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).
Additionally, 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.
6.Zegers-Hochschild F, Adamson GD, Dyer S, Racowsky C, de Mouzon J, Sokol R, Rienzi L, Sunde A, Schmidt L, Cooke IDet al. The international glossary on infertility and fertility care, 2017. Fertil Steril. 2017;108(3):393–406. [DOI] [PubMed] [Google Scholar]
17.Gaskins AJ, Nassan FL, Chiu Y-H, Arvizu M, Williams PL, Keller MG, Souter I, Hauser R, Chavarro JE; EARTH Study Team . Dietary patterns and outcomes of assisted reproduction. Am J Obstet Gynecol. 2019;220(6):567.e1–e18. [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Kermack AJ, Lowen P, Wellstead SJ, Fisk HL, Montag M, Cheong Y, Osmond C, Houghton FD, Calder PC, Macklon NS. Effect of a 6-week “Mediterranean” dietary intervention on in vitro human embryo development: the Preconception Dietary Supplements in Assisted Reproduction double-blinded randomized controlled trial. Fertil Steril. 2020;113(2):260–9. [DOI] [PubMed] [Google Scholar]
21.Vujkovic M, de Vries JH, Lindemans J, Macklon NS, van der Spek PJ, Steegers EAP, Steegers-Theunissen RPM. The preconception Mediterranean dietary pattern in couples undergoing in vitro fertilization/intracytoplasmic sperm injection treatment increases the chance of pregnancy. Fertil Steril. 2010;94(6):2096–101. [DOI] [PubMed] [Google Scholar]
25.Ravisankar S, Ting AY, Murphy MJ, Redmayne N, Wang D, McArthur CA, Takahashi DL, Kievit P, Chavez SL, Hennebold JD. Short-term Western-style diet negatively impacts reproductive outcomes in primates. JCI Insight. [Internet] 2021; [cited 2021 Apr 7];6(4). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934943/. [DOI] [PMC free article] [PubMed] [Google Scholar]
Eliran Mor26.Grieger JA, Grzeskowiak LE, Bianco-Miotto T, Jankovic-Karasoulos T, Moran LJ, Wilson RL, Leemaqz SY, Poston L, McCowan L, Kenny LCet al. Pre-pregnancy fast food and fruit intake is associated with time to pregnancy. Hum Reprod. 2018;33(6):1063–70. [DOI] [PubMed] [Google Scholar]
27.Bishop CV, Takahashi D, Mishler E, Slayden OD, Roberts CT, Hennebold J, True C. Individual and combined effects of 5-year exposure to hyperandrogenemia and Western-style diet on metabolism and reproduction in female rhesus macaques. Hum Reprod. 2021;36(2):444–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
30.Guasch-Ferré M, Salas-Salvadó J, Ros E, Estruch R, Corella D, Fitó M, Martínez-González MA; PREDIMED Investigators . The PREDIMED trial, Mediterranean diet and health outcomes: how strong is the evidence?. Nutr Metab Cardiovasc Dis. 2017;27(7):624–32. [DOI] [PubMed] [Google Scholar]
33.Willis SK, Wise LA, Wesselink AK, Rothman KJ, Mikkelsen EM, Tucker KL, Trolle E, Hatch EE. Glycemic load, dietary fiber, and added sugar and fecundability in 2 preconception cohorts. Am J Clin Nutr. 2020;112(1):27–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
35.Hatch EE, Wesselink AK, Hahn KA, Michiel JJ, Mikkelsen EM, Sorensen HT, Rothman KJ, Wise LA. Intake of sugar-sweetened beverages and fecundability in a North American preconception cohort. Epidemiology. 2018;29(3):369–78. [DOI] [PMC free article] [PubMed] [Google Scholar]
36.Machtinger R, Gaskins AJ, Mansur A, Adir M, Racowsky C, Baccarelli AA, Hauser R, Chavarro JE. Association between preconception maternal beverage intake and in vitro fertilization outcomes. Fertil Steril. 2017;108(6):1026–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
37.Schliep KC, Schisterman EF, Mumford SL, Pollack AZ, Perkins NJ, Ye A, Zhang CJ, Stanford JB, Porucznik CA, Hammoud AOet al. Energy-containing beverages: reproductive hormones and ovarian function in the BioCycle Study. Am J Clin Nutr. 2013;97(3):621–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
40.Mumford SL, Chavarro JE, Zhang C, Perkins NJ, Sjaarda LA, Pollack AZ, Schliep KC, Michels KA, Zarek SM, Plowden TCet al. Dietary fat intake and reproductive hormone concentrations and ovulation in regularly menstruating women. Am J Clin Nutr. 2016;103(3):868–77. [DOI] [PMC free article] [PubMed] [Google Scholar]
43.Wise LA, Wesselink AK, Tucker KL, Saklani S, Mikkelsen EM, Cueto H, Riis AH, Trolle E, McKinnon CJ, Hahn KAet al. Dietary fat intake and fecundability in 2 preconception cohort studies. Am J Epidemiol. 2018;187(1):60–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
44.Lefevre M, Lovejoy JC, Smith SR, Delany JP, Champagne C, Most MM, Denkins Y, de Jonge L, Rood J, Bray GA. Comparison of the acute response to meals enriched with cis- or trans-fatty acids on glucose and lipids in overweight individuals with differing FABP2 genotypes. Metabolism. 2005;54(12):1652–8. [DOI] [PubMed] [Google Scholar]
46.Mozaffarian D, Pischon T, Hankinson SE, Rifai N, Joshipura K, Willett WC, Rimm EB. Dietary intake of trans fatty acids and systemic inflammation in women. Am J Clin Nutr. 2004;79(4):606–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
48.Missmer SA, Chavarro JE, Malspeis S, Bertone-Johnson ER, Hornstein MD, Spiegelman D, Barbieri RL, Willett WC, Hankinson SE. A prospective study of dietary fat consumption and endometriosis risk. Hum Reprod. 2010;25(6):1528–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
49.Downs SM, Bloem MZ, Zheng M, Catterall E, Thomas B, Veerman L, Wu JH. The impact of policies to reduce trans fat consumption: a systematic review of the evidence. Curr Dev Nutr. 2017;1:(12):cdn.117.000778. [DOI] [PMC free article] [PubMed] [Google Scholar]
50.Li K, Huang T, Zheng J, Wu K, Li D. Effect of marine-derived n-3 polyunsaturated fatty acids on C-reactive protein, interleukin 6 and tumor necrosis factor α: a meta-analysis. PLoS One. 2014;9(2):e88103. [DOI] [PMC free article] [PubMed] [Google Scholar]
53.Mumford SL, Browne RW, Kim K, Nichols C, Wilcox B, Silver RM, Connell MT, Holland TL, Kuhr DL, Omosigho URet al. Preconception plasma phospholipid fatty acids and fecundability. J Clin Endocrinol Metab. 2018;103:4501–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
55.Chiu Y-H, Karmon AE, Gaskins AJ, Arvizu M, Williams PL, Souter I, Rueda BR, Hauser R, Chavarro JE; EARTH Study Team . Serum omega-3 fatty acids and treatment outcomes among women undergoing assisted reproduction. Hum Reprod. 2018;33(1):156–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
