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.

Associations between weight discrimination and the use of potentially harmful dietary supplements during the COVID-19 pandemic in the United States.

The dietary supplements industry disproportionately markets potentially harmful products promising weight loss, cleansing/detoxing, and boosted energy and immunity to women. The COVID-19 pandemic heightened consumer concerns around health and body weight, which may have increased women's risks of using supplements, particularly if they had a higher weight and experienced weight discrimination. This study aimed to estimate inequities in prevalence and change in use of weight-loss, cleanse/detox, immunity, and energy supplements in the first year of the pandemic and to assess the extent to which the relationship between weight and supplement use differs across discrimination experiences. We drew upon longitudinal data from cisgender women in the U.S. COVID-19 Pandemic Substudy of the Nurses' Health Study II and 3 and Growing Up Today Study cohorts, collected over 5 waves from April/May 2020 to April 2021 (N = 51,814). Modified Poisson generalized estimating equation models, adjusted for age, cohort, race/ethnicity, wave, and Census region, estimated the relative excess risk due to interaction (RERI) between weight status and weight discrimination on prevalence of supplement use. Weight status categories were derived from body mass index (BMI), and weight discrimination was assessed using the attributions item of the Everyday Discrimination Scale. Baseline prevalence of supplement use was 2.7% for weight-loss, 3.3% for cleanse/detox, 4.2% for energy, and 22.6% for immune. Respondents with BMIs of 25-29.9 kg/m2 and 30-34.9 kg/m2 who experienced weight discrimination had RERI values of 0.89 (95% CI 0.14, 1.65) and 1.00 (95% CI 0.25, 1.75) for weight-loss and 0.57 (95% CI 0.13, 1.02) and 0.60 (95% CI 0.19, 1.01) for energy supplements, respectively, indicating this group had excess risk of use compared to lower BMI respondents who experienced no weight discrimination. The findings demonstrate the disproportionate impact of weight discrimination on use of potentially harmful supplements among cisgender women with higher weights during the pandemic.

Financial precarity, food insecurity, and psychological distress prospectively linked with use of potentially dangerous dietary supplements during the pandemic in the US.

Introduction: Supplements sold with claims to promote weight loss, cleansing/detoxing, increased energy, or boosted immunity can be dangerous, and consumers experiencing extreme stressors may be especially vulnerable to deceptive claims. The purpose of our study was to investigate associations of financial strain and psychological distress during the COVID-19 pandemic with use of supplements sold for weight loss, cleanse/detox, energy, or immunity. Methods: We used repeated-measures data gathered over five survey waves from April/May 2020-April 2021 from the COVID-19 Substudy (N = 54,951), within three prospective US national cohorts (Nurses' Health Study 2, Nurses' Health Study 3, and Growing Up Today Study), to investigate longitudinal associations between financial strain and psychological distress and risk of use of potentially dangerous types of supplements. Surveys assessed use of supplements prior to and during the first year of the pandemic, as well as financial precarity, food insecurity, depressive and anxiety symptoms, perceived stress, and daily hassles. We fit sociodemographic-adjusted modified Poisson GEE models to estimate risk ratios (RRs) and 95% confidence intervals (CIs) for associations between baseline or lagged time-varying predictors and prevalent or incident (i.e., new-onset) use of each supplement type. Results: At baseline in April/May 2020, soon after pandemic onset, current use of supplement types was: weight loss 2.7%; cleanse/detox 3.2%; energy 4.4%; immune 22.6%. By the end of the study period, cumulative incidence was: weight loss 3.5%; cleanse/detox 3.7%; energy 4.5%; immune 21.3%. In prevalent-use analyses, financial precarity, food insecurity, and psychological distress were associated with up to 2.4 times the risk of use of these types of supplements across the study period. Similarly, in incident-use analyses, financial precarity and psychological distress were associated with up to 2.1 times the risk of initiating use; whereas, high food insecurity was associated with nearly 1.8 times higher risk of onset of weight-loss supplements use but was not associated with onset of use of other types of supplements. Discussion: We found consistent evidence that during the first year of the pandemic, participants experiencing elevated financial strain and psychological distress were at heightened risk of initiating use of potentially dangerous types of supplements. Our findings raise concerns about deceptive claims about the safety and product effectiveness by manufacturers of these supplements to profit from vulnerable consumers during the pandemic.

Habitual coffee consumption and subsequent risk of type 2 diabetes in individuals with a history of gestational diabetes - a prospective study.

BACKGROUND: Females with a history of gestational diabetes mellitus (GDM) are at higher risk of developing type 2 diabetes mellitus (T2D) later in life. OBJECTIVE: This study prospectively examined whether greater habitual coffee consumption was related to a lower risk of T2D among females with a history of GDM. METHODS: We followed 4522 participants with a history of GDM in the NHS II for incident T2D between 1991 and 2017. Demographic, lifestyle factors including diet, and disease outcomes were updated every 2-4 y. Participants reported consumption of caffeinated and decaffeinated coffee on validated FFQs. Fasting blood samples were collected in 2012-2014 from a subset of participants free of diabetes to measure glucose metabolism biomarkers (HbA1c, insulin, C-peptide; n = 518). We used multivariable Cox regression models to calculate adjusted HRs and 95% CIs for the risk of T2D. We estimated the least squares mean of glucose metabolic biomarkers according to coffee consumption. RESULTS: A total of 979 participants developed T2D. Caffeinated coffee consumption was inversely associated with the risk of T2D. Adjusted HR (95% CI) for ≤1 (nonzero), 2-3, and 4+ cups/d compared with 0 cup/d (reference) was 0.91 (0.78, 1.06), 0.83 (0.69, 1.01), and 0.46 (0.28, 0.76), respectively (P-trend = 0.004). Replacement of 1 serving/d of sugar-sweetened beverage and artificially sweetened beverage with 1 cup/d of caffeinated coffee was associated with a 17% (risk ratio [RR] = 0.83, 95% CI: 0.75, 0.93) and 9% (RR = 0.91, 95% CI: 0.84, 0.99) lower risk of T2D, respectively. Greater caffeinated coffee consumption was associated with lower fasting insulin and C-peptide concentrations (all P-trend <0.05). Decaffeinated coffee intake was not significantly related to T2D but was inversely associated with C-peptide concentrations (P-trend = 0.003). CONCLUSIONS: Among predominantly Caucasian females with a history of GDM, greater consumption of caffeinated coffee was associated with a lower risk of T2D and a more favorable metabolic profile.

A prospective analysis of red blood cell membrane polyunsaturated fatty acid levels and risk of non-Hodgkin lymphoma.

Published studies report inconsistent associations of polyunsaturated fatty acid (PUFA) intake with non-Hodgkin lymphoma (NHL) risk. We conducted a nested case-control study in Nurses' Health Study and Health Professionals Follow-Up Study participants to evaluate a hypothesis of inverse association of pre-diagnosis red blood cell (RBC) membrane PUFA levels with risk of NHL endpoints. We confirmed 583 NHL cases and matched 583 controls by cohort/sex, age, race and blood draw date/time. We estimated odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL endpoints using logistic regression. RBC PUFA levels were not associated with all NHL risk; cis 20:2n-6 was associated with follicular lymphoma risk (OR [95% CI] per one standard deviation increase: 1.35 [1.03-1.77]), and the omega-6/omega-3 PUFA ratio was associated with diffuse large B-cell lymphoma risk (2.33 [1.23-4.43]). Overall, PUFA did not demonstrate a role in NHL etiology; the two unexpected positive associations lack clear biologic explanations.

Pre-pregnancy fat intake in relation to hypertensive disorders of pregnancy.

BACKGROUND: Many studies have linked intakes of fat and of specific fatty acids during pregnancy with preeclampsia; however, information on the association of intake before pregnancy with hypertensive disorders of pregnancy (HDP) is scant. OBJECTIVES: We evaluated the associations of intakes of major and specific types of fat before pregnancy with the risks of HDP, including preeclampsia and gestational hypertension (GHTN). METHODS: We followed 11,535 women without chronic disease participating in the Nurses' Health Study II from 1991 and 2009. Pre-pregnancy dietary fat was assessed by an FFQ. Intakes of total fat, saturated fat, trans fatty acid (TFA), MUFAs, PUFAs, and fat subtypes (omega-3 and omega-6) were categorized into quintiles of intake. HDP were self-reported. The RRs (95% CIs) of HDP were estimated by log-binomial generalized estimating equation regression models, with an exchangeable correlation matrix to account for repeated pregnancies while adjusting for potential confounders. RESULTS: During 19 years of follow-up, there were 495 cases of preeclampsia (2.9%) and 561 (3.3%) cases of GHTN in 16,892 singleton pregnancies. The mean age at pregnancy was 34.6 years (SD, 3.9 years). Among major fat types, only pre-pregnancy TFA was related to a higher risk of HDP (RR, 1.32; 95% CI: 1.05-1.66), and only for preeclampsia (RR, 1.50; 95% CI: 1.07-2.10) but not for GHTN (RR, 1.21; 95% CI: 0.87-1.70). Among specific types of PUFAs, intake of arachidonic acid was positively related with GHTN (RR, 1.43; 95% CI: 1.00-2.04) but not preeclampsia (RR, 1.08; 95% CI: 0.75-1.57). In analyses restricted to pregnancies 1 year after the diet assessment, women with the highest intake of long-chain omega-3 fatty acids had a 31% lower risk of HDP (95% CI: 3%-51%), which was driven by preeclampsia (RR, 0.55; 95% CI: 0.33-0.92). CONCLUSIONS: Pre-pregnancy intakes of total fat, saturated fat, and MUFA were unrelated to HDP, whereas TFA was positively related to HDP. These findings highlight the importance of ongoing efforts to eliminate TFA from the global food supply.

Prenatal Diet as a Modifier of Environmental Risk Factors for Autism and Related Neurodevelopmental Outcomes.

PURPOSE OF REVIEW: Environmental chemicals and toxins have been associated with increased risk of impaired neurodevelopment and specific conditions like autism spectrum disorder (ASD). Prenatal diet is an individually modifiable factor that may alter associations with such environmental factors. The purpose of this review is to summarize studies examining prenatal dietary factors as potential modifiers of the relationship between environmental exposures and ASD or related neurodevelopmental outcomes. RECENT FINDINGS: Twelve studies were identified; five examined ASD diagnosis or ASD-related traits as the outcome (age at assessment range: 2-5 years) while the remainder addressed associations with neurodevelopmental scores (age at assessment range: 6 months to 6 years). Most studies focused on folic acid, prenatal vitamins, or omega-3 fatty acids as potentially beneficial effect modifiers. Environmental risk factors examined included air pollutants, endocrine disrupting chemicals, pesticides, and heavy metals. Most studies took place in North America. In 10/12 studies, the prenatal dietary factor under study was identified as a significant modifier, generally attenuating the association between the environmental exposure and ASD or neurodevelopment. Prenatal diet may be a promising target to mitigate adverse effects of environmental exposures on neurodevelopmental outcomes. Further research focused on joint effects is needed that encompasses a broader variety of dietary factors, guided by our understanding of mechanisms linking environmental exposures with neurodevelopment. Future studies should also aim to include diverse populations, utilize advanced methods to optimize detection of novel joint effects, incorporate consideration of timing, and consider both synergistic and antagonistic potential of diet.

Dietary patterns are associated with improved ovarian reserve in overweight and obese women: a cross-sectional study of the Lifestyle and Ovarian Reserve (LORe) cohort.

BACKGROUND: Growing evidence suggests that adherence to certain dietary patterns is associated with improved fecundity and reproductive outcomes in the general population and infertile couples assisted reproductive treatments. The objective of this study was to assess if dietary patterns are associated with ovarian reserve in reproductive age women without a history of infertility. METHODS: This was a cross-sectional study of 185 women in the Lifestyle and Ovarian Reserve (LORe) cohort. Women aged 18-44 without a history of infertility were recruited from the local community at an academic medical center. Subjects completed validated food frequency and physical activity questionnaires to assess patterns over the year prior to presentation. Dietary patterns including a Western (including meat, refined carbohydrates, high-calorie drinks), prudent (including fruits, vegetables, olive oil and nuts), fertility (lower intake of trans fat with higher intake of monounsaturated fatty acids, increased intake of plant based protein, high-fat dairy, lower glycemic load carbohydrates and supplemental iron) and profertility diet (PFD) (characterize by whole grains, soy and seafood, low pesticide residue produce, supplemental folic acid, B12 and vitamin D) were identified through principal component analysis. Main outcome measures were serum antimullerian hormone concentration (AMH) (ng/mL) and antral follicle count (AFC) obtained by transvaginal ultrasound. RESULTS: After stratifying by BMI, adjusting for age, smoking and physical activity, dietary patterns were not associated with ovarian reserve in normal weight women. Increased adherence to a profertility diet in overweight and obese women (BMI ≥ 25 kg/m2) was associated with a significantly higher AMH. Women in the third and fourth quartiles of PFD adherence had a mean AMH concentration of 1.45 ng/mL (95%CI 0.33-2.56, p = 0.01) and 1.67 ng/mL (95%CI 0.60-2.74, p = 0.003) higher than women in the lowest quartile respectively. The highest adherence to PFD was also associated with a higher AFC in women with a BMI ≥ 25 kg/m2 (ß = 7.8, 95%CI 0.003-15.34, p < 0.05). Other common dietary patterns were not significantly associated with ovarian reserve. CONCLUSIONS: Increased adherence to a profertility diet is associated with improved markers of ovarian reserve in overweight and obese women. These findings provide novel insight on potential modifiable lifestyle factors associated with ovarian reserve.

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.

Paternal adherence to healthy dietary patterns in relation to sperm parameters and outcomes of assisted reproductive technologies.

OBJECTIVE: To investigate whether men's adherence to dietary patterns promoted for the prevention of cardiovascular disease is associated with semen parameters and couples' assisted reproductive technology (ART) outcomes. DESIGN: Prospective cohort study. SETTING: Fertility center at an academic medical center. PATIENT(S): A total of 245 men and their female partners who underwent 438 ART cycles between 2007 and 2020. INTERVENTION(S): Male pretreatment dietary intake was assessed with a 131-item food frequency questionnaire from which we calculated eight a priori defined scores: Trichopoulou Mediterranean, Alternate Mediterranean, Panagiotakos Mediterranean, Healthy Eating Index, Alternative Healthy Eating Index, American Heart Association, Dietary Approaches to Stop Hypertension, and Plant-based. MAIN OUTCOME MEASURE(S): The primary outcome was live births per treatment cycle. The secondary outcomes were fertilization, implantation, and clinical pregnancy and seminogram parameters. RESULT(S): There was an inverse association between greater adherence by men to the Panagiotakos Mediterranean diet and the American Heart Association dietary pattern and lower fertilization rate. However, there were no significant associations between men's adherence to any of the analyzed dietary patterns and the probabilities of implantation, clinical pregnancy, or live birth in multivariable-adjusted models. No significant differences in any of the semen parameters were found between participants of the lowest quartile and those of the highest quartile of the eight dietary patterns. CONCLUSION(S): These findings suggest that men's adherence to several a priori defined dietary scores with documented cardiovascular benefits is not related to major outcomes of infertility treatment with ART or semen quality.

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.

Hair mercury levels, intake of omega-3 fatty acids and ovarian reserve among women attending a fertility center.

OBJECTIVE: To investigate the association of hair mercury (Hg) levels with antral follicle count (AFC), as a marker of ovarian reserve, and evaluate whether this relationship differed among women with high vs. low total intake of long chain omega-3 polyunsaturated fatty acids (n3PUFA) from foods and supplements. DESIGN: We included 353 women attending an academic fertility center (2007-2019) who had data on hair Hg levels, total n3PUFA intake, and AFC. METHODS: Hair Hg levels were assessed using a Direct Mercury Analyser, total n3PUFA intake was estimated using an extensively validated food frequency questionnaire, and AFC was assessed by transvaginal ultrasonography. Poisson regression models adjusted for potential confounders were used to evaluate the association of hair Hg levels (divided into tertiles, and as above vs below EPA reference (1 ppm)) with AFC. Associations were also evaluated after stratification by median n3PUFA intake (≤0.124% vs. >0.125% calories/week). RESULTS: Women's median hair Hg level was 0.60 ppm (range = 0.001-8.60 ppm), with more than 30% > 1 ppm (EPA reference level). Hair Hg was positively related to AFC after adjusting for age, BMI, smoking status, infertility diagnosis, and alcohol intake. However, associations became attenuated after adjustment for intake of total n3PUFA. The positive associations of hair Hg and AFC were observed only among women above the median total n3PUFA intake. Specifically, women who consumed >0.125% calories/week of total n3PUFA had mean AFCs of 11.9, 13.2 and 14.1, respectively, across increasing tertiles of hair Hg (p,trend = 0.004). Similar results were found when hair Hg was divided above vs below EPA reference (mean AFC = 12.7 vs. 14.1, p = 0.008). CONCLUSIONS: In these women, positive associations of hair Hg with AFC may be reflective of beneficial effects of n3PUFA on ovarian reserve rather than a beneficial effect of Hg per se. Our findings highlight the importance of considering diet when exploring Hg effects on women's reproductive health in urban settings.

Associations of Fish Oil Supplement Use With Testicular Function in Young Men.

Importance: Many young men have poor semen quality, and the causes are often unknown. Supplement intake of ω-3 polyunsaturated fatty acid has been found to improve semen quality among men with infertility, but the association with semen quality among healthy men is unknown. Objective: To determine if intake of ω-3 fatty acid supplements is associated with testicular function as measured by semen quality and reproductive hormone levels among healthy men. Design, Setting, and Participants: This cross-sectional study included young Danish men from the general population recruited between January 1, 2012, and December 31, 2017, at compulsory examinations to determine their fitness for military service. Young unselected men were approached after the examination and invited to participate in a study of reproductive function, regardless of their fitness for military service. Data analysis was conducted from September 1, 2018, to June 30, 2019. Exposures: Intake of supplements, including fish oil, during the past 3 months. Main Outcomes and Measures: Semen quality, measured as volume, concentration, total sperm count, percentage of morphologically normal spermatozoa, and motility, and serum reproductive hormone levels, measured as follicle-stimulating hormone, luteinizing hormone, testosterone, free testosterone, and inhibin B levels. Results: Among 1679 young Danish men (median [interquartile range] age, 18.9 [18.7-19.4] years) recruited to participate, 98 men (5.8%) reported use of fish oil supplements during the past 3 months, of whom 53 (54.1%) reported intake on 60 or more days. After adjustment and compared with men with no supplement intake, men with fish oil supplement intake on fewer than 60 days had semen volume that was 0.38 (95% CI, -0.03 to 0.80) mL higher, and men with fish oil supplement intake on 60 or more days had semen volume that was 0.64 (95% CI, 0.15 to 1.12) mL higher (P for trend < .001). Similarly, testicular size in men with supplement intake on fewer than 60 days was 0.8 (95% CI, -0.2 to 1.9) mL larger and in men with fish oil supplement intake on 60 or more days was 1.5 (95% CI, 0.2 to 2.8) mL larger compared with men with no supplement intake (P for trend = .007). After adjustment, men with fish oil supplement intake had a 20% (95% CI, 9%-31%) lower follicle-stimulating hormone level and 16% (95% CI, 8%-24%) lower luteinizing hormone level compared with men with no supplement intake. There were no associations of intake of other supplements with measures of testicular function. Conclusions and Relevance: These findings suggest that intake of fish oil supplements was associated with better testicular function, which is less likely to be due to confounding by indication, as no associations of intake of other supplements with testicular function were found. This cross-sectional study did not examine the actual content of ω-3 fatty acids in the supplements; therefore, these findings need confirmation in well-designed randomized clinical trials among unselected men.

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.

Intake of Antioxidants in Relation to Infertility Treatment Outcomes with Assisted Reproductive Technologies.

BACKGROUND: Randomized trials of supplementation with antioxidant mixtures during infertility treatment show no benefit on pregnancy or live birth rate. However, the roles of individual antioxidants are poorly understood. We examined the association of baseline intake of vitamins A, C, E, and carotenoids with outcomes of assisted reproductive technologies (ARTs). METHODS: We followed 349 women undergoing a total of 588 ART cycles for infertility treatment at the Massachusetts General Hospital. We assessed antioxidant intakes from food and supplements before treatment using a validated food frequency questionnaire. We used generalized linear mixed models to account for multiple ART cycles per woman while adjusting for confounding. RESULTS: Mean (SD) age and body mass index were 35.1 years (4.0 years) and 24.1 kg/m (4.3 kg/m), respectively. Total intake of vitamins A, C, and E was not associated with the probability of live birth. Women in the highest intake category of ß-carotene from foods had a lower probability of live birth than women in the lowest intake quartile (50% vs. 22%; P trend = 0.03); for lutein and zeaxanthin, the probability for the highest intake group was 44% vs. 28% for the lowest. Intake of ß-carotene from supplements and intakes of retinol and all other carotenoids were unrelated to live birth rates. CONCLUSIONS: We found unexpected inverse associations of ß-carotene intake from foods and of lutein and zeaxanthin intake with live birth rates. Within the observed intake ranges, total consumption of vitamins A, C, and E before starting infertility treatment with ART was not associated with live birth rates.