The proper concentration of minerals is essential for many physiological processes, including maintaining the normal quality of oocytes and embryo fertilization, maturation, and implantation (115). A deficiency of minerals may disturb fertility; therefore, women should pay attention to the proper intake of minerals and supplement the elements that could be deficient. One study showed that many women fail to meet nutrient needs—particularly in terms of folic acid, calcium, iodine, iron, selenium, vitamin D, and vitamin B-12—and thus have lower blood concentrations (116). Calcium, iron, zinc, magnesium, iodine, and selenium are especially essential with regard to fertility.
Calcium affects blood vessels, muscle contractions, nerve conduction, and hormone secretion. Additionally, the fetus uses the mother's skeletal calcium for bone growth. Therefore, the recommended dose of calcium constitutes a crucial element in the diet of women of childbearing age (117). Additionally, calcium deficiency may decrease vitamin D concentrations and increase the risk of hypertension, and pre-eclampsia. However, no studies refer to the validity of the supplementation of or fortification with calcium in the period before pregnancy to prevent pregnancy complications (118, 119).
Few studies have reported on the association between serum iron concentration and fertility. However, both excess and deficiency of iron may negatively affect fertility (120). According to Hahn et al. (121), total or heme iron intake was poorly associated with fecundity, particularly among women with a potential risk of iron deficiency, e.g., women with frequent and heavy periods. On the other hand, a prospective study showed that the supplementation of total and nonheme iron may decrease the risk of infertility due to disorders of ovulation (122).
Another key element is iodine, affecting thyroid gland function, which is essential for proper fertility. In a study conducted in 501 women experiencing moderate or severe iodine deficiency, pregnancy was delayed, and the chances of becoming pregnant in each cycle decreased by 46% when compared with women who were not iodine deficient. Among women with mild iodine deficiency, this association was minimal (123, 124). It is vital to note that mild and moderate iodine deficiency is common among women of reproductive age around the world (125–127).
Grieger et al. (128) reported that low serum concentrations of zinc and selenium were associated with a 1-mo longer period before achieving pregnancy. Additionally, a deficiency of selenium and copper, but not zinc, was linked to a higher risk of infertility. On the basis of limited studies, the impact of zinc and copper concentration on women's fertility remains unclear, and future research is required (128).
Selenium also affects thyroid gland function. Additionally, it is an antioxidant participating in the reduction of oxidative stress. In fact, selenium possibly influences the growth and maturation of oocytes. Therefore, an adequate supply of selenium is necessary (129).
The impact of phytoestrogens on fertility has been a highly controversial topic for years. Phytoestrogens are compounds of plant origin, including isoflavones found in soy products; lignans found in nuts, seeds, and cruciferous vegetables; as well as coumestans found in sprouts, peas, and beans (104).
On one hand, numerous scientific studies indicate the preventive effect of phytoestrogen consumption on the development of breast and endometrial cancer, fibroids, osteoporosis, cardiovascular diseases, inflammation, metabolic syndrome, and obesity (104–109). In fact, soy isoflavone supplementation was associated with an increase in the number of live births following clomiphene therapy, increased endometrial thickness, pregnancy rates following insemination, and in vitro fertilization. Furthermore, soy consumption was associated with an increased chance of live birth using ART (134–137).
On the other hand, certain studies point to endocrine system disorders as negative effects of phytoestrogen consumption. In the Adventist Health Study, women who consumed a greater amount of isoflavones were at an increased risk of never becoming pregnant and being childless (138). In contrast, a cohort study by Mumford et al. (139) found no association between soy intake and fertility.
In an analysis of 2 cohorts comprising women planning a pregnancy in North America and Denmark, which included 4880 and 2898 women, respectively, no strong association was observed between dietary phytoestrogen intake and the chances of becoming pregnant (140). At the same time, it is worth considering that, in Western countries, the average intake of phytoestrogen is <2 mg, and in European countries, the intake is even lower than 1 mg compared with the ∼50 mg consumed in Asian countries (141).
Among women struggling with infertility, a discussion of the negative influence of gluten on fertility is relatively common—for instance, the study by Harper and Bold (143) asked subjects about their motivations for eliminating gluten from their diet. However, according to the recommendations, the exclusion of gluten from the diet is not recommended for the general population, and there is no evidence that it is beneficial in non-celiac individuals (144).
Castaño et al. (145) conducted a meta-analysis that included a total of 23 research studies, and aimed to assess the prevalence of celiac disease seroprevalence in women with fertility disorders. The study group consisted of women with overall infertility, women with idiopathic infertility, and women with recurrent spontaneous abortions. The studies included in the meta-analysis did not comprise women with a diagnosed celiac disease or allergy to wheat proteins. The meta-analysis demonstrated that celiac disease seroprevalence among women with infertility amounted to ∼1.3–1.6%, which allows estimating that women experiencing such disorders are 3 times more likely to develop celiac disease. However, due to the small number of respondents, it is impossible to precisely calculate the total incidence of the association between celiac disease and fertility disorders.
There are no recommendations indicating the benefits of eliminating gluten from the diet of all women experiencing infertility. It should be noted that many research studies indicate a much lower nutritional value of gluten-free diets compared with traditional diets (146). Nevertheless, such frequent diagnoses of previously undiagnosed celiac disease among women experiencing infertility raises the question of whether it is not reasonable to conduct celiac disease screening tests in women with infertility (147). However, there can be no doubt that women diagnosed with celiac disease attempting pregnancy should follow a gluten-free diet (148).
It is assumed that cytochrome P450 is involved in the production of ROS, and oxidative stress subsequently promotes the development of endometriosis, hydrosalpinx, and PCOS. Importantly, oxidative stress has also been shown to be associated with idiopathic infertility, recurrent miscarriage, and pre-eclampsia (152–155).
It has been proven that ROS entering the ovum causes damage, which has an important impact on the fertilization process and its further success, as well as the entire process of embryogenesis, which constitutes the reason for a wider use of antioxidants in the treatment of infertility (152, 155). The possible mechanisms of their action include improving blood circulation in the endometrium, lowering sex hormone concentrations, increasing tissue insulin sensitivity, and affecting ovulation, prostaglandin synthesis, and steroidogenesis (155, 156).
A Cochrane review (157) indicates that there is evidence based on very-low-quality research suggesting that women experiencing infertility may benefit from antioxidant supplementation. The researchers emphasize that the quality of the available studies is not good enough to establish the possible side effects of the antioxidant supplementation. However, it is worth briefly discussing the individual antioxidants and their potential impact on fertility.
It is worth noting that women with endometriosis have been shown to have a lower supply of vitamins A, C, and E, as well as copper and zinc, than healthy women without fertility disorders (158–160). In fact, a 4-mo-long supplementation of vitamins C and E resulted in a reduction in oxidative stress (158). Additionally, higher levels of oxidative stress markers and lower serum concentrations of vitamins C and E have been observed in women suffering from PCOS (161, 162).
Vitamin C, vitamin E, and vitamin A are among some of the most potent antioxidants. Vitamin C, which is present in high concentrations in the cytosol of the oocyte, is essential, as it participates in collagen synthesis, which is significant for the growth of the Graaf follicle, ovulation, and the luteal phase. Moreover, vitamin C also helps restore oxidized vitamin E and glutathione (155). The benefits of vitamin E supplementation include improved epithelial growth in the blood vessels and the endometrium.
Moreover, inositol supplementation may be essential, particularly in PCOS, due to its insulin sensitivity–enhancing and insulin response–modulating effects (163, 164). Furthermore, inositol derivatives are important secondary messengers of the gonadotropins LH and FSH. Inositol has been shown to regulate the menstrual cycle, improve ovulation, and favorably influence metabolic parameters in women with PCOS, although there is a lack of research evaluating its association with the chances of pregnancy, miscarriage, or the number of deliveries (165).
Dr Eliran MorAdditionally, l-carnitine appears to be an important antioxidant. Research studies indicate that its supplementation relieves disorders of the reproductive system, such as PCOS, endometriosis, or amenorrhea (166–168). The alleviating effect of l-carnitine on endometriosis may be due to its impact on the hormonal balance, decreased cytokine release, and apoptosis. By means of its effect on the hypothalamic-pituitary-gonadal axis, l-carnitine regulates the concentrations of gonadotropins and sex hormones and thus may be beneficial for the course of PCOS and the menstrual cycle (166). l-Carnitine also increases energy production by oocytes through B-oxidation, and is involved in combating oxidative stress (166, 169). Interestingly, the bioavailability of carnitine from food is much higher than from supplements (170). Sharkwy et al. (171) conducted research to compare the clinical and metabolic profiles between N-acetylcysteine (NAC) and l-carnitine among women with clomiphene citrate–resistant PCOS. The study demonstrated that both NAC and l-carnitine were effective in improving pregnancy and ovulation rates among women with clomiphene citrate–resistant PCOS. However, although NAC was superior in increasing insulin sensitivity, only l-carnitine improved the lipid profile. In contrast, a study by Behrouzi Lak et al. (172) indicates that, in patients with PCOS without clomiphene citrate resistance, NAC is ineffective in inducing or augmenting ovulation in the PCOS patients who are able to undergo intrauterine insemination and, according to the authors, it cannot be recommended as an adjuvant to clomiphene citrate in such patients.
The composition of the diet also plays an essential role in shaping the intestinal microbiota. Dietary components can either directly impact the gut microbiota by promoting or inhibiting its growth, or indirectly by means of influencing metabolism and the immune system, which can also lead to changes in the gut microbiota composition (173).
Studies indicate that the consumption of a Western diet has been associated with an increase in Bacteroides phyla and Ruminococcus. On the other hand, a high-fat diet has been positively correlated with the amount of Bacteroides and Actinobacteria simultaneously decreasing Firmicutes and Proteobacteria, which are positively correlated with the consumption of a high-fiber diet. Moreover, diets that are based on animal products have been associated with higher levels of Alistipes, Bilophila, and Bacteroides and with reduced levels of Firmicutes. In contrast, diets high in complex carbohydrates contribute to a beneficial increase in Bifidobacteria, with Prevotella being the most dominant bacterial type among vegetarians. The composition of the intestinal microbiota, largely dependent on diet, plays a vital role in the proper functioning of the immune system. Additionally, intestinal dysbiosis induces local inflammation and an increase in intestinal permeability, which is associated with a decrease in Bifidobacteria. These bacteria, in turn, can reduce LPS and improve the state of the intestinal barrier. All of the above-mentioned facts mean that the Western diet may, in fact, increase the risk of systemic inflammation (174, 175).
A significant majority of research studies indicate that high caffeine consumption may constitute a potential factor associated with an increased time to achieving pregnancy and an increased risk of pregnancy loss (5, 7, 11, 176). In addition, a dose-dependent association has been observed between caffeine consumption during pregnancy and stillbirth, childhood acute leukemia, delayed fetal growth, and the negative effects on a child's birth weight, as well as on overweight and obesity in children (177, 178). According to the European Food Safety Authority, for pregnant women and for women attempting pregnancy, up to 200 mg of caffeine/d is recommended. Similarly, the American College of Obstetricians and Gynecologists indicates that the intake of up to 200 mg of caffeine does not appear to be a main factor leading to miscarriage or preterm delivery (179, 180). Nevertheless, in the latest review paper including 48 original observational studies and meta-analyses, James (178) emphasized that the assumptions about safe maternal caffeine consumption levels are not supported by the current evidence, and indicated a necessity for a radical revision of the current recommendations. Simultaneously, it is worth noting that the source of caffeine is not only coffee, but also tea, soft drinks, cocoa, or certain drugs (176).
On the other hand, there is evidence suggesting that alcohol consumption, especially heavy drinking and chronic alcohol consumption, has been connected to reduced fertility and a higher risk of developing menstrual disorders (22, 181). However, the mechanism in which excessive alcohol consumption negatively affects fertility has not been determined (5). A suggested hypothesis for the negative influence of alcohol intake on female fertility includes altering endogenous hormone concentrations, a direct impact on the maturation of the ovum, ovulation, early blastocyst development, and implantation (181). It is also crucial to stress that alcohol consumption during pregnancy can result in adverse effects in offspring development, such as fetal alcohol spectrum disorders (182).
Diet and nutritional patterns are undoubtedly significant for both male and female fertility; thus, it is worth investigating the components of the diet and their influence on fertility. Further research is needed to develop standardized dietary recommendations for women planning a pregnancy. The current knowledge on the effects of individual nutrients and their sources is summarized in Table 3. Further research is necessary to develop standardized dietary recommendations, which should be given to women planning a pregnancy, and individualized in case of problems with achieving pregnancy. It is important to emphasize the valid role of a clinical dietitian, who should actively participate in the care of women planning a pregnancy and, above all, be a member of a multidisciplinary team in infertility treatment centers.
Numerous questions remain unanswered, although there is no doubt that diet has an impact on female fertility. On the basis of the current knowledge, it can be confirmed that the consumption of TFAs, refined carbohydrates, and added sugars negatively affects female fertility. In contrast, a diet based on the recommendations of the MeD—rich in dietary fiber, ɷ-3 FAs, vegetable protein, vitamins, and minerals—has a positive effect on female fertility.
There are no clear guidelines on supplementation to enhance fertility in women. A properly balanced diet should provide all minerals and vitamins, except for vitamin D and folic acid, which should be supplemented. It may also be challenging to provide adequate amounts of iodine with the diet, especially in low-sodium diets and in elimination diets. Additionally, women in the period prior to pregnancy are also recommended to consume folic acid. Particularly in women considered as a risk group, serum concentrations of micronutrients and vitamins should be monitored, and in the case of deficiencies, supplementation should be introduced.
We thank TranslationLab, a biomedical translation company, for language proofreading. The authors’ responsibilities were as follows—KS and IK-K: conceptualization; KS, AER, and AMR: wrote and prepared the original draft; IK-K: reviewed and edited the manuscript, supervised the study, and had primary responsibility for the final content; AD: acquired funding; and all authors: read and approved the final manuscript.
Abbreviations used: ART, assisted reproductive technology; FA, fatty acid; FSH, follicle-stimulating hormone; IGF-I, insulin-like growth factor I; LH, luteinizing hormone; MeD, Mediterranean diet; NAC, N-acetylcysteine; PCOS, polycystic ovary syndrome; PPAR-γ, peroxisome proliferator–activated receptor γ; ROS, reactive oxygen species; SHGB, sex hormone–binding globulin; TFA, trans-fatty acid; WsD, Western-style diet.
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