Food, nutrition, and fertility: from soil to fork.

Food and nutrition-related factors, including foods and nutrients consumed, dietary patterns, use of dietary supplements, adiposity, and exposure to food-related environmental contaminants, have the potential to impact semen quality and male and female fertility; obstetric, fetal, and birth outcomes; and the health of future generations, but gaps in evidence remain. On 9 November 2022, Tufts University's Friedman School of Nutrition Science and Policy and the school's Food and Nutrition Innovation Institute hosted a 1-d meeting to explore the evidence and evidence gaps regarding the relationships between food, nutrition, and fertility. Topics addressed included male fertility, female fertility and gestation, and intergenerational effects. This meeting report summarizes the presentations and deliberations from the meeting. Regarding male fertility, a positive association exists with a healthy dietary pattern, with high-quality evidence for semen quality and lower quality evidence for clinical outcomes. Folic acid and zinc supplementation have been found to not impact male fertility. In females, body weight status and other nutrition-related factors are linked to nearly half of all ovulation disorders, a leading cause of female infertility. Females with obesity have worse fertility treatment, pregnancy-related, and birth outcomes. Environmental contaminants found in food, water, or its packaging, including lead, perfluorinated alkyl substances, phthalates, and phenols, adversely impact female reproductive outcomes. Epigenetic research has found that maternal and paternal dietary-related factors can impact outcomes for future generations. Priority evidence gaps identified by meeting participants relate to the effects of nutrition and dietary patterns on fertility, gaps in communication regarding fertility optimization through changes in nutritional and environmental exposures, and interventions impacting germ cell mechanisms through dietary effects. Participants developed research proposals to address the priority evidence gaps. The workshop findings serve as a foundation for future prioritization of scientific research to address evidence gaps related to food, nutrition, and fertility.

Traffic-related air pollution and supplemental folic acid intake in relation to DNA methylation in granulosa cells.

BACKGROUND: Higher exposure to traffic-related air pollution (TRAP) is related to lower fertility, with specific adverse effects on the ovary. Folic acid may attenuate these effects. Our goal was to explore the relation of TRAP exposure and supplemental folic acid intake with epigenetic aging and CpG-specific DNA methylation (DNAm) in granulosa cells (GC). Our study included 61 women undergoing ovarian stimulation at a fertility center (2005-2015). DNAm levels were profiled in GC using the Infinium MethylationEPIC BeadChip. TRAP was defined using a spatiotemporal model to estimate residence-based nitrogen dioxide (NO2) exposure. Supplemental folic acid intake was measured with a validated food frequency questionnaire. We used linear regression to evaluate whether NO2 or supplemental folic acid was associated with epigenetic age acceleration according to the Pan-tissue, mural GC, and GrimAge clocks or DNAm across the genome adjusting for potential confounders and accounting for multiple testing with a false discovery rate < 0.1. RESULTS: There were no associations between NO2 or supplemental folic acid intake and epigenetic age acceleration of GC. NO2 and supplemental folic acid were associated with 9 and 11 differentially methylated CpG sites. Among these CpGs, only cg07287107 exhibited a significant interaction (p-value = 0.037). In women with low supplemental folic acid, high NO2 exposure was associated with 1.7% higher DNAm. There was no association between NO2 and DNAm in women with high supplemental folic acid. The genes annotated to the top 250 NO2-associated CpGs were enriched for carbohydrate and protein metabolism, postsynaptic potential and dendrite development, and membrane components and exocytosis. The genes annotated to the top 250 supplemental folic acid-associated CpGs were enriched for estrous cycle, learning, cognition, synaptic organization and transmission, and size and composition of neuronal cell bodies. CONCLUSIONS: We found no associations between NO2, supplemental folic acid, and DNAm age acceleration of GC. However, there were 20 differentially methylated CpGs and multiple enriched GO terms associated with both exposures suggesting that differences in GC DNAm could be a plausible mechanism underlying the effects of TRAP and supplemental folic acid on ovarian function.

B vitamins, polycystic ovary syndrome, and fertility.

PURPOSE OF REVIEW: This review provides a general overview of the literature on B vitamins and fertility, as well as summarizes the evidence concerning B vitamin supplementation and fertility among polycystic ovary syndrome (PCOS) women. RECENT FINDINGS: Studies among women conceiving with and without medical assistance provide strong evidence for a beneficial effect of B vitamins, particularly folate and vitamin B12, on fecundability and fertility. Moreover, recent work suggests that effects may be even more pronounced among women with menstrual cycle dysfunction (a common symptom of PCOS). Among PCOS women, intervention studies have demonstrated that folic acid supplementation may reduce homocysteine levels, potentially improve women's metabolic profiles, and possibly ameliorate some hallmark features of PCOS. Although none of these intervention studies have included fertility endpoints, it is possible that by reducing homocysteine levels (or other clinical/biochemical features) in PCOS women, there may be a downstream improvement in fertility outcomes. SUMMARY: There is growing evidence folate (and possibly vitamin B12) supplementation may be beneficial to fertility in women. Although most studies have not exclusively focused on women with PCOS, there is biological plausibility and some evidence that B vitamin supplementation may be even more important for improving reproductive health outcomes in PCOS women.

Pesticide residue intake from fruits and vegetables and alterations in the serum metabolome of women undergoing infertility treatment.

BACKGROUND: Pesticide exposure is linked to a myriad of negative health effects; however, the mechanisms underlying these associations are less clear. We utilized metabolomics to describe the alterations in the serum metabolome associated with high and low pesticide residue intake from fruits and vegetables (FVs), the most common route of exposure in humans. METHODS: This analysis included 171 women undergoing in vitro fertilization who completed a validated food frequency questionnaire and provided a serum sample during controlled ovarian stimulation (2007-2015). FVs were categorized as high or low-to-moderate pesticide residue using a validated method based on pesticide surveillance data from the USDA. We conducted untargeted metabolic profiling using liquid chromatography with high-resolution mass spectrometry and two chromatography columns. We used multivariable generalized linear models to identified metabolic features (p < 0.005) associated with high and low-to-moderate pesticide residue FV intake, followed by enriched pathway analysis. RESULTS: We identified 50 and 109 significant features associated with high pesticide residue FV intake in the C18 negative and HILIC positive columns, respectively. Additionally, we identified 90 and 62 significant features associated with low-to-moderate pesticide residue FV intake in the two columns, respectively. Four metabolomic pathways were associated with intake of high pesticide residue FVs including those involved in energy, vitamin, and enzyme metabolism. 12 pathways were associated with intake of low-to-moderate pesticide residue FVs including cellular receptor, energy, intercellular signaling, lipid, vitamin, and xenobiotic metabolism. One energy pathway was associated with both high and low-to-moderate pesticide residue FVs. CONCLUSIONS: We identified limited overlap in the pathways associated with intake of high and low-to-moderate pesticide residue FVs, which supports findings of disparate health effects associated with these two exposures. The identified pathways suggest there is a balance between the dietary antioxidant intake associated with FVs intake and heightened oxidative stress as a result of dietary pesticide exposure.

Folate intake and ovarian reserve among women attending a fertility center.

OBJECTIVE: To examine the association between dietary folate intake and antral follicle count (AFC) among women seeing treatment for infertility. DESIGN: Cohort study. SETTING: Academic fertility center. PATIENTS: A total of 552 women attending the Massachusetts General Hospital Fertility Center (2007-2019) who participated in the Environment and Reproductive Health Study. INTERVENTIONS: None. Folate intake was measured with a validated food frequency questionnaire at study entry. Multivariable Poisson regression models with robust standard errors were used to estimate the association of folate intake with AFC adjusting for calorie intake, age, body mass index, physical activity, education, smoking status, year of AFC, and intakes of vitamin B12, iron, and vitamin D. Nonlinearity was assessed with restricted cubic splines. MAIN OUTCOME MEASURE: AFC as measured by transvaginal ultrasonography as part of routine care. RESULTS: Among the 552 women (median age, 35.0 years; median folate intake, 1,005 µg/d), total and supplemental folate intake had a significant nonlinear relationship with AFC. There was a positive linear association with AFC up to approximately 1,200 µg/d for total folate intake and up to 800 µg/d for supplemental folate intake; however, there was no additional benefit of higher folate intakes. The magnitude of the association was modest; for example, the predicted adjusted difference in AFC between a woman consuming 400 vs. 800 µg/d of supplemental folate was approximately 1.5 follicles. CONCLUSION: Higher intake of folate, particularly from supplements, was associated with modestly higher ovarian reserve as measured by AFC among women attending a fertility center. CLINICAL TRIAL REGISTRATION NUMBER: This trial was registered at clinicaltrials.gov as NCT00011713.

Paternal preconception folate intake in relation to gestational age at delivery and birthweight of newborns conceived through assisted reproduction.

RESEARCH QUESTION: Studies in rodents have shown that paternal folate intake prior to conception is associated with pregnancy and offspring outcomes. The aim of this study was to assess whether those associations might apply to humans as well. DESIGN: Between 2007 and 2017, the study prospectively analysed data from 108 couples participating in a preconception cohort of couples undergoing fertility treatment using their own gametes, whose treatment resulted in 113 pregnancies during the course of the study. Paternal and maternal preconception folate intake was assessed using a validated food frequency questionnaire. Linear mixed models were used to assess whether paternal preconception folate intake was associated with gestational age at delivery and gestational age-specific birthweight, while accounting for correlated data and potential confounders. RESULTS: In a multivariable-adjusted model, a 400 µg/day increase in preconception paternal folate intake was associated with a 2.6-day longer gestation (95% confidence interval 0.8-4.3) after adjusting for potential confounders, including maternal folate intake. Similar associations were found for folate from food and supplements. Maternal folate intake was not associated with gestational age at delivery. Neither paternal nor maternal folate intake was associated with gestational-age-specific birthweight. CONCLUSIONS: Higher paternal preconception folate intake was associated with slightly longer gestation among live births achieved through assisted reproduction. The results suggest that preconception exposures of the father may have an impact on the health of his offspring, and therefore that preconception care should shift from a woman-centric to a couple-based approach.

Marijuana smoking and outcomes of infertility treatment with assisted reproductive technologies.

STUDY QUESTION: What is the association of female and male partner marijuana smoking with infertility treatment outcomes with ART? SUMMARY ANSWER: Women who were marijuana smokers at enrollment had a significantly higher adjusted probability of pregnancy loss during infertility treatment with ART whereas, unexpectedly, there was a suggestion of more favorable treatment outcomes in couples where the man was a marijuana smoker at enrollment. WHAT IS KNOWN ALREADY: Data on the relation of female and male partner marijuana use with outcomes of infertility treatment is scarce despite increased use and legalization worldwide. STUDY DESIGN, SIZE, DURATION: We followed 421 women who underwent 730 ART cycles while participating in a prospective cohort (the Environment and Reproductive Health Study) at a fertility center between 2004 and 2017. Among them, 200 women (368 cycles) were part of a couple in which their male partner also enrolled in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants self-reported marijuana smoking at baseline. Clinical endpoints were abstracted from electronic medical records. We used generalized linear mixed models with empirical standard errors to evaluate the association of baseline marijuana smoking with ART outcomes adjusting for participants' age, race, BMI, tobacco smoking, coffee and alcohol consumption, and cocaine use. We estimated the adjusted probability of implantation, clinical pregnancy, and live birth per ART cycle, as well as the probability of pregnancy loss among those with a positive B-hCG. MAIN RESULTS AND THE ROLE OF CHANCE: The 44% of the women and 61% of the men had ever smoked marijuana; 3% and 12% were marijuana smokers at enrollment, respectively. Among 317 women (395 cycles) with a positive B-hCG, those who were marijuana smokers at enrollment (N = 9, cycles = 16) had more than double the adjusted probability of pregnancy loss than those who were past marijuana smokers or had never smoked marijuana (N = 308, 379 cycles) (54% vs 26%; P = 0.0003). This estimate was based on sparse data. However, couples in which the male partner was a marijuana smoker at enrollment (N = 23, 41 cycles) had a significantly higher adjusted probability of live birth than couples in which the male partner was a past marijuana smoker or had never smoked marijuana (N= 177, 327 cycles) (48% vs 29%; P = 0.04), independently of the women's marijuana smoking status. Treatment outcomes of past marijuana smokers, male and female, did not differ significantly from those who had never smoked marijuana. LIMITATIONS, REASONS FOR CAUTION: Marijuana smoking was self-reported with possible exposure misclassification. Chance findings cannot be excluded due to the small number of exposed cases. The results may not be generalizable to couples from the general population. WIDER IMPLICATIONS OF THE FINDINGS: Even though marijuana smoking has not been found in past studies to impact the ability to become pregnant among pregnancy planners in the general population, it may increase the risk of pregnancy loss among couples undergoing infertility treatment. Marijuana smoking by females and males may have opposing effects on outcomes of infertility treatment with ART. STUDY FUNDING/COMPETING INTEREST(S): The project was financed by grants R01ES009718, P30ES000002, and K99ES026648 from the National Institute of Environmental Health Sciences (NIEHS). None of the authors has any conflicts of interest to declare.

Men's Intake of Vitamin C and ß-Carotene Is Positively Related to Fertilization Rate but Not to Live Birth Rate in Couples Undergoing Infertility Treatment.

BACKGROUND: Randomized clinical trials show that men's use of antioxidant supplements during infertility treatment may improve clinical outcomes. However, important limitations in the design of most trials make it difficult to draw firm conclusions on their findings. OBJECTIVE: We examined whether men's intake of antioxidants and biologically related compounds without direct antioxidant capacity is associated with outcomes of assisted reproductive technologies (ARTs). METHODS: We conducted a prospective cohort study of men in couples who underwent infertility treatment with ART using their own gametes between 2007 and 2017. We followed 171 couples who presented at Massachusetts General Hospital Fertility Center and underwent 294 autologous ART cycles for infertility treatment. Diet was assessed in both partners using an FFQ. The primary study outcome was the probability of achieving a live birth as a result of infertility treatment. Secondary outcomes were fertilization, implantation, and clinical pregnancy rates. Generalized linear mixed models with random intercepts were fitted to account for multiple ART cycles per woman while adjusting for confounding. RESULTS: Men's vitamin C intake was positively associated with fertilization rate. The adjusted fertilization rate (95% CI) for couples in the lowest and highest quartiles of men's vitamin C intake were 69% (61-76%) and 81% (74-86%) (P-trend = 0.02). Men's ß-carotene intake was positively associated with fertilization rate in intracytoplasmic sperm injection cycles but not in conventional in vitro fertilization cycles (P-interaction = 0.01). Men's α-carotene intake was inversely related to the probability of live birth. The adjusted probabilities of live birth for men in the lowest and highest quartiles of α-carotene intake were 43% (28-60%) and 22% (12-36%), respectively. CONCLUSIONS: Men's intake of vitamin C and ß-carotene is positively related to fertilization rate but this does not translate into higher pregnancy or live birth rates in couples undergoing infertility treatment.

Supplemental Folate and the Relationship Between Traffic-Related Air Pollution and Livebirth Among Women Undergoing Assisted Reproduction.

Traffic-related air pollution has been linked to higher risks of infertility and miscarriage. We evaluated whether folate intake modified the relationship between air pollution and livebirth among women using assisted reproductive technology (ART). Our study included 304 women (513 cycles) presenting to a fertility center in Boston, Massachusetts (2005-2015). Diet and supplements were assessed by food frequency questionnaire. Spatiotemporal models estimated residence-based daily nitrogen dioxide (NO2), ozone, fine particulate, and black carbon concentrations in the 3 months before ART. We used generalized linear mixed models with interaction terms to evaluate whether the associations between air pollutants and livebirth were modified by folate intake, adjusting for age, body mass index, race, smoking, education, infertility diagnosis, and ART cycle year. Supplemental folate intake significantly modified the association of NO2 exposure and livebirth (P = 0.01). Among women with supplemental folate intakes of <800 µg/day, the odds of livebirth were 24% (95% confidence interval: 2, 42) lower for every 20-parts-per-billion increase in NO2 exposure. There was no association among women with intakes of ≥800 µg/day. There was no effect modification of folate on the associations between other air pollutants and livebirth. High supplemental folate intake might protect against the adverse reproductive consequences of traffic-related air pollution.

Prepregnancy Habitual Intakes of Total, Supplemental, and Food Folate and Risk of Gestational Diabetes Mellitus: A Prospective Cohort Study.

OBJECTIVE: To identify novel modifiable risk factors of gestational diabetes mellitus (GDM) by examining the association between prepregnancy habitual folate intake and GDM risk. RESEARCH DESIGN AND METHODS: The study included 14,553 women in the Nurses' Health Study II who reported at least one singleton pregnancy between the 1991 and 2001 questionnaires. Prepregnancy intakes of total folate, supplemental folate, and food folate were assessed using a food frequency questionnaire administered every 4 years. Incident GDM was ascertained from a self-reported physician diagnosis. Relative risks (RRs) of GDM were estimated using log-binomial models, with adjustment for demographic, lifestyle, and dietary factors. RESULTS: Over the study follow-up, 824 incident GDM cases were reported among 20,199 pregnancies. Women with adequate total folate intake (≥400 µg/day) had an RR of GDM of 0.83 (95% CI 0.72, 0,95, P = 0.007) compared with women with inadequate intake (<400 µg/day). This association was entirely driven by supplemental folate intake. The RRs of GDM for 1-399, 400-599, and ≥600 µg/day of supplemental folate intake were 0.83, 0.77, and 0.70, respectively, compared with no supplemental folate intake (P trend = 0.002). The association between supplemental folate intake and GDM risk largely persisted after additional adjustment for intake of multivitamins and other micronutrients, as well as among women who likely planned for the pregnancy. CONCLUSIONS: Higher habitual intakes of supplemental folate before pregnancy were significantly associated with lower GDM risk. If confirmed, these findings indicate that prepregnancy folic acid supplementation could offer a novel and low-cost avenue to reduce GDM risk.

Dietary patterns and outcomes of assisted reproduction.

BACKGROUND: There is growing acceptance that nutrition may be related to fertility and specifically to assisted reproductive technologies success in women; however, there is still no specific dietary guidance. OBJECTIVE: The objective of the study was to evaluate the relationship between pretreatment adherence to various dietary patterns and outcomes of assisted reproductive technologies. STUDY DESIGN: We followed up 357 women enrolled in the prospective Environment and Reproductive Health (EARTH) study, who underwent 608 assisted reproductive technologies cycles (2007-2017). Using a validated food frequency questionnaire completed prior to treatment, we assessed adherence to the Mediterranean diet, the alternate Healthy Eating Index 2010, the Fertility Diet (developed based on risk factors for anovulatory infertility), and a profertility diet we developed based on factors previously related to assisted reproductive technologies outcomes (higher intake of supplemental folic acid, vitamin B12, vitamin D, low- rather than high-pesticide residue produce, whole grains, dairy, soy foods, and seafood rather than other meats). RESULTS: Higher adherence to the alternate Healthy Eating Index 2010 and Fertility Diet was not related to live birth following assisted reproductive technologies. Women in the second through the fourth quartiles of Mediterranean diet adherence had significantly higher probability of live birth (0.44, 95% confidence interval, 0.39-0.49) compared with women in the first quartile (0.31, 95% confidence interval, 0.25-0.39); however, there was no additional benefit of adherence to the Mediterranean diet above the second quartile. Increased adherence to the profertility diet was linearly associated with assisted reproductive technologies outcomes. The adjusted odds (95% confidence interval) of implantation, clinical pregnancy, and live birth were higher by 47% (21%, 77%), 43% (19%, 72%), and 53% (26%, 85%), respectively, per SD increase. The adjusted difference in the proportion of cycles resulting in live birth for women in the fourth vs first quartile of adherence to the profertility diet was 0.28 (95% confidence interval, 0.16-0.38). While the profertility diet was not related to estradiol levels, oocyte counts, or endometrial thickness, it was inversely associated with clinical pregnancy loss (odds ratio, 0.69, 95% confidence interval, 0.53-0.90 per SD increase). CONCLUSION: Higher pretreatment adherence to the profertility diet was associated with an increased probability of live birth among women undergoing assisted reproductive technologies. Commonly recommended dietary advice such as adhering to the Mediterranean diet may not provide the most appropriate guidance for women undergoing infertility treatment in the United States.

Pre-pregnancy caffeine and caffeinated beverage intake and risk of spontaneous abortion.

PURPOSE: To investigate the relation between pre-pregnancy caffeine and caffeinated beverage intake and risk of spontaneous abortion (SAB). METHODS: Our prospective cohort study included 15,590 pregnancies from 11,072 women with no history of SAB in the Nurses' Health Study II (1991-2009). Beverage intake was assessed every 4 years using a validated questionnaire. Pregnancies were self-reported with case pregnancies lost spontaneously at <20 weeks gestation. Multivariable log-binomial regression models with generalized estimating equations were used to estimate the relative risks (RRs) and 95 % confidence intervals (CIs). RESULTS: There was a positive linear trend across categories of pre-pregnancy caffeine intake and risk of SAB such that women consuming >400 mg/day had 1.11 (95 % CI 0.98, 1.25) times the risk of SAB compared to women consuming <50 mg/day (p trend = 0.05). Total coffee intake had a positive, linear association with SAB. Compared to women with no pre-pregnancy coffee intake, women consuming ≥4 servings/day had a 20 % (6, 36 %) increased risk of SAB (p trend = 0.01). There was no difference in the association between caffeinated and decaffeinated coffee and risk of SAB. Pre-pregnancy intake of caffeinated tea, caffeinated soda, and decaffeinated soda had no association with SAB. CONCLUSIONS: Pre-pregnancy coffee consumption at levels ≥4 servings/day is associated with increased risk of SAB, particularly at weeks 8-19.

Association Between Pesticide Residue Intake From Consumption of Fruits and Vegetables and Pregnancy Outcomes Among Women Undergoing Infertility Treatment With Assisted Reproductive Technology.

Importance: Animal experiments suggest that ingestion of pesticide mixtures at environmentally relevant concentrations decreases the number of live-born offspring. Whether the same is true in humans is unknown. Objective: To examine the association of preconception intake of pesticide residues in fruits and vegetables (FVs) with outcomes of infertility treatment with assisted reproductive technologies (ART). Design, Setting, and Participants: This analysis included 325 women who completed a diet assessment and subsequently underwent 541 ART cycles in the Environment and Reproductive Health (EARTH) prospective cohort study (2007-2016) at a fertility center at a teaching hospital. We categorized FVs as having high or low pesticide residues using a validated method based on surveillance data from the US Department of Agriculture. Cluster-weighted generalized estimating equations were used to analyze associations of high- and low-pesticide residue FV intake with ART outcomes. Main Outcomes and Measures: Adjusted probabilities of clinical pregnancy and live birth per treatment cycle. Results: In the 325 participants (mean [SD] age, 35.1 [4.0] y; body mass index, 24.1 [4.3]), mean (SD) intakes of high- and low-pesticide residue FVs were 1.7 (1.0) and 2.8 (1.6) servings/d, respectively. Greater intake of high-pesticide residue FVs was associated with a lower probability of clinical pregnancy and live birth. Compared with women in the lowest quartile of high-pesticide FV intake (<1.0 servings/d), women in the highest quartile (≥2.3 servings/d) had 18% (95% CI, 5%-30%) lower probability of clinical pregnancy and 26% (95% CI, 13%-37%) lower probability of live birth. Intake of low-pesticide residue FVs was not significantly related to ART outcomes. Conclusions and Relevance: Higher consumption of high-pesticide residue FVs was associated with lower probabilities of pregnancy and live birth following infertility treatment with ART. These data suggest that dietary pesticide exposure within the range of typical human exposure may be associated with adverse reproductive consequences.

Diet and fertility: a review.

The literature on the relationship between diet and human fertility has greatly expanded over the last decade, resulting in the identification of a few clear patterns. Intake of supplemental folic acid, particularly at doses higher than those recommended for the prevention of neural tube defects, has been consistently related to lower frequency of infertility, lower risk of pregnancy loss, and greater success in infertility treatment. On the other hand and despite promising evidence from animal models, vitamin D does not appear to exert an important role in human fertility in the absence of deficiency. Antioxidant supplementation does not appear to offer any benefits to women undergoing infertility treatment, but it appears to be beneficial when it is the male partner who is supplemented. However, the available evidence does not allow discerning which specific antioxidants, or at which doses, are responsible for this benefit. Long-chain omega-3 fatty acids appear to improve female fertility, although it remains unclear to what extent contamination of shared food sources, such as fish with high levels of environmental toxicants, can dampen this benefit. Lastly, adherence to healthy diets favoring seafood, poultry, whole grains, fruits, and vegetables are related to better fertility in women and better semen quality in men. The cumulative evidence has also piled against popular hypotheses. Dairy and soy, once proposed as reproductive toxicants, have not been consistently related to poor fertility. In fact, soy and soy supplements appear to exert a beneficial effect among women undergoing infertility treatment. Similarly, because data from large, high-quality studies continue to accumulate, the evidence of a potentially deleterious effect of moderate alcohol and caffeine intake on the ability to become pregnant seems less solid than it once did. While a complete picture of the role of nutrition on fertility is far from complete, much progress has been made. The most salient gaps in the current evidence include jointly considering female and male diets and testing the most consistent findings in randomized trials.

Association between preconception maternal beverage intake and in vitro fertilization outcomes.

OBJECTIVE: To study whether maternal intake of beverage type affects IVF outcomes. DESIGN: A prospective study. SETTING: Tertiary, university-affiliated center. PATIENT(S): Three hundred forty women undergoing IVF from 2014 through 2016 for infertility as well as for pregenetic diagnosis for autosomal recessive diseases were enrolled during ovarian stimulation and completed a questionnaire describing their usual beverage consumption. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): IVF outcomes were abstracted from medical records. Total caffeine intake was estimated by summing the caffeine content for specific beverages multiplied by frequency of intake. Associations between specific types of beverages and IVF outcomes were analyzed using Poisson and logistic regression models adjusting for possible confounders. RESULT(S): Higher intake of sugared soda was associated with lower total, mature, and fertilized oocytes and top-quality embryos after ovarian stimulation. Women who consumed sugared soda had, on average, 1.1 fewer oocytes retrieved, 1.2 fewer mature oocytes retrieved, 0.6 fewer fertilized oocytes, and 0.6 fewer top-quality embryos compared with women who did not consume sugared soda. Furthermore, compared with women who did not drink sugared soda, the adjusted difference in percent of cycles resulting in live birth for women consuming 0.1-1 cups/day and >1 cup/day were -12% and -16%, respectively. No associations were found between consumption of coffee, caffeine, or diet sodas and IVF outcome. CONCLUSION(S): Sugared beverages, independent of their caffeine content, may be a bigger threat to reproductive success than caffeine and caffeinated beverages without added sugar.

Folate, homocysteine and the ovarian cycle among healthy regularly menstruating women.

STUDY QUESTION: How are concentrations of plasma homocysteine and serum folate associated with reproductive hormones and anovulation in regularly menstruating women? SUMMARY ANSWER: Higher homocysteine was associated with sporadic anovulation and hormonal changes that may be indicative of impaired ovulatory function, but higher serum folate was associated only with higher luteal phase progesterone. WHAT IS KNOWN ALREADY: Higher folate levels as well as some variants in genes relevant to one-carbon metabolism, are associated with improved reproductive outcomes and responses to fertility treatment, but only a few small studies have explored the relationship between markers of one-carbon metabolism and menstrual cycle characteristics. STUDY DESIGN, SIZE, DURATION: The BioCycle Study (2005-2007) is a prospective, longitudinal cohort of 259 regularly menstruating women not using hormonal contraceptives or dietary supplements who were followed for up to two menstrual cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum folate and reproductive hormones were measured up to eight times per cycle and plasma homocysteine up to three times. Linear mixed models were used to estimate associations between serum folate or plasma homocysteine and log-transformed reproductive hormone levels while accounting for multiple observations and cycles per woman. Generalized estimating equations were used to examine risk of sporadic anovulation. All models were adjusted for age, race, body mass index, cigarette and alcohol use, and energy and fiber intake. MAIN RESULTS AND THE ROLE OF CHANCE: Higher plasma homocysteine concentrations were associated with lower total estradiol across the cycle (adjusted percent change per unit increase in homocysteine [aPC] -2.3%, 95% CI: -4.2, -0.03), higher follicle stimulating hormone around the time of expected ovulation (aPC 2.4%, 95% CI: 0.2, 4.7) and lower luteal phase progesterone (aPC -6.5%, 95% CI: -11.1, -1.8). Higher serum folate concentrations were associated with higher luteal phase progesterone (aPC per unit increase in folate 1.0%, 95% CI: 0.4, 1.6). Higher homocysteine concentrations at expected ovulation were associated with a 33% increased risk of sporadic anovulation. We observed no risk associated with decreased folate concentrations, but a higher ratio of folate to homocysteine at ovulation was associated with a 10% decreased risk of anovulation. LIMITATIONS, REASONS FOR CAUTION: Our results are generalizable to healthy women with adequate serum folate levels. The independent influence of homocysteine should be confirmed in larger cohorts and among women with folate deficiency or increased risks of anovulation. WIDER IMPLICATIONS OF THE FINDINGS: If these findings are confirmed, it is possible that lowering homocysteine with B-vitamins through diet or supplementation could improve ovulatory function in some women. Study FUNDING/COMPETING INTEREST(S): This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (Contract numbers: HHSN275200403394C, HHSN275201100002I and Task one HHSN27500001). None of the authors has any conflicts of interest to disclose.

Coenzyme Q10 Intake From Food and Semen Parameters in a Subfertile Population.

OBJECTIVE: To assess the association between coenzyme Q10 (CoQ10) intake from food sources and semen quality. We assessed this association in a prospective cohort of men attending a fertility clinic. CoQ10 supplementation has been associated with improvements in semen parameters. However, the impact of CoQ10 intake from food sources on semen quality has not been investigated. MATERIALS AND METHODS: Subfertile couples seeking fertility evaluation at the Massachusetts General Hospital Fertility Center were invited to participate in an ongoing study of environmental factors and fertility. In total, 211 male participants completed a validated food frequency questionnaire and provided 476 semen samples. Multivariable linear mixed models were used to examine the relation between CoQ10 intake from food and semen parameters while adjusting for potential confounders and accounting for within-person correlations. RESULTS: Mean dietary CoQ10 intake was 19.2 mg/day (2.4-247.2 mg/day). No subjects were taking CoQ10 supplements. There were no associations between dietary CoQ10 intake from food and conventional semen parameters. The adjusted mean difference (95% confidence interval) comparing men in the top and bottom quartiles of CoQ10 intake from food were -3.1 mil/mL (95% confidence interval -29.5, 38.8 mil/mL) for sperm concentration, -4.5% (-15.1%, 6.0%) for total motility, -1.3% for progressive motility (-8.4%, 5.7%), and 0.3% (-1.4%, 2.0%) for sperm morphology. CONCLUSION: CoQ10 intake from food was not related to semen parameters among subfertile men. Mean dietary intake of CoQ10 in this study was 10-fold lower than the supplemental dose used in clinical trials showing improved sperm motility. CoQ10 intake from food alone may be insufficient to optimize semen parameters.

Serum 25-hydroxyvitamin D concentrations and treatment outcomes of women undergoing assisted reproduction.

BACKGROUND: Vitamin D deficiency impairs fertility in animal models, but the role of vitamin D in human fertility or treatment of infertility is less clear. OBJECTIVE: We examined the association between circulating 25-hydroxyvitamin D [25(OH)D] concentrations and the outcome in women undergoing assisted reproduction technologies (ARTs). DESIGN: We randomly selected 100 women undergoing infertility treatment with ART enrolled in an ongoing prospective cohort study who underwent 168 treatment cycles. Serum 25(OH)D concentrations were measured in samples collected from women between days 3 and 9 of gonadotropin treatment. Generalized linear mixed models were used to evaluate the association of 25(OH)D concentrations with ART outcomes while adjusting for potential confounders and accounting for repeated treatment cycles per woman. RESULTS: Median (range) serum 25(OH)D concentrations were 86.5 (33.5-155.5) nmol/L. Ninety-one percent of participants consumed multivitamins. Serum 25(OH)D concentrations were positively related to fertilization rate. The adjusted fertilization rate for women in increasing quartiles of serum 25(OH)D were 0.62 (95% CI: 0.51, 0.72), 0.53 (95% CI: 0.43, 0.63), 0.67 (95% CI: 0.56, 0.76), and 0.73 (95% CI: 0.63, 0.80), respectively (P-trend = 0.03). This association persisted when analyses were restricted to women with serum 25(OH)D between 50 and 125 nmol/L when models were further adjusted for season of blood draw and when analyses were restricted to the first treatment cycle. However, 25(OH)D concentrations were unrelated to probability of pregnancy (P-trend = 0.83) or live birth after ART (P-trend = 0.47). CONCLUSION: Vitamin D may be associated with higher fertilization rates, but this apparent benefit does not translate into higher probability of pregnancy or live birth. This trial was registered at www.clinicaltrials.gov as NCT00011713.

Soy Intake Modifies the Relation Between Urinary Bisphenol A Concentrations and Pregnancy Outcomes Among Women Undergoing Assisted Reproduction.

CONTEXT: Experimental data in rodents suggest that the adverse reproductive health effects of bisphenol A (BPA) can be modified by intake of soy phytoestrogens. Whether the same is true in humans is not known. OBJECTIVE: The purpose of this study was to evaluate whether soy consumption modifies the relation between urinary BPA levels and infertility treatment outcomes among women undergoing assisted reproduction. SETTING: The study was conducted in a fertility center in a teaching hospital. DESIGN: We evaluated 239 women enrolled between 2007 and 2012 in the Environment and Reproductive Health (EARTH) Study, a prospective cohort study, who underwent 347 in vitro fertilization (IVF) cycles. Participants completed a baseline questionnaire and provided up to 2 urine samples in each treatment cycle before oocyte retrieval. IVF outcomes were abstracted from electronic medical records. We used generalized linear mixed models with interaction terms to evaluate whether the association between urinary BPA concentrations and IVF outcomes was modified by soy intake. MAIN OUTCOME MEASURE: Live birth rates per initiated treatment cycle were measured. RESULTS: Soy food consumption modified the association of urinary BPA concentration with live birth rates (P for interaction = .01). Among women who did not consume soy foods, the adjusted live birth rates per initiated cycle in increasing quartiles of cycle-specific urinary BPA concentrations were 54%, 35%, 31%, and 17% (P for trend = .03). The corresponding live birth rates among women reporting pretreatment consumption of soy foods were 38%, 42%, 47%, and 49% (P for trend = 0.35). A similar pattern was found for implantation (P for interaction = .02) and clinical pregnancy rates (P for interaction = .03) per initiated cycle, where urinary BPA was inversely related to these outcomes among women not consuming soy foods but unrelated to them among soy consumers. CONCLUSION: Soy food intake may protect against the adverse reproductive effects of BPA. As these findings represent the first report suggesting a potential interaction between soy and BPA in humans, they should be further evaluated in other populations.

Dietary folate and reproductive success among women undergoing assisted reproduction.

OBJECTIVE: To prospectively evaluate the associations of folate with assisted reproductive technology outcomes within a population in the United States. METHODS: This analysis included women (n=232) in a prospective cohort study at the Massachusetts General Hospital Fertility Center. Diet was assessed before assisted reproductive technology treatment using a validated food frequency questionnaire. Intermediate and clinical endpoints of assisted reproductive technology were abstracted from medical records. Generalized linear mixed models with random intercepts to account for multiple cycles per woman were used to evaluate the association of folate intake with assisted reproductive technology outcomes adjusting for calorie intake, age, body mass index, race, smoking status, infertility diagnosis, and protocol type. RESULTS: Among the 232 women (median age 35.2 years, median folate intake 1,778 micrograms/day), higher folate intake was associated with higher rates of implantation, clinical pregnancy, and live birth. The adjusted percentage (95% confidence interval [CI]) of initiated assisted reproductive technology cycles resulting in a live birth for women in increasing quartiles of folate intake were 30% (95% CI 21-42%), 47% (95% CI 35-59%), 42% (95% CI 30-35%) and 56% (95% CI 43-67%) (P for trend=0.01). Live birth rates were 20% (95% CI 8-31%) higher among women in the highest quartile of supplemental folate intake (more than 800 micrograms/day) than among women in the lowest quartile (less than 400 micrograms/day). Higher supplemental folate intake was associated with higher fertilization rates and lower cycle failure rates before embryo transfer (P for trend=0.03 and 0.02). CONCLUSION: Higher intake of supplemental folate was associated with higher live birth rates after assisted reproductive technology treatment. LEVEL OF EVIDENCE: : II.