Emerging Trends in Research on Food Compounds and Women’s Fertility: A Systematic Review

Featured Application: The application of this systematic review is a comprehensive study of food compounds, nutrition, food production, health and environmental sciences in improving female fertility. Abstract: Pro ‐ healthy behaviours, including the diet, are significant factors in maintaining women’s fertility health. However, to improve the patient’s nutrition management, it is important to seek food ‐ derived bioactive compounds to support fertility treatment. This review analysed recent studies of food compounds related to fertility, using databases including PubMed, Web of Science and Science Direct as well as PRISMA (preferred reporting items for systematic reviews) to ensure complete and transparent reporting of systematic reviews. This review lists foods associated with a higher birth rate, using original papers from the last five years (2015). The analysis included the impact of food compounds such as caffeine, fatty acids, folates and vitamin D, as well as the intake of fish, whole grains, dairy and soya. In addition, dietary patterns and total diet composition supporting women’s fertility were also analysed. The results will encourage further research on the relationship between food components and fertility.


Introduction
Fertility, known as the ability to establish a clinical pregnancy, is dependent on multiple factors, including female age, environmental pollution, diet, tobacco use, alcohol intake, as well as diseases affecting endocrine function and the anatomy of the reproduction system [1,2]. In turn, infertility is medically defined as a failure to establish a clinical pregnancy after 12 months of regular and unprotected sexual intercourse. It is estimated that infertility in women of child-bearing age is 1 in 7 couples in developed countries and 1 in 4 couples in developing countries, which is increasing significantly [1]. The demand for infertility services is still growing and can be improved thanks to technological advances and the development of medicine.
Factors influencing fertility may be unmodifiable, such as age and environment, or could be medically treated, such as health status-including endocrine disorders. Furthermore, some factors could be modifiable, such as health behaviours, dietary patterns and micronutrient intake.
It has been confirmed that in-vitro fertilisation success rate seems to be highest during the summer months when the pollution of particulate matter (PM) is at its lowest [3]. Phthalates, which may negatively influence the fertility health of women [4], were found to affect the occupational health of hairdressers [5]. Some primary factors, such as excess body weight or underweight, also decrease the rate of fertility [6,7]. Body saturation with vitamin D was suggested to have a beneficial influence on fertility [8][9][10][11][12].
The recommendations by the Committee of the American Society for Reproductive Medicine in collaboration with the Society for Reproductive Endocrinology and Infertility American Society for Reproductive Medicine, advise females to follow a healthy diet, avoid alcohol and decrease caffeine intake to a moderate level [13]. It is also advisable for women to supplement folate (400 μg/day) to decrease the chance of neural tube defects [13]. However, there is some evidence showing that some food ingredients and specific dietary patterns in women may be positively associated with pregnancy and live birth rates [14][15][16].
One of the food ingredients widely discussed in the context of fertility is sugar. It was shown that its presence in the diet reduces nutritional density and worsens its nutritional quality [17]. The possible mechanism between sugar-sweetened beverages and fertility was explained by increased insulin resistance, leading to oxidative stress. This relation may deleteriously affect semen quality and ovulatory function. Such a mechanism was hypothesised by Hatz, et al. [18], who studied a group of nearly five thousand women and found that fertility and the amount of sugar consumed in sugarsweetened beverages (particularly sodas and energy drinks) was associated with lower fecundability [18].
A large group of compounds that are still being studied are bioactive compounds in food. Their roles in oxidative stress and fertility have been presented in many studies [19][20][21][22], including several studies on female animal models and bioactive food compounds [23][24][25]. Their role is hypothesised to diminish the effect on the endocrine system of disruptive chemicals. For example, there is some evidence that animals treated with BPA (Bisphenol A), after maternal supplementation of folate and a high phytoestrogen diet, influence oocyte growth and foetal methylation of DNA [26,27]. Other studies have highlighted that a low dose (but not a high dose) of ginger powder, improved the follicle counts of rats [23]. Therefore, it is not clear what dose will be as effective on humans. Additionally, human fertility is affected by complex and multiple factors which could be difficult to expose animals to.
The time of preconception may motivate couples to adopt healthier behaviours and to seek information on factors improving fertility. Even though medical consultation is still the most common source for seeking advice for fertility, social media and the internet also play significant roles [28]. The choice of supplement options is vast, as the fertility supplement market is continuously growing and it has been estimated to be worth USD 1.45 billion globally in 2018 [29]. The use of supplements is not always recommended by healthcare professionals, and their misuse may even pose a threat to health.
The literature related to food compounds and fertility has not been extensively collected, and there is no consensus on what the trends are in these studies or what groups of food ingredients should be considered as supportive or detrimental to fertility. In light of this evidence, an analysis of diet ingredients, food research (e.g., ginger, BPA) and fertility could lead to new supporting therapy strategies that affect the birth rate through the modulation of eating habits. Accordingly, this review provides an analysis of new food compound research influencing fertility and revises recent studies involving the impact of food bioactive compounds on women's fertility.

Search Strategy
A systematic search of literature published before December 2019 was performed in PubMed (National Institiute of Health, USA)(https://www.ncbi.nlm.nih.gov/pubmed), Web of Science (Clarivate Analytics, USA) (https://www.webofknowledge.com), Scopus (Elsevier, RELX Group plc),(https://www.scopus.com) and Science Direct (Elsevier, RELX Group plc) (https://www.sciencedirect.com/) to identify studies describing the association between bioactive food compound intake and women's fertility. The search strategy was restricted to English language original articles. The following types of documents were excluded: review, book and book chapters.
The search was based upon the following index terms, titles or abstracts listed below: ((bioactive OR nutrient OR food OR ingredient OR vitamin OR mineral OR antioxidant OR phytonutrient) AND (fertility)). The protocol was registered in the "PROSPERO International prospective register of systematic reviews" PROSPERO 2020: CRD42020160223 and is available on https://www.crd.york.ac.uk/prospero/display_record.php?ID = CRD42020160223.

Inclusion and Exclusion Criteria
Studies on the influence of food compounds on infertility, signs and symptom changes in patients affected by infertility were included. Studies using different food components concerning changes in the concentration of biomarkers for the assessment of infertility and changes in symptoms were analysed. The systematic search included a population of women in the reproductive age 21-50 with diagnosed infertility or healthy women trying to conceive. All studies conducted on animals and case reports were excluded. The studies included were both qualitative and quantitative. A quality assessment of questionable articles was performed with a checklist described by Kmet et al. [30]. Articles written in a language other than English were excluded. Since the search included new trends in food research, it only included articles within the last five years (2015).

Study Extraction Process
The study selection process includes an assessment of articles based upon titles, abstracts and full text, which were performed by two independent researchers in parallel in each database. At each step of the assessment, all disagreements between the researchers were resolved after consultation with the review coordinator. Only in the case of disagreement during the title assessment process was the paper included in the next step. Full-texts of all records that were selected in the abstract review phase were searched for through the library of Poznan University of Life Sciences.

Discussion
This systematic review aimed to identify emergent trends in food compounds studies which influence women's fertility. We qualified a total of 29 studies from the past five years among women planning to conceive either naturally or with assisted reproductive technologies.

Dietary Patterns, Intake of Fruits, Vegetables and Whole Grains
The modern diet and nutrition analysis based on dietary patterns also assessed the nutrition behaviours as a whole, rather than looking at a single nutrient. Dietary patterns are defined as the quantity, variety, or combination of different foods and beverages in a diet and the frequency in which they are habitually consumed. The frequency reflects food compounds consumed in the diet directly. The most common dietary patterns are pro-healthy, Mediterranean, western and dairyrelated [61,62]. The results of this systematic review (presented in Table 1) showed that a high intake of fruits and vegetables and adherence to a pro-healthy dietary pattern is associated with a higher average number of oocytes [51] and embryo quality [53]. The Mediterranean dietary pattern has been associated with supporting fertility health in women. Karayannis et al. found that this dietary pattern is only related to the live birth rate in women under the age of 35 [14]. Another study showed that it was related only to higher oocyte number and clinical pregnancy in women over 35 [57]. The Mediterranean diet is characterised by a high intake of extra virgin olive oil, vegetables, fruits, cereals, nuts and legumes, a moderate intake of fish and other meat, dairy products and red wine and low intakes of eggs and sweets [63]. Another dietary pattern used in the studies was a fertility diet dietary pattern characterised by the intake of supplemental folate and B12, low-pesticide residue produce, high intake of whole grains, seafood, dairy and soy foods. This dietary pattern was positively related to the likelihood of live birth [31].

Fatty Acids and Fish Intake
The current review has shown that there is no conclusive evidence about the impact of polyunsaturated fatty acids, including the intake of omega-3 on human fertility [13]. The results of the review are inconclusive: two studies found an association between omega-3 fatty acids and fertility [40,41], while another study found no impact of these fatty acids on fertility [39]. However, all of the studies analysing fatty acid intake found that the amount of trans fatty acid consumed is negatively related to the live birth ratio [39,41]. These results also support Grieger et al., who found that a high consumption of fast foods (a rich source of trans fatty acids) influences fertility [46].

Dairy
For many years, the topic of high dairy intake has been controversial and linked with both a positive and negative impact on the health of women [16, 64,65]. Nevertheless, to date, most of the studies concerning female reproductive health have been skewed towards a positive association. Moreover, all of the studies in this systematic search, including the period 2015-2019 concerning dairy intake and fertility, have found at least a small positive relationship between these variables [15, 43,44]. It should be noted that dairy foods are generally perceived as a pro-healthy dietary attribute. We studied this group of foods previously and found that a more significant effect on dairy consumption by women was the family environment than health-related protective factors [66].

Caffeine
Decreasing the caffeine intake to moderate during the time of preconception has been recommended to couples who plan pregnancy [13]. A high intake of caffeine, especially black tea [45] and coffee with added sugar and diet soft drinks [54] has been related to a lower live birth rate. However, coffee intake of 1-5 cups daily has been associated with higher chances of a live birth than none [50]. The intake of caffeine and coffee may be associated with more favourable dietary patterns and health behaviours which could influence fertility [67]. This could be the reason why different types of caffeinated beverages bring contrasting results.

Soy
The use of nutrients as factor diminishing adverse health effects of environmental pollutants was found in research concerning soy. Soy, as the food product containing phytosterols, could alleviate the effect of endocrine disruptor bisphenol A. This hypothesis is supported by a study concerning women undergoing ART, urinary bisphenol A and soy intake and their influence on live birth rate [32]. Intake of soya, regardless of environmental pollutants, was also related to a higher probability of life birth [33]. High soy intake has also been related to weight loss in women with polycystic ovary syndrome (PCOS), which may improve health and disease results [68]. The results of the above studies show that food ingredients may not always have a direct impact on fertility and their indirect impact is equally important. However, more studies concerning soy intake on fertility and women's health are needed. Many studies suggest that high soy intake may cause interference with ovarian function because of its high phytoestrogen content [69,70]. More studies are needed to determine the appropriate intake of soy of women trying to conceive, since an excessive intake of soy may not be safe.

Folate
The Center for Disease Control and Prevention (CDC) in the United States, recommends that healthy women with a low risk of birth defects should supplement 400 μg a day of folic acid at least 12 weeks before conception and early pregnancy to avoid neural tube defects [71]. However, it is unknown whether folate intake is related to female fertility. Recent studies have turned to methylenetetrahydrofolate reductase (MTHFR) gene mutations as the cause of recurrent miscarriages [72]. It seems that supplementation of vitamins B6, B12 and supraphysiologic methylfolate could help women with MTHFR gene mutations to conceive [73]. A high intake of folate and B12 was associated with an increased birth rate in women undergoing ART [59]. A high folate-to-homocysteine ratio was related to a lower risk of anovulation in regularly menstruating females [60]. Interesting retrospective studies were also conducted on supplemental folate intake and pollutant exposure among women undergoing ART. The subjects with high pollutant exposure had a lower rate of live birth [35] or implantation ratio [34]; however, folate supplementation positively modified these results in both studies. These results agree with the animal studies mentioned previously [26,27].

Vitamin D
During the current study, a number of studies were found which analysed the effect of vitamin D [8][9][10][11]36,49,[74][75][76][77][78]. Nine of them showed a positive, statistically significant association with female fertility [8,9,11,36,49,74,[76][77][78]. However, since only possible interactions with food compounds were searched for, and vitamin D is mostly formed under sun exposure, two of them concerning vitamin D dietary intake were included in the review. Summing up the issues of vitamin D and fertility, it should be emphasised that food products fortified with vitamin D could be advisable [49] for some populations, not only because of the fertility support but also overall health [79].

Antioxidants
The search also resulted in study findings involved in other single micronutrients. In a Russian study concerning serum metal concentration in the blood of women, it was found that females with infertility and miscarriage had a lower concentration of copper than pregnant women [55]. Moreover, there was no difference between the copper levels of pregnant women and a healthy control group, which supports the hypothesis that copper may play a role in female fertility.
A diet rich in antioxidants, such as the Mediterranean dietary pattern could improve fertility, although the only recent study concerning the intake of antioxidants did not support this hypothesis. Moreover, the intake of foods with a high concentration of β-carotene, lutein and zeaxanthin was inversely associated with live birth rates [37]. The reasoning of these results may be variable, starting from the accuracy of the food frequency questionnaire used in the study to the dietary pattern which leads to these results. The most important is the fact that supplementing antioxidants as fertility support or for other health conditions could be dangerous and should not be advised to the patients.

Other Food Compounds
Most of the studies found in the systematic search were qualitative and retrospective, although four prospective randomised trials published between 2015 and 2019 were also included in the review ( Table 2). The studies concerned coenzyme Q10 [48], melatonin [58] and multiple nutrient supplementation of vitamin E and D [52] as well as numerous micronutrient or only folate supplement [47]. All of the included study interventions had a positive effect on the pregnancy rate and should be further studied to support fertility treatment nutritionally.

Conclusions
In conclusion, it should be noted that reproductive performance is influenced by food and type of nutrition. The findings of the current study suggest that the importance of food production. In particular, the availability and intake of pro-healthy food compounds is a significant factor supporting fertility in females. Women planning pregnancy should especially ensure an intake of fruits and vegetables, folate and vitamin D. A high intake of sweetened beverages and trans-fatty acids appears to decrease the chance of pregnancy and live birth rate. Soy food intake needs to be further analysed because of its endocrine-disruptive properties. Environmental pollution influences fertility around the world, and the appropriate intake of bioactive food compounds could diminish this effect. However, the excessive intake of specific micronutrients, such as antioxidants, may decrease fertility. More randomised prospective studies are needed to analyse the impact of micronutrients on fertility, taking into consideration the patient environment and environmental pollution.