Introduction

Infertility can be described as the inability to conceive after 12 months of consistent intercourse without contraceptives.^[1] Research indicates that roughly 12% of women between the ages of 15 and 44 years have sought medical intervention for fertility-related concerns.^[2] Examination of couples reporting difficulties in conception reveal that at least 33.33% of cases are attributable to the woman and female fertility rates have been shown to decrease significantly with age.^[3,4] Although couples opt for assisted reproductive technology, such techniques are expensive and inaccessible.^[5] Modifying lifestyle habits, including body weight and diet can affect fertility rates.^[6] Vitamins and supplements also play a role in improving fertility but comprehensive reviews of their effects are limited. Macronutrients can be easily obtained from dietary sources, but it is difficult to obtain suggested levels of micronutrients. The present systematic review aims at providing an improved understanding of the role that micronutrients play in female fertility.

Methodology

This systematic review aimed to examine the impact of dietary components on female infertility using selected keywords. The review was conducted through electronic databases such as PubMed, Cochrane, Medline, POPLINE, Science Direct, and Nature. The search strings included 'female infertility diet', 'dietary factors', 'infertility women diet factors', 'infertility in women diet', and 'female infertility "diet." Corresponding research articles published between 2007 and 2018 were selected for further analysis. The review was based on PRISMA guidelines and narrowed the scope to a discussion on the impact of supplements. The inclusion criteria included published, English-language research studies involving human participants, a minimum number of participants, clearly mentioned dietary factors, and studies that demonstrated an investigation of their impact on fertility. A final screening step included papers discussing the specific impact of supplements.

The exclusion criteria included macronutrients, diet components already known or widely believed to be detrimental to female fertility, systematic reviews and meta-analyses, research studies not explicitly focusing on female fertility or infertility as an outcome, and papers with incomplete or inadequately defined information.

Data extraction was performed from each study, including title, authors, year of publication, participants, investigated factors, outcome, and type of study. Additional notes were recorded to evaluate papers and critically evaluate their inclusion in the systematic review. The extracted information was reviewed and assessed.

Results

A systematic review of 3077 articles was conducted using relevant keywords, and a total of 47 studies were considered for inclusion. The quality assessment of the included papers was carried out using the Newcastle Ottawa Scale (NOS) scale for cohort and case control studies. All the cohort studies and both case control studies were found to be of good quality as per the scale. The pilot study assessing the impact of micronutrients on ovulation infertility was treated as a case control study and was found to be of fair quality.

One paper focused on the potential impact of dietary antioxidants and fertility rates, specifically examining the consumption of these supplements by women. Information collected from a cohort of 437 women participating in the randomized control trial (RCT) was analyzed to ascertain if antioxidants could enhance the rates of successful conception in women. The study concluded that an increase in the consumption of antioxidants appeared to be associated with a decrease in the time required for women to conceive, although the precise effect varied according to the nature of the antioxidant and demographic factors, including age and BMI.

The findings from this study were explained based on previously available information. Vitamin C is known to be responsible for not only decelerating detrimental oxidizing reactions but also is hypothesized to aid in the production of luteal collagen. β-carotene levels were associated with the success of IVF techniques. The antioxidant activity of vitamin E was believed to reduce potential damage to the corpus luteum and the epithelium on the ovarian surface.

Three of the included studies focused on the effect that consumption of folic acid and related supplements had on women’s fertility. The three papers included a total study population of 778 women, all of whom were undergoing treatment for infertility. Two studies explicitly examined the impact of folic acid provided as a supplement, while the third paper examined the indirect effect that dietary folate had on the implantation success.

A longitudinal cohort study was employed to analyze the effect that dietary folate had on Swedish women seeking clinical assistance for fertilization. Findings from the study indicated that infertile women reported higher folate levels than fertile controls and interestingly, reported a relationship between women experiencing miscarriages and higher folate levels. The Swedish cohort investigation, which also included a case control analysis, was unable to detect conclusive evidence of folic acid exhibiting a significant effect on pregnancy and live births.

Two studies examined the impact of vitamin D on female fertility, involving 313 women. Both studies found that insufficient vitamin D led to reduced chances of clinical pregnancy and that respondents with fertility issues reported higher vitamin deficiencies. These findings emphasize the importance of consuming the prescribed dosage of   vitamins   and   relying   on   supplements   to   complement   dietary   intake. A prospective RCT was conducted to compare the efficiency of providing multiple micronutrients (MMN) and solely folic acid to a selected group of subfertile female participants preparing to undergo ovulation induction. Findings indicated that providing multiple micronutrients was more efficient than solely administering folic acid. The pilot study included women exhibiting either ovulatory or unexplained infertility. Subjects were randomly administered either MMN or folic acid supplements. Four weeks after initiation of the supplementation, ovulation induction was carried out and ultrasound studies were used to affirm the success of the procedure.

Individuals who received MMN supplements showed significantly higher rates of conception and less time to become pregnant compared to those who only received folic acid supplements. Nearly 70% of MMN- receiving group successfully conceived after three treatment cycles, a value significantly higher than the approximately 40% success rate recorded among women who only received folic acid. The consumption of MMN also facilitated more rapid conception, with 15 women in the MMN treatment group being able to conceive on their first attempt.

However, a limitation of this pilot study is the reliance on self-recall for dietary habits, which introduced room for error in the comparison of dietary sources of various micronutrients. The comparison of MMNs with folic acid highlights the importance of the combination of micronutrients in improved fertility but prevents the identification of which micronutrient provided the maximal contribution to fertility. A prospective cohort study involved the collection of data from 18555 nurses and the investigation of the impact of multivitamins on ovulatory infertility. Researchers reported that habitual consumption of multivitamins significantly reduced the chances of ovulatory infertility in the study population. However, the failure to confirm self-reports of infertility using medical records or clinical documents reduced the reliability of the collected data.

Discussion

This systematic review of studies on the importance of supplemental micronutrients, particularly vitamins, in the diet of women aiming to conceive has found a significant positive correlation between the studied factor and successful conception despite fertility issues. Fertility issues affect a significant portion of the population, with some studies arguing that reliance on medical assistance has increased in the recent decade. The inability to conceive successfully and carry out a full-term pregnancy is a stressful event for any couple, highlighting the need for identifying methods to successfully address these concerns.

Modifying lifestyle factors, including improved nutritional intake, can enhance fertility rates and outcome. Studies have indicated that modifying lifestyle factors, including weight reduction and obesity reduction, can improve fertility rates and outcomes. However, the exact nature of prescriptions can vary, and a more comprehensive understanding of the role of individual micronutrients in humans can help regularize prescriptions and dosages for women, leading to improved outcomes.

Consumption of vitamins appears to be linked to a reduction in the time needed for conception, successful clinical pregnancy, and live births, in populations with regular and impaired fertility. Adequate consumption of vitamins has the potential to contribute to both preventive and curative aspects in cases of infertility and improve the outcome of clinical methods designed to assist in reproduction. Data collected from the studies emphasizes the necessity of supplemental intake of vitamins prior to and during pregnancy, as evidence collected from the respondents indicates that women relying on solely dietary intake to meet their vitamin requirements were often nutrient deficient.

The findings from the present review match previous studies, which have discussed the concept of providing multivitamins to reduce the time needed to conceive and improve fertility. Folic acid supplements have also been investigated, with a positive association between fertility and the vitamin being observed. However, the prospective case control focusing on folic acid supplementation in women undergoing IVF treatment did not record significant benefits associated with the supplement, which is in contradiction to common medical advice and previous research results.

A key concern from the analysis of these papers is the variation among the studied populations, such as subfertile women, those with no suspected history of infertility, and women undergoing medical assistance for conception.

Conclusion

Infertility is a prevalent issue affecting many couples, and while clinical treatments are available, they are often not cost-effective or easily accessible. Preventive measures, including lifestyle changes, are crucial, particularly focusing on the impact of dietary factors on infertility. A systematic review of eight studies found that regular supplement use significantly improves fertility, reducing conception time, increasing conception chances, and improving live pregnancy chances. However, most respondents did not consume enough micronutrients in their diet, necessitating supplement use. The review suggests the need for standardization of tests and increased focus on both preventive and curative properties of dietary factors.

References

1. Zegers-Hochschild F, Adamson GD, de Mouzon J, Ishihara O, Mansour R, Nygren K, Sullivan E, Van der Poel S. ICfMAR Technology, WH Organization, The international committee for monitoring assisted reproductive technology (ICMART) and the world health organization (WHO) revised glossary on ART terminology, 2009. Fertil. Steril.. 2009;92:1520-4.

2. Kessler LM, Craig BM, Plosker SM, Reed DR, Quinn GP. Infertility evaluation and treatment among women in the United States. Fertil. Steril.. 2013 Oct 1;100(4):1025-32.

3. Datta J, Palmer MJ, Tanton C, Gibson LJ, Jones KG, Macdowall W, Glasier A, Sonnenberg P, Field N, Mercer CH, Johnson AM. Prevalence of infertility and help seeking among 15 000 women and men. Human Reproduction. 2016 Aug 19;31(9):2108-18.

4. van Rooij IA, Broekmans FJ, Scheffer GJ, Looman CW, Habbema JD, de Jong FH, Fauser BJ, Themmen AP, te Velde ER. Serum antimüllerian hormone levels best reflect the reproductive decline with age in normal women with proven fertility: a longitudinal study. Fertil. Steril.. 2005 Apr 1;83(4):979-87.

5. Chambers GM, Sullivan EA, Ishihara O, Chapman MG, Adamson GD. The economic impact of assisted reproductive technology: a review of selected developed countries. Fertil. Steril. 2009 Jun 1;91(6):2281-94.

6. Homan GF, Davies M, Norman R. The impact of lifestyle factors on reproductive performance in the general population and those undergoing infertility treatment: a review. Human Reproduction Update. 2007 Jan 5;13(3):209-23.

7. Ruder EH, Hartman TJ, Reindollar RH, Goldman MB. Female dietary antioxidant intake and time to pregnancy among couples treated for unexplained infertility. Fertil. Steril. 2014 Mar 1;101(3):759-66.

8. Murto T, Svanberg AS, Yngve A, Nilsson TK, Altmäe S, Wånggren K, Salumets A, Stavreus-Evers A. Folic acid supplementation and IVF pregnancy outcome in women with unexplained infertility. Reproductive Biomedicine Online. 2014 Jun 1;28(6):766-72.

9. Gaskins AJ, Afeiche M, Wright DL, Toth TL, Williams PL, Gillman MW, Hauser R, Chavarro JE. Dietary folate and reproductive success among women undergoing assisted reproduction. Obstetrics and Gynecology. 2014 Oct;124(4):801.

10. Mínguez-Alarcón L, Gaskins AJ, Chiu YH, Souter I, Williams PL, Calafat AM, Hauser R, Chavarro JE, EARTH Study team. Dietary folate intake and modification of the association of urinary bisphenol A concentrations with in vitro fertilization outcomes among women from a fertility clinic. Reproductive Toxicology. 2016 Oct 1;65:104-12.

11. Fung JL, Hartman TJ, Schleicher RL, Goldman MB. Association of vitamin D intake and serum levels with fertility: results from the Lifestyle and Fertility Study. Fertil. Steril. 2017 Aug 1;108(2):302-11.

12. Al-Jaroudi D, Al-Banyan N, Aljohani NJ, Kaddour O, Al-Tannir M. Vitamin D deficiency among subfertile women: case-control study. Gynecological Endocrinology. 2016 Apr 2;32(4):272-5.

13. Agrawal R, Burt E, Gallagher AM, Butler L, Venkatakrishnan R, Peitsidis P. Prospective randomized trial of multiple micronutrients in subfertile women undergoing ovulation induction: a pilot study. Reproductive Biomedicine Online. 2012 Jan 1;24(1):54-60.

14. Chavarro JE, Rich-Edwards JW, Rosner BA, Willett WC. Use of multivitamins, intake of B vitamins, and risk of ovulatory infertility. Fertil. Steril. 2008 Mar 1;89(3):668-76.

15. Klonoff-Cohen HS. Prevailing knowledge about Male and Female lifestyle habits and In Vitro Fertilization in the 21st century. Medical Research Archives. 2017 Nov 15;5(11).

16. Scholl TO, Johnson WG. Folic acid: influence on the outcome of pregnancy–. The American Journal of Clinical Nutrition. 2000 May 1;71(5):1295S-303S.

17. Sharma R, Biedenharn KR, Fedor JM, Agarwal A. Lifestyle factors and reproductive health: taking control of your fertility. Reproductive Biology and Endocrinology. 2013 Dec;11(1):66.

18. Steures P, Eijkemans MJ, Habbema JD, Hompes PG, Burggraaff JM, Oosterhuis GJ, Bossuyt PM, Mol BW. Obesity affects spontaneous pregnancy chances in subfertile, ovulatory women. Human Reproduction (Oxford, England). 2008 Feb;23(2):324-8.

19. Bellver J, Ayllón Y, Ferrando M, Melo M, Goyri E, Pellicer A, Remohí J, Meseguer M. Female obesity impairs in vitro fertilization outcome without affecting embryo quality. Fertil. Steril. 2010 Jan 15;93(2):447- 54.

20. Wilson RD, Audibert F, Brock JA, Carroll J, Cartier L, Gagnon A, Johnson JA, Langlois S, Murphy- Kaulbeck L, Okun N, Pastuck M. Pre-conception folic acid and multivitamin supplementation for the primary and secondary prevention of neural tube defects and other folic acid-sensitive congenital anomalies. Journal of Obstetrics and Gynaecology Canada. 2015 Jun 1;37(6):534-49.

21. Czeizel AE. Nutritional supplementation and prevention of congenital abnormalities. Current Opinion in Obstetrics & Gynecology. 1995 Apr;7(2):88-94.

22. Agarwal A, Allamaneni SS. Oxidants and antioxidants in human fertility. Middle East Fertility Society Journal. 2004;9(3).

23. Ebisch IM, Thomas CM, Peters WH, Braat DD, Steegers-Theunissen RP. The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility. Human Reproduction Update. 2006 Nov 11;13(2):163-74.

24. Ruder EH, Hartman TJ, Goldman MB. Impact of oxidative stress on female fertility. Current Opinion in Obstetrics & Gynecology. 2009 Jun;21(3):219.

25. Viteri FE, Berger J. Importance of pre-pregnancy and pregnancy iron status: can long-term weekly preventive iron and folic acid supplementation achieve desirable and safe status?. Nutrition Reviews. 2005 Dec 1;63(suppl_2):S65-76.

26. Nilsen RM, Vollset SE, Gjessing HK, Magnus P, Meltzer HM, Haugen M, Ueland PM. Patterns and predictors of folic acid supplement use among pregnant women: the Norwegian Mother and Child Cohort Study. American Journal of Clinical Nutrition. 2006 Nov 1;84(5):1134-41.

27. Lerchbaum E, Obermayer-Pietsch B. Mechanisms in endocrinology: Vitamin D and fertility: a systematic review. European Journal of Endocrinology. 2012 May 1;166(5):765-78.

28. Altmäe S, Stavreus-Evers A, Ruiz JR, Laanpere M, Syvänen T, Yngve A, Salumets A, Nilsson TK. Variations in folate pathway genes are associated with unexplained female infertility. Fertil. Steril. 2010 Jun 1;94(1):130-7.