trial or control product assessed by post event survey of study participants ; [9 months post randomisation] Implementation ‐ Adherence to the abstinence of trying to conceive for 2 reproductive cycles following the introduction of the multivitamin via meeting update data collected throughout the trial. ; [Assessed at 4, 6, 8 and every 6 weeks thereafter until conclusion of study (December 30, 2023).] Implementation ‐ Adherence to the dietary requirement of avoiding folic acid fortified foods using 24‐hour and 7‐day recall of diet assessed by diet diary at check in meetings. ; [Assessed at 6, 8, 12 and every 6 weeks thereafter until study conclusion (December 30, 2023).] Implementation ‐ Practicalities and adherence by participant and Dr for the confirmation processes. Rate of consenting participants and their practitioners that ; completed the confirmation sheets within two weeks of the requirements assessed by audit of study database. ; [9 months post randomisation] Implementation ‐ Study participants perceptions of the support provided through online meetings assessed by post event survey of study participants. ; [9 months post randomisation] Implementation – Participant adherence to data collection requirements (ie. whether or not assessments were completed within two weeks of the required timepoints) assessed by audit of study database. ; ; ; [assessed at week 2, 4, 12, 18, at 9 months post‐randomisation] Investigate the 'folate for miscarriage trial' study participants behaviours and attitudes towards taking 5‐MTHF vs folic acid via a post study survey of trial participants created specifically for this study.[At 12 months post randomisation] Levels of Unmetabolised folic acid, serum folate, red cell folate, Vitamin B 12, homocysteine and MTHFR polymorphisms assessed using blood samples. ; [At baseline: ie: first two week of the trial, 8 weeks post‐randomisation, 3 months post randomisation and once only during second and third trimesters (if pregnant) ; ] Number of researcher hours requred to manage the trial assessed by study‐specific diary kept by researchers.[At 9 months post randomisation] Participant retention overall and between the groups ; ‐ Rate of participant retention amongst the allocation groups, and reasons for study withdrawal assessed by audit of study database. ; [9 months post randomisation] Practicalities associated with clinicians adherence to the study protocol assessed by audit of study database. ; [9 month post randomisation] Practicalities of data collection processes including time to data completion assessed by post event participant survey. ; ; [9 months post randomisation] Practicalities, ease of use of the online booking system and meeting scheduling system. Participant perceptions of the online booking system including ease of use, errors, failures in booking procedures assessed via post event survey of study participants. ; [9 month post randomisation] Practicality and effectiveness of recruitment methods including screening and eligibility processes. The dollar cost per participant for recruitment including the most cost‐effective method used for recruitment via audit of recruitment strategy and execution. ; [9 months post randomisation] Protocol changes required to achieve objectives assessed via audit of study database. ; [9 months post randomisation] Rate of errors associated with booking procedures using the online booking system assessed by audit of study database. ; [9 months randomisation] Recruitment rates per week/month, recruitment and screening/eligibility process evaluation via audit of recruitment strategy and execution. ; [9 months post randomisation] Research team challenges in conducting the study assessed via researcher diary ; ; ; [9 months post randomisation] Resources required by researchers. Financial, capital, and perishable resources required to run the trial via a researcher study diary ; [9 months post randomisation] Side effects associated with the dose of 5‐MTHF or folic acid assessed via research/participant regular update meetings ; [Identified at time points: week 2, 8, 14 and every 6 weeks thereafter until conclusion of study (December 30, 2023) ] Treatment effects/outcome expectations . Time to pregnancy versus expected time to pregnancy in the intervention group (2‐4 reproductive ; cycles post the abstinence period) assessed by audit of study database. ; ; [9 month post randomisation] INCLUSION CRITERIA: 1. Women aged 20‐49 years of age with two or more pregnancy losses before 22 weeks and their reproductive partners 2. Ability to speak and understand English sufficiently to comprehend the purpose and risks of the study and to provide consent 3. Ability to attend a pathology centre for specimen collection 4. Ability to not take concomitant medications, vitamins, food containing folic acid