Background: In preconception and pregnancy, women are encouraged to take folic acid-based supplements over and above food intake. The upper tolerable limit of folic acid is 1000 mcg per day; however, this level was determined to avoid masking a vitamin B12 deficiency and not based on folic acid bioavailability and metabolism. This review’s aim is to assess the total all-source intake of folate in women of childbearing age and in pregnancy in high-income countries with folate food fortification programs. Methods: A systematic search was conducted in five databases to find studies published since 1998 that reported folate and folic acid intake in countries with a mandatory fortification policy. Results: Women of childbearing age do not receive sufficient folate intake from food sources alone even when consuming fortified food products; however, almost all women taking a folic acid-based supplement exceed the upper tolerable limit of folic acid intake. Conclusions: Folic acid supplement recommendations and the upper tolerable limit of 1000 mcg set by policy makers warrant careful review in light of potential adverse effects of exceeding the upper tolerable limit on folic acid absorption and metabolism, and subsequent impacts on women’s health during their childbearing years.

Over 48.5 million couples are reported with infertility worldwide. Health policy recommends folic acid in women of childbearing age, particularly in preconception and pregnancy which results in women purchasing over-the-counter prenatal multivitamins containing folic acid through pharmacies and other retail outlets. Emerging studies are investigating whether other forms of supplemental folate are more suitable, particularly for those with methylenetetrahydrofolate reductase (MTHFR) polymorphisms. This case series aimed to document variations in forms and dosage of folate prescribed by Australian practitioners to patients with diagnosed infertility and MTHFR polymorphisms. Australian practitioners were invited to complete a retrospective case report form for patients that presented with unexplained infertility. This case report form documented the form and dose of folate that practitioners were prescribing to their infertility patient with MTHFR polymorphisms, together with their fertility history. Six practitioners submitted case information for 12 patients with diagnosed infertility and MTHFR polymorphisms. All patients had been advised by their practitioner to remove folic acid in supplemental form and were prescribed 5-methyltetrahydrofolate (5-MTHF) or a combination of 5-MTHF and folinic acid, at higher doses than the Australian recommended dose (mean daily maximum prescribed dose: 2325μg). Eleven patients conceived within the treatment period (average treatment of one year) and ten were reported as having a live birth. This case series has highlighted clinical practices that vary from the recommendations by Australian policy. Further research is required to verify the clinical importance of variations in folate prescriptions for women with MTHFR polymorphisms and how folate recommendations may need to change depending on these polymorphisms. This has direct relevance to those prescribing at the pharmacy and retail level, specifically pharmacists and pharmacy assistants.

Adequate folate is essential to prevent neural tube defects; therefore, supplementation with folic acid is widely recommended for women during preconception and early pregnancy. However, the potential risks associated with excessive intake of folic acid and/or an elevated blood folate concentration are not well recognized. The aim of this review was to evaluate the potential adverse health outcomes associated with excessive intake of folic acid and/or an elevated blood folate concentration during preconception and pregnancy. The review included studies that measured intake of folic acid via dietary sources and supplements, and/or quantified serum/plasma and red blood cell folate concentrations. Excessive intake of folic acid and an elevated blood folate concentration were associated with several adverse outcomes. The most notable association was with gestational diabetes mellitus, where elevated intake of folic acid and a high blood folate concentration were found to increase the risk. Excessive intake of folic acid supplements and a high blood folate concentration were associated with gestational diabetes mellitus, and adverse neurodevelopmental issues in offspring, as well as large-for-gestational-age infants and higher birth weight. Clear definitions of safe upper limits for intake of folic acid and blood folate concentration are needed urgently to prevent potential adverse outcomes.

To assess the feasibility of a randomized controlled trial (RCT) comparing 5-methyltetrahydrofolate (5-MTHF) and folic acid (FA) in couples with recurrent pregnancy loss. Pregnancy loss affects up to 15% of pregnancies, with over half of cases remaining unexplained. Emerging evidence suggests that folate metabolism, particularly in individuals carrying methylenetetrahydrofolate reductase polymorphisms such as C677T and A1298C variants, may influence reproductive outcomes. A double-blind, RCT feasibility trial was conducted in Australia with 22 reproductive dyads randomized to receive either 5-MTHF or FA prenatal multivitamins. Participants adhered to dietary restrictions, abstained from conception for two cycles, and completed regular assessments. Primary outcomes included feasibility, adherence, acceptability, and preliminary efficacy based on biochemical markers and pregnancy outcomes. The trial demonstrated high acceptability (86% in arm A [MTHF-A] and 94% in arm B [FA-B]) and adherence rates for supplement use over 78% in each arm. Unmetabolized FA concentration decreased in the 5-MTHF group but rose significantly in the FA group. A critical finding was the degradation of 5-MTHF in retained samples, highlighting formulation instability as a confounder. A fully online RCT comparing 5-MTHF and FA is feasible. Future trials should address formulation stability and expand sample size to evaluate clinical efficacy and personalized folate strategies.

The risk of pregnancy loss prior to 24 weeks gestation has been found to be 15.3% of all pregnancies, around 23 million losses each year. Recurrent pregnancy loss (RPL) - two or more pregnancy losses - are now presumed to affect 5% of couples. Clinical guidelines for health professionals for RPL are conflicting, lacking in good quality evidence and fail to involve those who experience RPL, especially the male partner. Despite folate being recommended for preconception support, no mention of folate exists in RPL guidelines. A national cross-sectional survey which assessed health professionals’ recommendations, testing, prescribing and referral practices when providing care for couples in preconception and RPL was conducted. Clinical guidelines for RPL were found to be critically important for health professionals to provide care to couples experiencing RPL, however health professionals (n = 175) require stronger clinical guidance and more specialised training (47.3%), education (62.8%) and funding to better assist couples with RPL. Only 34% of health professionals reported having the necessary resources to support couples with RPL. Health professionals are aware of how important folate is to support preconception in females but are unaware of the critical role it plays in male fertility and as a result males are largely ignored in preconception care. Given the importance of folate supplementation in preconception and pregnancy, the guidelines for RPL fail to include dosing recommendations or variations in the type of folate that should be prescribed. Improved clinical guidelines, better resourcing and funding are required for health professionals to better support couples with RPL. Male partners need to be included in the preconception care and folate form and dosing must be considered.