Association of the Serum Folate and Total Calcium and Magnesium Levels Before Ovarian Stimulation With Outcomes of Fresh In Vitro Fertilization Cycles in Normogonadotropic Women

Abstract

BackgroundWomen of reproductive age are recommended to consume folic acid and other supplements before conception and during pregnancy. We aimed to investigate the association of the serum folate and total magnesium (Mg) and calcium (Ca) levels before ovarian stimulation with the outcomes of assisted reproductive technology (ART) in normogonadotropic women.MethodsWe used a subanalysis of data obtained from a multicentre, randomized prospective study (NCT03088137). A total of 110 normogonadotropic, non-advanced aged, non-obese women with tubal and/or male infertility factors were enrolled for the single fresh ovarian stimulation GnRH antagonist cycle. The main outcome measures were the total oocyte yield, mature oocytes, fertilization rate, biochemical, clinical pregnancy, and live birth. Multivariable generalized linear models adjusted for covariates were used with a Poisson distribution and the log link function for adjusted oocyte counts, and a binomial distribution and the log link function were used for adjusted clinical ART outcomes.ResultsThe medians (interquartile range (IQR)) were as follows: baseline serum folate, 20.55 ng/ml (10.8, 32.9); Mg, 19.4 mg/L (18.7, 20.7); Ca, 94 mg/L (91.2, 96.4); and Ca/Mg ratio, 4.78 (4.55, 5.02). Women with higher serum folate concentrations (Q4≥33.0 ng/ml) had significantly lower total numbers of oocytes retrieved (adjusted mean (95% CI) 9.2 (7.6-11.3) vs 12.9 (10.9-15.4, p-trend=0.006)) and lower odds ratios (ORs) (95% CI) of 0.12 (0.02, 0.79) for clinical pregnancy and 0.10 (0.01, 0.70) for live birth compared with women in the lowest quartile (<10.8 ng/ml), all p-trend<0.001. Women in the highest Ca/Mg ratio quartile (≥5.02) had ORs (95% CI) of 6.58 (1.31, 33.04) for biochemical pregnancy, 4.85 (1.02, 23.08) for clinical pregnancy and 4.07 (0.83, 19.9) for the live birth rate compared with women in the lowest quartile (<4.55), all p-trend<0.001.ConclusionsUsing multivariable models, we suggested that a baseline elevated serum folate level (≥33.0 ng/ml) and a lower Ca/Mg ratio were associated with worse ART outcomes in normogonadotropic women. Our findings might be useful for choosing safe dosages of folate, calcium, magnesium and complex supplementation for both fertile women and women undergoing infertility treatment. Further preconception large-scale studies with known micro- and macronutrient statuses of both parents and serum folate, Ca, Mg, and hormone levels, are needed.

Magnesium Status and Calcium/Magnesium Ratios in a Series of Cystic Fibrosis Patients

“…In T2D patients, some studies suggested that a Mg deficiency and iron metabolism are involved in the induction of hemolysis, which contributes to iron release [113]. Folic acid is an essential micronutrient for many physiological processes [115]. In an in vitro study in rats, added extracellular Mg and folic acid decreased the homocysteine-induced matrix metalloproteinase-2 (MMP-2), which plays an essential role in the formation and progression of atherosclerotic lesions secretion [116].…”

Magnesium Status and Ca/Mg Ratios in a Series of Children and Adolescents with Chronic Diseases

“…Serum folate level (≥33.0 ng/mL) and a lower Ca/Mg ratio were associated with worse assisted reproductive technology (ART) outcomes in normogonadotropic women. A baseline lower Ca/Mg ratio (<4.55) was associated with worse clinical ART outcomes in a dose-dependent manner [ 143 ].…”

Status of maternal serum B vitamins and pregnancy outcomes: New insights from in vitro fertilization and embryo transfer (IVF-ET) treatment

“…This putative feature has been supported by a recent animal study, which demonstrates that while 200 pM of cyanocobalamin supplement during in vitro oocyte maturation results in a higher likelihood of blastulation, and lower preimplantation development arrest and degeneration, doses as high as 300 or 500 pM undermine embryo developmental potential and increase the probability of degeneration (11). For folate, although most researchers demonstrated a positive correlation of the serum folate level with reproductive outcomes (17, 18, 43), some showed an impaired outcome if the serum folate level is higher than 33.0 ng/mL (21). These biphasic patterns for vitamin B12 and folate may also exist in other conditions, such as coronary artery disease and fracture risk (22,23).…”

“…Previous studies have attempted to validate the biological relevance of pre-conception B vitamins for female reproduction in couples under infertility treatments, but they have contradictory conclusions. While some show that supplementation with folate and vitamin B12 before oocyte retrieval may improve embryo quality, implantation potential, and live birth during IVF-ET treatment (16)(17)(18), others found no beneficial effects on pregnancy outcomes (19,20), or even reached an opposite association (21). Moreover, all published clinical studies exclusively focus on folate and vitamin B12, the two major vitamins related to the one-carbon metabolism pathway, with no examination of the clinical effects of other B vitamins during infertility treatment, despite their recommendation for general health.…”