RESUMO
OBJECTIVE: To examine whether semen parameters are associated with live birth among couples seeking infertility treatment after accounting for semen parameter variability. DESIGN: Folic Acid and Zinc Supplementation Trial (FAZST) prospective cohort. SETTING: Four US reproductive endocrinology and infertility care study centers, 2013-2017. PATIENT(S): Couples (n = 2,369) seeking fertility consultations at 4 US infertility care study centers. INTERVENTION(S): Semen volume, pH, sperm viability, morphology, progressive and total motility, concentration, count, and total and progressive motile count assessed at baseline and at 2, 4, and 6 months after enrollment. MAIN OUTCOME MEASURE(S): Log-binomial models stratified by fertility treatment received (in vitro fertilization [IVF], intrauterine insemination [IUI], ovulation induction [OI], or no treatment) estimated risk differences (RDs) between semen parameter quartiles and live birth and accounted for multiple semen assessments per person. We accounted for abstinence time, the biological interdependence of semen parameters, and potential selection bias because of loss to follow-up. RESULT(S): Among couples using OI only or no treatment, 39% had a live birth, and relative to the highest quartile, the lowest quartiles of morphology (RD, -19 [95% CI, -23 to -15] per 100 couples), motility (RD, -13 [95% CI, -17 to -9]), concentration (RD, -22 [95% CI, -26 to -19]), and total motile count (RD, -18 [95% CI, -22 to -14]) were associated with fewer live births. For IUI, 26% had a live birth, and the lowest quartiles of volume (RD, -6 [95% CI, -11 to -0.4]), concentration (RD, -6 [95% CI, -11 to -0.1]), count (RD, -10 [95% CI, -15 to -4]), and total motile count (RD, -7 [95% CI, -13 to -1]) were associated with fewer live births. For IVF, 61% had a live birth, and only morphology (Q1 RD, -7 [95% CI, -14 to 0.2]; Q2 RD, -10 [95% CI, -17 to -2.2]) was associated with live birth. CONCLUSION(S): Semen parameters are critical in couples undergoing OI/IUI. Only low morphology was important for live birth after IVF. Although data supporting the use of semen parameters are fragmented across differing populations, current findings are generalizable across the range of male fertility and couple fertility treatments, providing evidence about which semen parameters are most relevant in which settings. CLINICAL TRIAL REGISTRATION NUMBER: NCT#01857310.
Assuntos
Infertilidade Masculina , Nascido Vivo , Feminino , Humanos , Masculino , Gravidez , Ácido Fólico , Infertilidade Masculina/terapia , Infertilidade Masculina/tratamento farmacológico , Taxa de Gravidez , Estudos Prospectivos , Sêmen , Zinco/uso terapêuticoRESUMO
OBJECTIVE: To determine if 6-month folic acid (5 mg) and zinc (30 mg) supplementation impacts sperm DNA methylation patterns. DESIGN: A multicenter, double-blind, block randomized, placebo-controlled trial titled "The Folic Acid and Zinc Supplementation Trial (FAZST)." SETTING: Infertility care centers. PATIENT(S): Male partners (18 years and older) from heterosexual couples (female partners aged 18-45 years) seeking fertility treatment were recruited. INTERVENTION(S): Men were randomized 1:1 to receive folic acid (5 mg) and elemental zinc (30 mg) (n = 713) or a matching placebo (n = 757) daily for 6 months. MAIN OUTCOME MEASURE(S): Sperm DNA methylation was analyzed using the EPIC methylation array (Illumina) at 6 months. Differential sperm DNA methylation was assessed at multiple levels (regional, single cytosine phosphate guanine, etc.). We additionally assessed the impact of supplementation on epigenetic age. RESULT(S): No significant differences were identified between the treatment and placebo groups although some trends appeared to be present. To determine if these trends were noteworthy, we implemented various permutations and found that the patterns we identified were no more than would be expected by random chance. CONCLUSION(S): The data presented here strongly suggest that this supplementation regimen is not effective at altering sperm DNA methylation. These data comport well with previous findings from the FAZST study that found no impact of supplementation on basic semen analysis parameters or live birth. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01857310.
Assuntos
Metilação de DNA/efeitos dos fármacos , Ácido Fólico/administração & dosagem , Espermatozoides/efeitos dos fármacos , Zinco/administração & dosagem , Adolescente , Adulto , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Humanos , Recém-Nascido , Infertilidade Masculina/dietoterapia , Infertilidade Masculina/epidemiologia , Infertilidade Masculina/metabolismo , Nascido Vivo/epidemiologia , Masculino , Pessoa de Meia-Idade , Gravidez , Taxa de Gravidez , Análise do Sêmen , Espermatozoides/metabolismo , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Diet, lifestyle, and psychosocial factors might influence fertility for men and women, although evidence is mixed, and couple-based approaches are needed for assessing associations with reproductive outcomes. The Impact of Diet, Exercise, and Lifestyle (IDEAL) on Fertility Study is a prospective cohort with contemporaneous detailed follow-up of female partners of men enrolled in the Folic Acid and Zinc Supplementation Trial studying couples seeking infertility treatment (2016-2019). Follow-up of men continued for 6 months, while female partners were followed for 9 months while attempting pregnancy and throughout any resulting pregnancy (up to 18 months). Longitudinal data on diet, physical activity (including measurement via wearable device), sleep, and stress were captured at multiple study visits during this follow-up. A subset of women (IDEALplus) also completed daily journals and a body fat assessment via dual-energy x-ray absorptiometry. IDEAL enrolled 920 women, and IDEALPlus enrolled 218. We demonstrated the ability to enroll women in a prospective cohort study contemporaneous to a partner-enrolled randomized trial. In combination with data collected on male partners, IDEAL data facilitates a couple-based approach to understanding associations between lifestyle factors and infertility treatment outcomes. We describe in detail the study design, recruitment, data collection, lessons learned, and baseline characteristics.
Assuntos
Dieta/métodos , Exercício Físico/fisiologia , Fertilidade/fisiologia , Infertilidade/terapia , Estilo de Vida , Adulto , Dieta/efeitos adversos , Inquéritos sobre Dietas , Método Duplo-Cego , Feminino , Fertilização in vitro , Seguimentos , Humanos , Infertilidade/etiologia , Infertilidade/fisiopatologia , Estudos Longitudinais , Masculino , Seleção de Pacientes , Gravidez , Resultado da Gravidez , Taxa de Gravidez , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de PesquisaRESUMO
Importance: Dietary supplements marketed for male fertility commonly contain folic acid and zinc based on limited prior evidence for improving semen quality. However, no large-scale trial has examined the efficacy of this therapy for improving semen quality or live birth. Objective: To determine the effect of daily folic acid and zinc supplementation on semen quality and live birth. Design, Setting, and Participants: The Folic Acid and Zinc Supplementation Trial was a multicenter randomized clinical trial. Couples (n = 2370; men aged ≥18 years and women aged 18-45 years) planning infertility treatment were enrolled at 4 US reproductive endocrinology and infertility care study centers between June 2013 and December 2017. The last 6-month study visit for semen collection occurred during August 2018, with chart abstraction of live birth and pregnancy information completed during April 2019. Interventions: Men were block randomized by study center and planned infertility treatment (in vitro fertilization, other treatment at a study site, and other treatment at an outside clinic) to receive either 5 mg of folic acid and 30 mg of elemental zinc (n = 1185) or placebo (n = 1185) daily for 6 months. Main Outcomes and Measures: The co-primary outcomes were live birth (resulting from pregnancies occurring within 9 months of randomization) and semen quality parameters (sperm concentration, motility, morphology, volume, DNA fragmentation, and total motile sperm count) at 6 months after randomization. Results: Among 2370 men who were randomized (mean age, 33 years), 1773 (75%) attended the final 6-month study visit. Live birth outcomes were available for all couples, and 1629 men (69%) had semen available for analysis at 6 months after randomization. Live birth was not significantly different between treatment groups (404 [34%] in the folic acid and zinc group and 416 [35%] in the placebo group; risk difference, -0.9% [95% CI, -4.7% to 2.8%]). Most of the semen quality parameters (sperm concentration, motility, morphology, volume, and total motile sperm count) were not significantly different between treatment groups at 6 months after randomization. A statistically significant increase in DNA fragmentation was observed with folic acid and zinc supplementation (mean of 29.7% for percentage of DNA fragmentation in the folic acid and zinc group and 27.2% in the placebo group; mean difference, 2.4% [95% CI, 0.5% to 4.4%]). Gastrointestinal symptoms were more common with folic acid and zinc supplementation compared with placebo (abdominal discomfort or pain: 66 [6%] vs 40 [3%], respectively; nausea: 50 [4%] vs 24 [2%]; and vomiting: 32 [3%] vs 17 [1%]). Conclusions and Relevance: Among a general population of couples seeking infertility treatment, the use of folic acid and zinc supplementation by male partners, compared with placebo, did not significantly improve semen quality or couples' live birth rates. These findings do not support the use of folic acid and zinc supplementation by male partners in the treatment of infertility. Trial Registration: ClinicalTrials.gov Identifier: NCT01857310.
Assuntos
Suplementos Nutricionais , Ácido Fólico/farmacologia , Infertilidade Masculina/tratamento farmacológico , Sêmen/efeitos dos fármacos , Zinco/farmacologia , Adolescente , Adulto , Fragmentação do DNA/efeitos dos fármacos , Suplementos Nutricionais/efeitos adversos , Feminino , Fertilização in vitro , Ácido Fólico/efeitos adversos , Ácido Fólico/uso terapêutico , Humanos , Nascido Vivo , Masculino , Pessoa de Meia-Idade , Análise do Sêmen , Contagem de Espermatozoides , Falha de Tratamento , Adulto Jovem , Zinco/efeitos adversos , Zinco/uso terapêuticoRESUMO
The Folic Acid and Zinc Supplementation Trial (FAZST) was a multicenter, double-blind, block-randomized, placebo-controlled trial to determine whether folic acid and zinc supplementation in men improves semen quality and increases livebirth rate among couples seeking infertility treatment (2013-2017). Eligible men were aged 18 years or older with female partners aged 18-45 years, seeking infertility treatment. Men were randomized (1:1) to 5 mg folic acid and 30 mg elemental zinc daily or matching placebo for 6 months. Randomization was stratified by site and intended infertility treatment (in vitro fertilization (IVF), non-IVF/study site, and non-IVF/outside clinic). Follow-up of men continued for 6 months, and female partners were passively followed for a minimum of 9 months. Women who conceived were followed throughout pregnancy. Overall, 2,370 men were randomized during 2013-2017 (1,185 folic acid and zinc, 1,185 placebo); they had a mean age of 33 years and body mass index (weight (kg)/height (m)2) of 29.8. Most participants were white (82%), well educated (83% with some college), and employed (72%). Participant characteristics were balanced across intervention arms. Study visits were completed by 89%, 77%, and 75% of men at months 2, 4, and 6, respectively. Here we describe the study design, recruitment, data collection, lessons learned, and baseline participant characteristics.