Learning Objectives:After participating in this continuing professional development activity, the provider should be better able to:

1. Describe how macro- and micronutrients are associated with fertility.

2. Identify dietary patterns that are associated with improved fertility outcomes.

3. Summarize patient counseling regarding evidence-based dietary changes that may be beneficial to optimize their fertility and reproductive outcomes.

It is estimated that 10% to 15% of women of reproductive age experience infertility.1 Approximately 1.7% of all children born in the United States in 2015 were born via assisted reproductive technology (ART), with the most common causes of infertility being ovulatory dysfunction, male factor, or unexplained infertility.2,3 There are few modifiable lifestyle factors that have been associated with fertility treatment success. However, increasing evidence suggests that adherence to certain dietary patterns can be positively and negatively associated with reproductive outcomes.4

As the incidence of infertility and use of assisted reproductive technologies continues to increase, it is imperative that we recognize and make women aware of modifiable lifestyle factors that can optimize reproductive outcomes. Obstetrics and gynecology providers have a unique opportunity to provide evidence-based lifestyle guidance during annual health maintenance and preconception visits to optimize future fertility. In this article, we aim to summarize the research surrounding dietary patterns, fertility, and reproductive outcomes to help physicians to provide optimal counseling to women who are planning to achieve pregnancy now or in the future.

Dietary Nutrients, Fertility, and ART Outcomes

Carbohydrates

Carbohydrate intake plays an integral role in altering and maintaining blood glucose levels and insulin sensitivity. Glycemic index, a value assigned to carbohydrates based on how they affect blood glucose levels, and glycemic load, measured as the total carbohydrate intake per serving of a particular food multiplied by the glycemic index of that food, are two methods of describing the quality of carbohydrate-rich foods in the diet.5,6 Studies indicate that hyperinsulinemia and insulin resistance act in the direct inhibition of insulin-like growth factor-binding protein-1 (IGFBP-1).7 This inhibition can decrease decidualization needed for endometrial proliferation and decrease the production of sex hormone-binding globulin.7 Increased insulin has also been associated with upregulation of P450C17[alpha] (17[alpha]-hydroxylase), which, by increasing androgen production, can have a negative effect on endometrial proliferation and implantation.7,8 Further, high levels of C-reactive protein (CRP), an acute-phase inflammatory protein, are associated with poorer reproductive outcomes and may be improved by whole grain intake.9 Therefore, much research has focused on the quality in addition to the quantity of carbohydrates consumed in women trying to conceive.

Carbohydrates and Fertility

Data from the Nurses' Health Study II (NHS-II) cohort revealed that when substituting carbohydrates for naturally occurring fats and animal protein, total carbohydrate consumption and increased glycemic load were associated with a higher risk of ovulatory infertility.6 Consistent with the NHS-II, the Pregnancy Study Online (PRESTO) and the Danish Snart Foraeldre (SF) cohort noted that higher average daily glycemic load intake of 141 or more compared with 100 or less was negatively associated with fecundability (likelihood of achieving pregnancy in one menstrual cycle) in both cohorts [SF: fecundability ratio (FR), 0.89; 95% confidence interval (CI), 0.73-1.08; PRESTO: FR, 0.87; 95% CI, 0.77-0.98].10 Additionally, although there was no significant association between total carbohydrate intake and fecundability in SF, PRESTO noted a slight inverse association (FR, 0.87; 95% CI, 0.77-0.97). Unlike glycemic load, total carbohydrate intake does not take into account the quality of carbohydrates.10 In general, women in the PRESTO cohort consumed carbohydrates with a higher glycemic load, which may account for the difference in results comparing total carbohydrate intake and fecundability in the 2 cohorts.10

Whole grains are typically lower in glycemic index and glycemic load than refined grains and have higher fiber content. They also contain antioxidants, vitamins, and minerals that have been associated with reduced formation of reactive oxygen species, which contribute to mitochondrial, peroxisomal, and DNA damage.8 Among women in the BioCycle study, a prospective cohort study of 259 eumenorrheic women aged 18 to 44 years, whole grain intake had a dose-dependent inverse relationship with CRP levels, which is a surrogate marker of inflammation.9 The PRESTO study also demonstrated that fecundability decreased with an increased carbohydrate-to-fiber ratio in the American cohort (FR, 0.87; 95% CI, 0.78-0.98) but slightly increased with total fiber intake from less than 16 to more than 25 g/d (SF: FR, 0.99; 95% CI, 0.81-1.22; PRESTO: FR, 1.06; 95% CI, 0.94-1.20).10

Carbohydrates and ART Outcomes

Although high glycemic load and carbohydrate intake are associated with ovulatory infertility and decreased fecundability in healthy, eumenorrheic women not undergoing in vitro fertilization (IVF), another 2020 cohort study demonstrated no association between dietary carbohydrates and glycemic load and IVF outcomes.11 In contrast, results from the EARTH study demonstrate that increasing dietary whole grains was positively associated with ART outcomes following IVF and embryo transfer despite an increase in caloric intake.8 Whole grain intake in the year before fertility treatment was associated with increased endometrial thickness on the day of embryo transfer, which is considered a surrogate marker of endometrial receptivity.8 Increasing whole grain intake from less than 21.4 to more than 52.4 g/d was associated with a significant increase in the chances of implantation and live birth by nearly 20% in the age-/weight-adjusted model.8

Carbohydrate Summary

In healthy, eumenorrheic women, consuming carbohydrates with a lower glycemic load and increasing dietary fiber intake may reduce the risk of ovulatory infertility and improve fecundability. Increased consumption of low-glycemic-load carbohydrates and whole grains in women undergoing IVF may improve reproductive outcomes.

Fatty Acids

There are 3 main forms of fatty acids: saturated, unsaturated, and polyunsaturated fatty acids (PUFAs). Studies indicate that fatty acids serve as energy substrates for critical early reproductive processes including oocyte maturation, early embryonic development, and implantation.12 Fatty acids are also precursors of essential reproductive hormones. In addition, fatty acids and eicosanoids like PUFAs and omega-3 fatty acids upregulate the effects of peroxisome proliferator-activated receptor-gamma (PPAR-[gamma]), a receptor that plays a role in mediating carbohydrate and lipid metabolism and anti-inflammatory pathways.13

Fatty Acids and Fertility

PUFAs, like omega-3 and omega-6 fatty acids, have properties that affect processes of inflammation. Omega-3 fatty acids found in salmon, flaxseeds, walnuts, soybeans, algae, and canola oil are natural PPAR-[gamma] ligands that reduce inflammation.14 In fact, increased omega-3 to omega-6 ratio has demonstrated anti-inflammatory properties by upregulating the effects of PPAR-[gamma].13 The PRESTO study noted that omega-3 fatty acid intake was associated with higher fecundability in women who did not consume fish oil supplements when comparing the highest to lowest quartiles of intake (FR, 1.40; 95% CI, 1.13-1.73).15

The BioCycle study also found a positive relationship between marine omega-3 intake and progesterone levels and an inverse relationship between docosapentaenoic acid, a PUFA, and risk of anovulation [risk ratio (RR), 0.42; 95% CI, 0.18-0.95].16 In contrast, the PRESTO/SF study demonstrated in both cohorts that total intake of pro-inflammatory omega-6 fatty acids found in seed and vegetable oils was not significantly associated with the risk of ovulatory infertility or fecundability in healthy women without a history of infertility.15 The LIFE study, a prospective cohort study of 501 couples trying to conceive, demonstrated that couples who consumed 8 servings or more of seafood per cycle, or 2 per week on average, had higher fecundity (shorter time to pregnancy) (fecundity odds ratio, 1.61; 95% CI, 1.17-2.22) compared with couples who consumed 1 serving or less per cycle.17

In contrast to PUFA, studies show that trans fatty acids (TFAs, commonly found in fried foods and prepackaged baked goods) are directly related to increased inflammation and insulin resistance via downregulation of PPAR-[gamma] expression-both of which have been negatively associated with ovulatory infertility.15 In the PRESTO cohort, higher TFA intake in healthy, eumenorrheic women was associated with reduced fecundability in North American women (FR, 0.86; 95% CI, 0.71-1.04).15 Notably, total fat intake was not associated with fecundability. TFAs are significantly associated with increased risk of ovulatory infertility when replacing dietary carbohydrate, monounsaturated fatty acid (MUFA), or omega-6 fatty acid with trans fat intake in age- and lifestyle-adjusted models.15

Fatty Acids and ART Outcomes

The Mediterranean diet (characterized by increased intake of fruit and vegetables, whole grains, nuts, olive oils, and seafood sources of protein) has long been studied for its general health benefits. In nonobese women younger than 35 years, Karayiannis et al18 found that increased adherence to a Mediterranean diet in the year before IVF resulted in a higher chance of clinical pregnancy and live birth. A prospective cohort study in Guangdong, China, demonstrated that patients with an increased adherence to a Mediterranean diet was positively associated with a higher number of available embryos compared with patients with a lower adherence and may also increase quantity and quality of oocytes retrieved during IVF.19

In contrast, another 2019 study of women in Italy failed to find a significant association between Mediterranean diet and IVF outcomes.20 This discrepancy may be due to the study location, as participants in Italy may have a stronger adherence to the Mediterranean diet at baseline than women in other geographic locations.

The FOod, Lifestyle and Fertility Outcome-project (FOLFO-project) among women in the Netherlands concluded that although no association was found between adherence to a Mediterranean diet and fertilization rate or embryo quality, greater adherence to the Mediterranean diet was associated with 40% higher odds of pregnancy after IVF or intracytoplasmatic sperm injection [odds ratio (OR), 1.4; 95% CI, 1.0-1.9).21 Studies indicate that red meat, high in saturated fatty acids, may be associated with decreased blastocyst formation and likelihood of clinical pregnancy when consumed before IVF.22

Fatty Acid Summary

Increased intake of dietary omega-3 and reduced intake of unsaturated and TFAs may be associated with improved fertility and reproductive outcomes in women trying to conceive or undergoing fertility treatments.

Protein

It is important to consider the effect of different sources of protein, such as vegetable protein, dairy, soy, and seafood, on reproductive outcomes. Red meat, while a good source of protein, is high in saturated fats and, when consumed before IVF, has been associated with decreased likelihood of clinical pregnancy.22 Seafood is another excellent source of dietary protein and that has been noted for its higher omega-3 content but can also often be contaminated with mercury and other heavy metals. Vegetable proteins may provide a more beneficial alternative to animal protein in terms of reproductive outcomes.

Protein and Fertility

The NHS-II concluded that while holding calories constant, women who consumed more animal protein than vegetable protein were generally heavier, younger, and less active and consumed more saturated fats. In contrast, women who consumed more vegetable protein were generally leaner, older, more active, and consumed less saturated fats, MUFAs, and TFAs.23 After adjusting for confounding variables, increased animal protein intake was associated with a higher risk of ovulatory infertility (RR, 1.39; 95% CI, 1.01-1.09) whereas increased intake of vegetable protein was associated with a lower risk (RR, 0.78; 95% CI, 0.54-1.12). When vegetable protein replaced 5% of dietary carbohydrate intake, the risk of ovulatory infertility decreased by 43% (P = 0.05), and when vegetable protein replaced animal protein, the risk of ovulatory infertility decreased by 50%.23

Dairy and soy are important sources of protein, especially in vegetarian or low animal protein diets, that may impact fertility. Existing data in this area are conflicting. A 2003 study demonstrated that dairy intake may be protective against infertility in women who consumed more than 3 glasses of milk per day (OR, 0.3; 95% CI, 0.1-0.7).24 The NHS-II demonstrated that although full-fat dairy was associated with a decreased risk of ovulatory infertility (RR, 0.73; 95% CI, 0.52-1.01), low-fat dairy was associated with an increased risk (RR, 1.85; 95% CI, 1.24-2.77).25 However, the PRESTO/SF study comparing dairy intakes of American and Danish women demonstrated only weak associations between dairy and reproductive outcomes.26

Phytoestrogens are found in soy, grains, and some vegetables and can alter endogenous hormone activity. The Adventist Health Study-2 noted a 13% increased risk of never having a child with increased isoflavone intake.27 However, the more recent PRESTO study demonstrated a slight positive association between soy isoflavone intake and fecundability (FR, 1.12; 95% CI, 0.94-1.34) and an inverse relationship between soy lignan intake and fecundability (FR, 0.83; 95% CI, 0.72-0.97).28

The potential benefits of seafood were supported by the LIFE study, which demonstrated that couples who consumed 2 or more servings of seafood per week on average had a 60% shorter time to pregnancy and 13% lower incidence of infertility compared with couples who consumed 1 or fewer servings per week. Interestingly, intercourse frequency was higher in couples with higher seafood consumption, but effects remained significant after controlling for this.17

Protein and ART Outcomes

A 2016 study of participants in the EARTH Health Study did not find a significant difference between full-fat and low-fat dairy foods in relation to pregnancy rates after IVF with embryo transfer, although a positive association was found between total intake of dairy food and live birth rate among women older than 35 years (P = 0.04).29

In women undergoing ART, soy protein intake has been associated with a higher fertilization rate and higher odds of live birth and clinical pregnancy.30 Soy foods were not, however, associated with peak estradiol levels, endometrial thickness, embryo quality, or cleavage rates.30

Within the EARTH study cohort, women undergoing IVF and embryo transfer with increased adherence to a profertility diet consisting of a higher intake of supplemental folic acid, vitamins D and B₁₂, and dietary whole grains, dairy, soy, and seafood in place of conventional animal meat noted higher rates of implantation, clinical pregnancy, and live birth.4

Protein Summary

Prioritizing intake of high-quality, plant-based and seafood sources of protein over conventional animal meats may be beneficial for women trying to conceive or undergoing ART.

Sugar-Sweetened Beverages

The increased consumption of sugar-sweetened beverages (SSB) and their impact on obesity urge consideration of their effect on fertility. High-fructose corn syrup has a direct association with glycemic load and insulin resistance, which can cause oxidative stress and affect ovulation.31 It is important to consider whether the impact of SSB on fertility is due to the fructose or caffeine content or other variables.

Sugar-Sweetened Beverages and Fertility

In a Danish cohort study, soda drinkers displayed a dose-dependent decrease in fecundability compared with those who did not drink soda for less than 1, 1, 2, and 3 or more servings of soda per day (FR, 0.89; 95% CI, 0.80-0.98; FR, 0.85; 95% CI, 0.71-1.02; FR, 0.84; 95% CI, 0.57-1.25; and FR, 0.48; 95% CI, 0.21-1.13).32 In general, soda drinkers were found to be younger, less active, and have a higher body mass index than women who did not drink soda.32 In the NHS-II population, soft drinks, both sugared and diet, were associated with an increased risk of ovulatory infertility when comparing consumption of these beverages twice daily versus 1 or less serving per week (sugared soft drinks: RR, 1.41; 95% CI, 1.07-1.85) (diet soft drinks: RR, 1.33; 95% CI, 0.94-1.87).33 In both studies, the relationship between sugar-sweetened sodas and ovulatory infertility was independent of fructose and caffeine content of the drink. Among women in the PRESTO cohort, although consumption of more than 7 servings of SSBs per week (average of one per day) was associated with reduced fecundability, there was no significant association found between fecundability and diet soda, sports drinks, or fruit juices.34

Sugar-Sweetened Beverages and ART Outcomes

In women undergoing IVF, limited evidence has shown that increased sugar-sweetened soda and energy drink intake is inversely associated with the total number of mature oocytes retrieved, fertilization rates, and proportion of clinical pregnancies, and live births following embryo transfer.35

Sugar-Sweetened Beverage Summary

Reducing intake of sugar-sweetened sodas would be beneficial to women trying to conceive or undergoing IVF treatment. Data regarding intake of diet soda or other SSBs are limited and conflicting.

Folic Acid

Folate (vitamin B₉) is known for its role in the prevention of neural tube defects and DNA synthesis. Folic acid (synthetic B₉) supplements before and during pregnancy have been shown to prevent neural tube defects and other congenital abnormalities and are routinely recommended to reproductive-age women for that reason.36 The impact of folic acid supplementation on fertility is limited and is a topic of interest.

Folic Acid and Fertility

Vitamin B₁₂ and folic acid are important cofactors in homocysteine metabolism, so decreased levels of these vitamins can lead to hyperhomocysteinemia, which has been related to longer time-to-pregnancy and spontaneous abortion.37 Risk of spontaneous abortion decreased in patients who took folic acid supplements at higher doses than those recommended for the prevention of neural tube defects, compared with women who did not supplement folic acid (RR, 0.80; 95% CI, 0.71-0.90).37 In the BioCycle study, although there was no association between total dietary folate intake and hormone levels or reproductive outcomes, folic acid supplements did have an inverse relationship with odds of anovulation and a positive relationship with luteal progesterone levels.38 In a Danish cohort of healthy, premenopausal women planning a pregnancy, folic acid supplements were related to increased fecundability, with a stronger correlation seen in women with irregular cycles (FR, 1.35; 95%, CI 1.12-1.65).39

Folic Acid and ART Outcomes

The EARTH study demonstrated that higher intake of folic acid supplements (>=800 [micro]g/d) was associated with higher fertilization, implantation, and live birth rates in women undergoing IVF with embryo transfer.40 These levels are higher than those recommended for the prevention of neural tube defects (400 [micro]g). Folic acid intake and rates of cycle failure before embryo transfer were also inversely related.40

Increased serum folate and B₁₂ levels have also been associated with an increased probability of live birth compared with women with lower levels.41 However, another prospective case-control study demonstrated that supplemental folic acid was unrelated to pregnancy outcomes and live birth after ART in women with unexplained fertility.42 This conflicting evidence may be due to the exclusion of subjects who had IVF cycle failure before embryo transfer; therefore, women who might have benefitted from folic acid supplements were excluded.

Folic Acid Summary

Recommendations regarding folic acid and reproductive outcomes are similar in healthy reproductive-age women who are and are not undergoing ART. Women trying to conceive may benefit from taking a prenatal vitamin with at least 800 [micro]g of folic acid in terms of pregnancy and fertility outcomes.

Vitamin B₁₂

B₁₂, an essential vitamin cofactor commonly found in animal products and meats, is important for the production of red blood cells and DNA synthesis. B₁₂ passes a methyl group from folate to homocysteine, converting homocysteine into methionine. B₁₂ deficiency can lead to high levels of homocysteine, which can result in hypercoagulation, changes in ovulation or ovum development, defective implantation, or fetal loss.43,44

Vitamin B₁₂ and Fertility

B₁₂ deficiency and hyperhomocysteinemia are risk factors for pregnancy complications. One study demonstrated that B₁₂ deficiency during the first and second trimesters was associated with low-birth-weight babies.45 Vegetarian mothers, who are typically at higher risk for B₁₂ and iron deficiency, were also at higher risk for lower birth-weight babies.46

Vitamin B₁₂ and ART Outcomes

In women undergoing IVF, the FOLFO-project demonstrated that increased serum and monofollicular fluid B₁₂ levels in the early follicular phase were positively related to embryo quality.47 The EARTH study concluded that together B₁₂ and folic acid supplements were beneficial in regard to birth weight in both natural and IVF pregnancies.41 Increased B₁₂ intake as a part of the profertility diet (increased supplemental folic acid, B₁₂, and vitamin D, low-pesticide fruit and vegetables, dairy, whole grains, soy, and seafood) was associated with higher rates of implantation, clinical pregnancy, and live birth.4

Vitamin B₁₂ Summary

Additional B₁₂ supplementation may be beneficial for reproductive and obstetric outcomes.

Vitamin D

Vitamin D is important in maintaining calcium and phosphate metabolism in cells. Receptors found in ovarian tissue indicate that vitamin D may have a role in fertility and ovulation as well.48,49

Vitamin D and Fertility

In general, studies have not consistently shown a relationship between vitamin D, fecundity, and reproductive outcomes. Among participants of the BioCycle study, vitamin D levels were directly related to estradiol levels.50 However, a prospective study by Chavarro et al25 failed to find a significant relationship between vitamin D levels and anovulatory infertility. A recent meta-analysis examining maternal vitamin D insufficiency with adverse pregnancy and birth outcomes demonstrated no relationship between the 2.51 Similarly, another meta-analysis concluded that low vitamin D does not have an association with spontaneous pregnancy loss.52

Vitamin D ART Outcomes

Findings regarding vitamin D and ART outcomes are conflicting. In women undergoing euploid blastocyst transfer, vitamin D levels had no impact on ongoing pregnancy rates nor pregnancy outcomes.53 A 2019 meta-analysis concluded that there was no significant relationship between vitamin D supplementation and IVF outcomes; however, vitamin D deficiency was associated with negative IVF outcomes such as higher CRP levels, and lower implantation and live birth rates.54 On the contrary, Chu et al55 found no relationship between vitamin D deficiency and live birth rate in women undergoing ART.

Vitamin D Summary

Studies indicate that although vitamin D may have an impact on some hormone levels, vitamin D levels have no statistically significant effect on fertility and birth outcomes, regardless of infertility status or IVF treatment. Although a recent 2020 study with a small sample size indicates that vitamin D levels may be positively associated with implantation rate in IVF, additional large studies are needed to make strong recommendations regarding dietary vitamin D intake and reproductive outcome.56

Conclusion

Dietary intake of many macro- and micronutrients is a modifiable lifestyle factor that can impact reproductive outcomes. Dietary patterns that decrease insulin resistance, such as a low-glycemic-load diet, can positively affect fertility in both women trying to conceive naturally and women undergoing ART. Omega-3 fatty acids and other polyunsaturated fatty acids may be beneficial in decreasing insulin resistance and chances of ovulatory infertility, whereas TFAs have the opposite effects. Prioritizing intake of protein from plant-based and seafood-based sources appears to be beneficial. Further research is needed to make strong conclusions and recommendations regarding soy, dairy, and vitamin D supplementation on fertility. As most of the studies done were observational, prospective cohort studies, additional randomized controlled trials are important to strengthen the conclusions made about dietary effects on reproductive outcomes.

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