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The overarching goal of this trial is to determine if an intervention comprising folic acid and zinc dietary supplementation improves semen quality and indirectly fertility outcomes (i.e., live birth rate) among couples trying to conceive and seeking assisted reproduction. The following study objectives underlie successful attainment of the overarching research goal:
Two micronutrients fundamental to the process of spermatogenesis, folic acid (folate) and zinc, are of particular interest for fertility as they are of low cost and wide availability. Though the evidence has been inconsistent, small randomized trials and observational studies show that folate and zinc have biologically plausible effects on spermatogenesis and improved semen parameters. These results support the potential benefits of folate on spermatogenesis and suggest that dietary supplementation with folate and zinc may help maintain and improve semen quality, and perhaps, fertility rates.
The Epidemiology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development intends to conduct a multi-site double-blind, randomized controlled clinical trial to evaluate the effect of folic acid and zinc dietary supplementation on semen quality and conception rates among male partners of couples seeking assisted reproduction. Randomization will be stratified (with random sequences of block sizes) by site and assisted reproduction technique (IVF, non-IVF receiving fertility treatment at a study site, and non-IVF receiving fertility treatment at a nonstudy site) to ensure that balance between the treatment groups is maintained within site and within fertility treatment type over the enrollment period.
The study is designed with a sample size of 2,400 randomized participants based on obtaining adequate power to detect meaningful differences in the live birth rate between cohorts. Since the comparison of sperm parameters are differences between continuous assay measurements, this sample size will be more than sufficient for the primary sperm parameter comparisons. Additionally, calculations were done to demonstrate adequate statistical power when stratified analysis is to be performed (i.e., sample size distributions among the strata and their corresponding live birth RRs detected at 80% statistical power, with an alpha level of 0.05 and a total sample size of 2400 couples divided among the folic acid/zinc and placebo arms of the trial).
Data collection will include screening male and female partners for eligibility, administering baseline questionnaires, and collecting biospecimens in both partners of the couple, body measurements for both partners, daily journal reporting for male partners, medical record abstraction related to required treatment and outcome data, and semen quality of four samples collected at baseline, two, four, and six months following study enrollment. A data coordinating center (DCC) will support the trial.
The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two cohorts based on the randomized assignment, both overall and by treatment strata (IVF, non-IVF receiving fertility treatment at a study site, and non-IVF receiving fertility treatment at a nonstudy site).This approach will be applied to the two primary endpoints (semen parameters and live birth rate) as well as designated secondary endpoints (number of follicles, number and proportion of oocytes fertilized).
The DCC will perform periodic safety analyses and present interim reports to the Data and Safety Monitoring Board (DSMB) as requested, during the recruitment phases of the trial. It is anticipated that safety analyses will be performed every 6-12 months. The final analysis will be performed upon completion of data collection and editing in the follow-up and close-out phase of the trial. Also one full formal interim analysis is planned and the power calculations with considerations for the choice of optimal time for the analysis have been conducted.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Folic acid and zinc supplementation | Experimental | 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. |
|
| Placebo | Placebo Comparator | Matching placebo, taken orally daily for 6 months. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 5 mg folic acid and 30 mg elemental zinc | Dietary Supplement |
| ||
| Placebo Comparator: Placebo |
| Measure | Description | Time Frame |
|---|---|---|
| Live Birth | Based on hospital delivery records | At delivery |
| Semen Volume | Volume of the ejaculate, mL Assessed utilizing the World Health Organization (WHO) semen analysis procedure 5th edition World Health Organization. WHO laboratory manual for the Examination and processing of human semen. 5th Edition ed. Switzerland: 2010. | 6 months |
| Sperm Concentration | Number of spermatozoa per unit of volume of semen Assessed utilizing the World Health Organization (WHO) semen analysis procedure 5th edition World Health Organization. WHO laboratory manual for the Examination and processing of human semen. 5th Edition ed. Switzerland: 2010. | 6 months |
| Sperm Motility | % motile (including percentage of progressive motile sperm and percentage of nonprogressive motile sperm) Assessed utilizing the World Health Organization (WHO) semen analysis procedure 5th edition World Health Organization. WHO laboratory manual for the Examination and processing of human semen. 5th Edition ed. Switzerland: 2010. | 6 months |
| Sperm Morphology | % normal morphology Assessed utilizing the World Health Organization (WHO) semen analysis procedure 5th edition World Health Organization. WHO laboratory manual for the Examination and processing of human semen. 5th Edition ed. Switzerland: 2010. | 6 months |
| DNA Fragmentation Index | Comet assay used to measure sperm DNA integrity based on excess DNA strand breaks Assessed utilizing the World Health Organization (WHO) semen analysis procedure 5th edition World Health Organization. WHO laboratory manual for the Examination and processing of human semen. 5th Edition ed. Switzerland: 2010. |
| Measure | Description | Time Frame |
|---|---|---|
| Human Chorionic Gonadotropin (hCG) Detected Pregnancy (Implantation) | A quantitative hCG evaluation in serum > 5 milli-international units per milliliter (mIU/ml) | For IVF, 12 days post embryo transfer for day 5 embryo transfers, and 14 days post embryo transfer for day 3 embryo transfers; for couples undergoing OI/IUI, after self-report of positive pregnancy test |
| Measure | Description | Time Frame |
|---|---|---|
| Reproductive Hormones and Other Measured Biomarkers | Urinary, serum, and salivary concentrations of reproductive hormones, particularly androgens, proteomic analysis of human sperm and cardiometabolic risk factors and markers of oxidative stress, as well as measures of trace elements in toenails (collected at month 4 clinic visit). Biospecimens have been collected but laboratory analysis still needs to be done to be able to evaluate these endpoints. |
Couples Inclusion Criteria:
Couples Exclusion Criteria:
Male Inclusion Criteria:
Male Exclusion Criteria:
Age <18 years.
Unwilling to abstain from use of non-study approved dietary supplements or medications containing folic acid or oral preparations containing zinc throughout the study.
Unwilling to abstain from use of testosterone supplementation throughout the study.
Diagnosis of Vitamin B12 deficiency or pernicious anemia.
Consuming a vegan diet.
A known genetic cause of male factor subfertility, including chromosomal disorders related to subfertility (e.g., Y chromosome deletions).
Males currently using and unwilling (or unable) to discontinue the following drugs known to interact with folic acid or interfere with the biosynthesis of folic acid will be excluded.
History of organ transplantation.
Physician diagnosed:
History of vasectomy without reversal, obstructive azoospermia such as Congenital Bilateral Aplasia of Vas Deferens (CBAVD), or ejaculatory duct obstruction.
Known allergy to folic acid or zinc dietary supplements.
Female Exclusion Criteria:
Age <18 or >45 years.
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| Name | Affiliation | Role |
|---|---|---|
| Enrique F. Schisterman, PhD | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Study Director |
| Sunni L. Mumford, PhD | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Study Director |
| C. Matthew Peterson, MD | University of Utah | Principal Investigator |
| Jared C. Robins, MD | Northwestern University | Principal Investigator |
| Ginny L. Ryan, MD, MA | University of Iowa | Principal Investigator |
| Bradley J. Van Voorhis, MD | University of Iowa | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Northwestern University | Chicago | Illinois | 60611 | United States | ||
| University of Iowa |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41875434 | Derived | Nobles C, Canty TP, Mendola P, Russo LM, Rabeya K, Schliep KC, Shaaban M, Singh A, Ring AM, Hemmert R, Perkins NJ, Oluwayiose OA, Peterson CM, Nowak K, Pilsner JR. Heat exposure during susceptible windows of spermatogenesis and sperm epigenetic age. Hum Reprod. 2026 Jun 1;41(6):969-980. doi: 10.1093/humrep/deag048. | |
| 39173703 | Derived |
| Label | URL |
|---|---|
| The FAZST trial home page | View source |
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Only the male partners in couples attempting to conceive were enrolled and assigned to treatment arms.
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| ID | Title | Description |
|---|---|---|
| FG000 | Folic Acid and Zinc Supplementation | 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc |
| FG001 | Placebo | Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary Analysis: Live Birth |
| |||||||||||||
| Secondary Analysis: Semen Quality at 6m |
|
Only male partners randomized to each folic acid/zinc (n = 1185) and placebo (n = 1185) arms
| ID | Title | Description |
|---|---|---|
| BG000 | Folic Acid and Zinc Supplementation | 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc |
| BG001 | Placebo | Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Male partner age, continuous |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Live Birth | Based on hospital delivery records | Complete randomized cohort | Posted | Count of Participants | Participants | At delivery |
|
Adverse events were collected over the 6 month duration of the study.
Adverse events were only collected from the male partners.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Folic Acid and Zinc Supplementation | 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Myocardial infarction | Cardiac disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal discomfort or pain | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Enrique Schisterman | NICHD | 3014356893 | schistee@mail.nih.gov |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 6, 2018 | Jul 24, 2020 | Prot_SAP_000.pdf |
Not provided
| ID | Term |
|---|---|
| D000022 | Abortion, Spontaneous |
| ID | Term |
|---|---|
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
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| ID | Term |
|---|---|
| D005492 | Folic Acid |
| ID | Term |
|---|---|
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
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| Drug |
|
| 6 months |
| Total Motile Sperm Count | Calculated as semen volume (mL) * sperm concentration (10^6 spermatozoa/mL) * motility (% motile) | 6 months |
| Clinical Intrauterine Pregnancy | Visualized gestational sac in the uterus on ultrasound | approximately 6.5 weeks gestation |
| Ectopic Pregnancy | Either visualization of no gestational sac in the uterus with a suspicious mass in the adnexa on ultrasound, an hCG level more than 1500 mIU/ml without visualization of an intrauterine gestational sac on ultrasound, or a slowly rising or plateauing serum hCG level without visualization of an intrauterine gestation on ultrasound. | approximately 6.5 weeks gestation |
| Early Pregnancy Loss | hCG pregnancy loss will be defined as a serum hCG > 5 mIU/ml followed by a decline. Clinically recognized pregnancy losses will be defined as visualization of an intrauterine gestational sac followed by a loss prior to 20 weeks gestation. | hcG-detected pregnancy until 20 weeks of pregnancy |
| Preeclampsia or Gestational Hypertension | Abstracted from hospital records and medical charts | Delivery |
| Gestational Diabetes | Abstracted from hospital records and medical charts | Delivery |
| Cesarean Delivery | Abstracted from hospital records and medical charts | Delivery |
| Preterm Delivery | Abstracted from hospital records and medical charts | Delivery |
| Small for Gestational Age | Abstracted from hospital records and medical charts | Delivery |
| Gestational Age | Abstracted from hospital records and medical charts | Delivery |
| Birth Weight | Abstracted from hospital records and medical charts | Delivery |
| Stillbirth | Loss at or after 20 weeks gestation. Determined based on hospital records and medical chart abstraction. | Delivery |
| Neonatal Mortality | Abstracted from hospital records and medical charts | Delivery |
| Major Neonatal Complications | Abstracted from hospital records and medical charts: includes bronchopulmonary dysplasia, necrotizing enterocolitis, severe intraventricular hemorrhage, periventricular leukomalacia, and retinopathy of prematurity | Delivery |
| Structural Malformations | Abstracted from birth record: includes major (n = 21; 6 with known genetic cause), minor (n = 6), and unclassified (n = 2) defects Structural birth defects: includes hydronephrosis/ureteropelvic junction obstruction, transposition of the great arteries, renal agenesis, cleft lip, club feet, multicystic/dysplastic kidney, tetralogy of fallot, gastroschisis, atrioventricular septal defects, other oral-facial defects, other cardiovascular defects, other CNS defects, other eye defects, other oral-facial defects, other anomalies, other syndromes | Delivery |
| Severe Maternal Morbidity | Abstracted from delivery record: including postpartum hemorrhage, anemia requiring transfusion, sepsis, seizure, HELLP syndrome or preeclampsia with pulmonary edema | Delivery |
| Fertilization Rate Per Cycle, % | Among participants in the IVF stratum Oocytes will be assessed 16-18 hours after insemination or microinjection to determine whether fertilization occurred. Fertilization will be considered normal if two pronuclei and two polar bodies are identified. Oocytes without visible pronuclei will be considered unfertilized. Oocytes with more than two pronuclei will be considered abnormally fertilized, and will thus be discarded. | Up to 9 months of fertility treatment post-randomization |
| Number of Good Quality Embryos on Day 5 Per Cycle | Among participants in the IVF stratum For couples who meet criteria for blastocyst culture, embryos will be graded 5 days after fertilization based on Society for Assisted Reproductive Technologies (SART) morphology criteria. | Up to 9 months of fertility treatment post-randomization |
| Percentage of Good Quality Embryos on Day 5 Per Cycle | Among participants in the IVF stratum For couples who meet criteria for blastocyst culture, embryos will be graded 5 days after fertilization based on Society for Assisted Reproductive Technologies (SART) morphology criteria. | Up to 9 months of fertility treatment post-randomization |
| Number of Embryos Transferred Per Cycle | Among participants in the IVF stratum | Up to 9 months of fertility treatment post-randomization |
| Number of Embryos Cryopreserved Per Cycle | Among participants in the IVF stratum | Up to 9 months of fertility treatment post-randomization |
| Sperm Penetration Per Cycle, % | Among participants in the IVF stratum | Up to 9 months of fertility treatment post-randomization |
| Cells on Day 3 Per Embryo Per Cycle | Among participants in the IVF stratum | Up to 9 months of fertility treatment post-randomization |
| Cells on Day 3 Per Embryo Per Cycle, Categorical | Number of cells per embryo among women in the IVF stratum | Up to 9 months of fertility treatment post-randomization |
| Cells on Day 5 Per Embryo Per Cycle, Categorical | Among participants in the IVF stratum | Up to 9 months of fertility treatment post-randomization |
| Embryo Morphology on Day 3 Per Cycle, Categorical | Among participants in the IVF stratum Embryos will be scored three days after fertilization according to the size and shape of blastomeres and to their degree of fragmentation. Veeck LL. Oocyte assessment and biological performance. Ann N Y Acad Sci 1988;541:259-74.:259-74. | Up to 9 months of fertility treatment post-randomization |
| Embryo Morphology on Day 5 Per Cycle, Categorical | Among participants in the IVF stratum For couples who meet criteria for blastocyst culture, embryos will be graded 5 days after fertilization based on Society for Assisted Reproductive Technologies (SART) morphology criteria. | Up to 9 months of fertility treatment post-randomization |
| Method of Fertilization Per Cycle | Among participants in the in vitro fertilization (IVF) stratum: method of fertilization classified into intracytoplasmic sperm injection (ICSI) and other | Up to 9 months of fertility treatment post-randomization |
| Quality of Embryos Transferred Per Cycle, Categorical | Among participants in the IVF stratum Embryonic grading based on Society for Assisted Reproductive Technologies (SART) morphology criteria | Up to 9 months of fertility treatment post-randomization |
| Chromosomal Complement of Embryo Per Cycle | Among participants in the IVF stratum Chromosomal complement in the embryo assessed using methodology cited by Rubio et al. Rubio C, Rodrigo L, Mir P et al. Use of array comparative genomic hybridization (array-CGH) for embryo assessment: clinical results. Fertil Steril 2013 March 15;99(4):1044-8. | Up to 9 months of fertility treatment post-randomization |
| 4 or 6 months |
| Iowa City |
| Iowa |
| 52242 |
| United States |
| Center for Reproductive Medicine | Minneapolis | Minnesota | 55407 | United States |
| University of Utah | Salt Lake City | Utah | 84132 | United States |
| DiTosto JD, Caniglia EC, Hinkle SN, Sealy N, Schisterman EF, Johnstone E, Mendola P, Mills J, Hotaling J, Ryan G, Mumford SL. Target trial emulation of preconception serum vitamin D status on fertility outcomes: a couples-based approach. Fertil Steril. 2025 Feb;123(2):300-312. doi: 10.1016/j.fertnstert.2024.08.332. Epub 2024 Aug 20. |
| 36192231 | Derived | DeVilbiss EA, Sjaarda LA, Peterson CM, Hotaling JM, Mills JL, Mendola P, Carrell DT, Johnstone E, Chen Z, Perkins NJ, Ryan G, Schisterman EF, Mumford SL. Longitudinal semen parameter assessments and live birth: variability and implications for treatment strategies. Fertil Steril. 2022 Nov;118(5):852-863. doi: 10.1016/j.fertnstert.2022.08.012. Epub 2022 Oct 1. |
| 34656303 | Derived | Jenkins T, Aston K, Carrell D, DeVilbiss E, Sjaarda L, Perkins N, Mills JL, Chen Z, Sparks A, Clemons T, Chaney K, Peterson CM, Emery B, Hotaling J, Johnstone E, Schisterman E, Mumford SL. The impact of zinc and folic acid supplementation on sperm DNA methylation: results from the folic acid and zinc supplementation randomized clinical trial (FAZST). Fertil Steril. 2022 Jan;117(1):75-85. doi: 10.1016/j.fertnstert.2021.09.009. Epub 2021 Oct 14. |
| 31910279 | Derived | Schisterman EF, Sjaarda LA, Clemons T, Carrell DT, Perkins NJ, Johnstone E, Lamb D, Chaney K, Van Voorhis BJ, Ryan G, Summers K, Hotaling J, Robins J, Mills JL, Mendola P, Chen Z, DeVilbiss EA, Peterson CM, Mumford SL. Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment: A Randomized Clinical Trial. JAMA. 2020 Jan 7;323(1):35-48. doi: 10.1001/jama.2019.18714. |
| NOT COMPLETED |
|
|
| BG002 | Total | Total of all reporting groups |
| Male-female couples |
|
Male partners
| Mean |
| Standard Deviation |
| years |
| Participants |
|
|
| Age, Continuous | Female partner age, continuous | Female partners | Mean | Standard Deviation | years | Participants |
|
|
| Sex: Female, Male | Count of Participants | Participants | Participants |
|
|
| Race/Ethnicity, Customized | Male partner race/ethnicity, customized | Male partners | Count of Participants | Participants | Participants |
|
|
| Race/Ethnicity, Customized | Female partner race/ethnicity, customized | Female partners | Count of Participants | Participants | Participants |
|
|
| Body mass index (BMI) | Male partner body mass index | Male partners | Mean | Standard Deviation | kg/m^2 | Participants |
|
|
| Systolic blood pressure | Male partner systolic blood pressure | Male partners | Mean | Standard Deviation | mmHg | Participants |
|
|
| Diastolic blood pressure | Male partner diastolic blood pressure | Male partners | Mean | Standard Deviation | mmHg | Participants |
|
|
| Education | Male partner education | Male partners | Count of Participants | Participants | Participants |
|
|
| Employment status | Male partner employment status | Male partners: 89 participants in the FA/Zn arm and 90 participants in the placebo arm did not provide this information. | Count of Participants | Participants | Participants |
|
|
| Marital status | Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo) | Count of Units | Male-female couples | Male-female couples |
|
|
| Annual household income | Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo) | Count of Units | Male-female couples | Male-female couples |
|
|
| Taking multivitamin within past 3 mo | Male partner taking multivitamin within past 3 mo | Male partners: 434 participants in the FA/Zn arm and 433 participants in the placebo arm did not provide this information. | Count of Participants | Participants | Participants |
|
|
| Male factor infertility diagnosis | Baseline male factor infertility diagnosis includes low sperm count, low sperm motility, abnormal morphology, poor DNA fragmentation, testicular failure, and other. | Male partners: 427 participants in the FA/Zn arm and 426 participants in the placebo arm did not provide this information. | Count of Participants | Participants | Participants |
|
|
| Male health insurance | Male partners: 12 participants in the FA/Zn arm and 14 participants in the placebo arm did not provide this information. | Count of Participants | Participants | Participants |
|
|
| Male infertility insurance | Male partners: 79 participants in the FA/Zn arm and 69 participants in the placebo arm did not provide this information. | Count of Participants | Participants | Participants |
|
|
| Time trying to conceive | Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo): 83 couples in the FA/Zn arm and 80 couples in the placebo arm did not provide this information. | Median | Inter-Quartile Range | months | Male-female couples |
|
|
| Units |
|---|
| Counts |
|---|
| Participants |
|
|
|
| Primary | Semen Volume | Volume of the ejaculate, mL Assessed utilizing the World Health Organization (WHO) semen analysis procedure 5th edition World Health Organization. WHO laboratory manual for the Examination and processing of human semen. 5th Edition ed. Switzerland: 2010. | Analyzed overall and by fertility treatment stratum (subgroup) 870 and 903 men in the active and placebo treatment arms, respectively, returned for the 6-month study visit. 76 men in the active arm and 67 men in the placebo arm did not provide semen samples at this visit. | Posted | Mean | Standard Deviation | mL | 6 months |
|
|
|
|
| Primary | Sperm Concentration | Number of spermatozoa per unit of volume of semen Assessed utilizing the World Health Organization (WHO) semen analysis procedure 5th edition World Health Organization. WHO laboratory manual for the Examination and processing of human semen. 5th Edition ed. Switzerland: 2010. | 870 and 903 men in the active and placebo treatment arms, respectively, returned for the 6-month study visit. 76 men in the active arm and 67 men in the placebo arm did not provide semen samples at this visit. Additionally, one male participant in the placebo arm had insufficient quantity or quality to assess concentration. | Posted | Mean | Standard Deviation | 10^6 spermatozoa/mL | 6 months |
|
|
|
|
| Primary | Sperm Motility | % motile (including percentage of progressive motile sperm and percentage of nonprogressive motile sperm) Assessed utilizing the World Health Organization (WHO) semen analysis procedure 5th edition World Health Organization. WHO laboratory manual for the Examination and processing of human semen. 5th Edition ed. Switzerland: 2010. | 870 and 903 men in the active and placebo treatment arms, respectively, returned for the 6-month study visit. 76 men in the active arm and 67 men in the placebo arm did not provide semen samples at this visit. Additionally, one male participant in the placebo arm had insufficient quantity or quality to assess motility. | Posted | Mean | Standard Deviation | % motile | 6 months |
|
|
|
|
| Primary | Sperm Morphology | % normal morphology Assessed utilizing the World Health Organization (WHO) semen analysis procedure 5th edition World Health Organization. WHO laboratory manual for the Examination and processing of human semen. 5th Edition ed. Switzerland: 2010. | 870 and 903 men in the active and placebo treatment arms, respectively, returned for the 6-month study visit. 76 men in the active arm and 67 men in the placebo arm did not provide semen samples at this visit. Additionally, 19 men in the active arm and 17 men in the placebo arm had insufficient quantity or quality to assess morphology. | Posted | Mean | Standard Deviation | % normal | 6 months |
|
|
|
|
| Primary | DNA Fragmentation Index | Comet assay used to measure sperm DNA integrity based on excess DNA strand breaks Assessed utilizing the World Health Organization (WHO) semen analysis procedure 5th edition World Health Organization. WHO laboratory manual for the Examination and processing of human semen. 5th Edition ed. Switzerland: 2010. | 870 and 903 men in the active and placebo treatment arms, respectively, returned for the 6-month study visit. 76 men in the active arm and 67 men in the placebo arm did not provide semen samples at this visit. Additionally, 44 men in the active arm and 55 men in the placebo arm had insufficient quantity or quality to assess DFI. | Posted | Mean | Standard Deviation | % breakage | 6 months |
|
|
|
|
| Primary | Total Motile Sperm Count | Calculated as semen volume (mL) * sperm concentration (10^6 spermatozoa/mL) * motility (% motile) | 870 and 903 men in the active and placebo treatment arms, respectively, returned for the 6-month study visit. 76 men in the active arm and 67 men in the placebo arm did not provide semen samples at this visit. Additionally, 1 man in the active arm and 2 men in the placebo arm had insufficient quantity or quality to assess total motile count. | Posted | Mean | Standard Deviation | million motile sperm | 6 months |
|
|
|
|
| Secondary | Human Chorionic Gonadotropin (hCG) Detected Pregnancy (Implantation) | A quantitative hCG evaluation in serum > 5 milli-international units per milliliter (mIU/ml) | Posted | Count of Participants | Participants | For IVF, 12 days post embryo transfer for day 5 embryo transfers, and 14 days post embryo transfer for day 3 embryo transfers; for couples undergoing OI/IUI, after self-report of positive pregnancy test |
|
|
|
|
| Secondary | Clinical Intrauterine Pregnancy | Visualized gestational sac in the uterus on ultrasound | Posted | Count of Participants | Participants | approximately 6.5 weeks gestation |
|
|
|
|
| Secondary | Ectopic Pregnancy | Either visualization of no gestational sac in the uterus with a suspicious mass in the adnexa on ultrasound, an hCG level more than 1500 mIU/ml without visualization of an intrauterine gestational sac on ultrasound, or a slowly rising or plateauing serum hCG level without visualization of an intrauterine gestation on ultrasound. | Posted | Count of Participants | Participants | approximately 6.5 weeks gestation |
|
|
|
|
| Secondary | Early Pregnancy Loss | hCG pregnancy loss will be defined as a serum hCG > 5 mIU/ml followed by a decline. Clinically recognized pregnancy losses will be defined as visualization of an intrauterine gestational sac followed by a loss prior to 20 weeks gestation. | Posted | Count of Participants | Participants | hcG-detected pregnancy until 20 weeks of pregnancy |
|
|
|
|
| Secondary | Preeclampsia or Gestational Hypertension | Abstracted from hospital records and medical charts | Posted | Count of Participants | Participants | Delivery |
|
|
|
|
| Secondary | Gestational Diabetes | Abstracted from hospital records and medical charts | Posted | Count of Participants | Participants | Delivery |
|
|
|
|
| Secondary | Cesarean Delivery | Abstracted from hospital records and medical charts | Posted | Count of Participants | Participants | Delivery |
|
|
|
|
| Secondary | Preterm Delivery | Abstracted from hospital records and medical charts | Posted | Count of Participants | Participants | Delivery |
|
|
|
|
| Secondary | Small for Gestational Age | Abstracted from hospital records and medical charts | Posted | Count of Participants | Participants | Delivery |
|
|
|
|
| Secondary | Gestational Age | Abstracted from hospital records and medical charts | Among participants with live birth | Posted | Mean | Standard Deviation | weeks | Delivery |
|
|
|
|
| Secondary | Birth Weight | Abstracted from hospital records and medical charts | Among participants with live birth | Posted | Mean | Standard Deviation | grams | Delivery |
|
|
|
|
| Secondary | Stillbirth | Loss at or after 20 weeks gestation. Determined based on hospital records and medical chart abstraction. | Posted | Count of Participants | Participants | Delivery |
|
|
|
|
| Secondary | Neonatal Mortality | Abstracted from hospital records and medical charts | Posted | Count of Participants | Participants | Delivery |
|
|
|
|
| Secondary | Major Neonatal Complications | Abstracted from hospital records and medical charts: includes bronchopulmonary dysplasia, necrotizing enterocolitis, severe intraventricular hemorrhage, periventricular leukomalacia, and retinopathy of prematurity | Posted | Count of Participants | Participants | Delivery |
|
|
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| Secondary | Structural Malformations | Abstracted from birth record: includes major (n = 21; 6 with known genetic cause), minor (n = 6), and unclassified (n = 2) defects Structural birth defects: includes hydronephrosis/ureteropelvic junction obstruction, transposition of the great arteries, renal agenesis, cleft lip, club feet, multicystic/dysplastic kidney, tetralogy of fallot, gastroschisis, atrioventricular septal defects, other oral-facial defects, other cardiovascular defects, other CNS defects, other eye defects, other oral-facial defects, other anomalies, other syndromes | Posted | Count of Participants | Participants | Delivery |
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| Secondary | Severe Maternal Morbidity | Abstracted from delivery record: including postpartum hemorrhage, anemia requiring transfusion, sepsis, seizure, HELLP syndrome or preeclampsia with pulmonary edema | Posted | Count of Participants | Participants | Delivery |
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| Secondary | Fertilization Rate Per Cycle, % | Among participants in the IVF stratum Oocytes will be assessed 16-18 hours after insemination or microinjection to determine whether fertilization occurred. Fertilization will be considered normal if two pronuclei and two polar bodies are identified. Oocytes without visible pronuclei will be considered unfertilized. Oocytes with more than two pronuclei will be considered abnormally fertilized, and will thus be discarded. | 124 and 135 participants randomized to active and placebo arms, respectively Fertilization rate unavailable in medical records for 17 and 28 participants in the active and placebo arms, respectively | Posted | Mean | Standard Deviation | percent per cycle | Up to 9 months of fertility treatment post-randomization | cycles | cycles |
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| Secondary | Number of Good Quality Embryos on Day 5 Per Cycle | Among participants in the IVF stratum For couples who meet criteria for blastocyst culture, embryos will be graded 5 days after fertilization based on Society for Assisted Reproductive Technologies (SART) morphology criteria. | 124 and 135 participants randomized to active and placebo arms, respectively Day 5 good quality embryos unavailable in medical records for 56 and 64 participants in the active and placebo arms, respectively | Posted | Mean | Standard Deviation | embryos per cycle | Up to 9 months of fertility treatment post-randomization | cycles | cycles |
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| Secondary | Percentage of Good Quality Embryos on Day 5 Per Cycle | Among participants in the IVF stratum For couples who meet criteria for blastocyst culture, embryos will be graded 5 days after fertilization based on Society for Assisted Reproductive Technologies (SART) morphology criteria. | 124 and 135 participants randomized to active and placebo arms, respectively Proportion day 5 good quality embryos unavailable in medical records for 17 and 28 participants in the active and placebo arms, respectively | Posted | Mean | Standard Deviation | percent per cycle | Up to 9 months of fertility treatment post-randomization | cycles | cycles |
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| Secondary | Number of Embryos Transferred Per Cycle | Among participants in the IVF stratum | 124 and 135 participants randomized to active and placebo arms, respectively Proportion day 5 good quality embryos unavailable in medical records for 7 and 9 participants in the active and placebo arms, respectively | Posted | Mean | Standard Deviation | embryos per cycle | Up to 9 months of fertility treatment post-randomization | cycles | cycles |
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| Secondary | Number of Embryos Cryopreserved Per Cycle | Among participants in the IVF stratum | 124 and 135 participants randomized to active and placebo arms, respectively Number of embryos cryopreserved unavailable in medical records for 40 and 35 participants in the active and placebo arms, respectively | Posted | Mean | Standard Deviation | embryos per cycle | Up to 9 months of fertility treatment post-randomization | cycles | cycles |
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| Secondary | Sperm Penetration Per Cycle, % | Among participants in the IVF stratum | 124 and 135 participants randomized to active and placebo arms, respectively Sperm penetration & unavailable in medical records for 114 and 121 participants in the active and placebo arms, respectively | Posted | Mean | Standard Deviation | percent penetration | Up to 9 months of fertility treatment post-randomization |
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| Secondary | Cells on Day 3 Per Embryo Per Cycle | Among participants in the IVF stratum | 1215 embryos among cycles among women in the FA/Zn arm; 1129 embryos among cycles among women in the placebo arm 124 and 135 participants randomized to active and placebo arms, respectively # of cells on day 3 unavailable in medical records for 25 and 36 participants in the active and placebo arms, respectively | Posted | Mean | Standard Deviation | cells per embryo | Up to 9 months of fertility treatment post-randomization | cycles | cycles |
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| Secondary | Cells on Day 3 Per Embryo Per Cycle, Categorical | Number of cells per embryo among women in the IVF stratum | 1222 embryos among cycles among women in the FA/Zn arm; 1140 embryos among cycles among women in the placebo arm 124 and 135 participants randomized to active and placebo arms, respectively # of cells on day 3 (categorical) unavailable in medical records for 25 and 36 participants in the active and placebo arms, respectively | Posted | Number | predicted probability | Up to 9 months of fertility treatment post-randomization | cycles | cycles |
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| Secondary | Cells on Day 5 Per Embryo Per Cycle, Categorical | Among participants in the IVF stratum | 1160 embryos among cycles among women in the FA/Zn arm and 1205 embryos among cycles among women in the placebo arm 124 and 135 participants randomized to active and placebo arms, respectively # of cells on day 5 (categorical) unavailable in medical records for 5 and 14 participants in the active and placebo arms, respectively | Posted | Number | predicted probability | Up to 9 months of fertility treatment post-randomization | cycles | cycles |
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| Secondary | Embryo Morphology on Day 3 Per Cycle, Categorical | Among participants in the IVF stratum Embryos will be scored three days after fertilization according to the size and shape of blastomeres and to their degree of fragmentation. Veeck LL. Oocyte assessment and biological performance. Ann N Y Acad Sci 1988;541:259-74.:259-74. | 961 embryos among cycles among women in the FA/Zn arm; 931 embryos among cycles among women in the placebo arm 124 and 135 participants randomized to active and placebo arms, respectively Embryo morphology on day 3 (categorical) unavailable in medical records for 27 and 37 participants in the active and placebo arms, respectively | Posted | Number | predicted probability | Up to 9 months of fertility treatment post-randomization | cycles | cycles |
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| Secondary | Embryo Morphology on Day 5 Per Cycle, Categorical | Among participants in the IVF stratum For couples who meet criteria for blastocyst culture, embryos will be graded 5 days after fertilization based on Society for Assisted Reproductive Technologies (SART) morphology criteria. | 973 embryos among cycles among women in the FA/Zn arm; 1009 embryos among cycles among women in the placebo arm 124 and 135 participants randomized to active and placebo arms, respectively Embryo morphology on day 5 (categorical) unavailable in medical records for 10 and 19 participants in the active and placebo arms, respectively | Posted | Number | predicted probability | Up to 9 months of fertility treatment post-randomization | cycles | cycles |
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| Secondary | Method of Fertilization Per Cycle | Among participants in the in vitro fertilization (IVF) stratum: method of fertilization classified into intracytoplasmic sperm injection (ICSI) and other | 1689 embryos among cycles among women in the active treatment arm; 1800 embryos among cycles among women in the placebo arm 124 and 135 participants randomized to active and placebo arms, respectively Method of fertilization unavailable in medical records for 2 and 5 participants in the active and placebo arms, respectively | Posted | Number | predicted probability | Up to 9 months of fertility treatment post-randomization | cycles | cycles |
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| Secondary | Quality of Embryos Transferred Per Cycle, Categorical | Among participants in the IVF stratum Embryonic grading based on Society for Assisted Reproductive Technologies (SART) morphology criteria | 172 embryos among cycles among women in the FA/Zn arm; 187 embryos among cycles among women in the placebo arm 124 and 135 participants randomized to active and placebo arms, respectively Quality of embryos transferred (categorical) unavailable in medical records for 21 and 30 participants in the active and placebo arms, respectively | Posted | Number | predicted probability | Up to 9 months of fertility treatment post-randomization | cycles | cycles |
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| Secondary | Chromosomal Complement of Embryo Per Cycle | Among participants in the IVF stratum Chromosomal complement in the embryo assessed using methodology cited by Rubio et al. Rubio C, Rodrigo L, Mir P et al. Use of array comparative genomic hybridization (array-CGH) for embryo assessment: clinical results. Fertil Steril 2013 March 15;99(4):1044-8. | 124 and 135 participants randomized to active and placebo arms, respectively Chromosomal complement of embryo unavailable in medical records for 121 and 124 participants in the active and placebo arms, respectively | Posted | Number | predicted probability | Up to 9 months of fertility treatment post-randomization | cycles | cycles |
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| Other Pre-specified | Reproductive Hormones and Other Measured Biomarkers | Urinary, serum, and salivary concentrations of reproductive hormones, particularly androgens, proteomic analysis of human sperm and cardiometabolic risk factors and markers of oxidative stress, as well as measures of trace elements in toenails (collected at month 4 clinic visit). Biospecimens have been collected but laboratory analysis still needs to be done to be able to evaluate these endpoints. | Not Posted | 4 or 6 months | Participants |
| 0 |
| 1,185 |
| 7 |
| 1,185 |
| 189 |
| 1,185 |
| EG001 | Placebo | Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo | 0 | 1,185 | 5 | 1,185 | 162 | 1,185 |
| Pericardial effusion | Cardiac disorders | Systematic Assessment |
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| Eosinophilic oesophagitis | Gastrointestinal disorders | Systematic Assessment |
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| Chest pain | General disorders | Systematic Assessment |
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| Appendicitis | Infections and infestations | Systematic Assessment |
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| Clostridium difficile infection | Infections and infestations | Systematic Assessment |
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| Staphylococcal infection | Infections and infestations | Systematic Assessment |
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| Gun shot wound | Injury, poisoning and procedural complications | Systematic Assessment |
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| Rhabdomyolysis | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Respiratory failure | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Hospitalisation | Surgical and medical procedures | Systematic Assessment |
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| Variococele repair | Surgical and medical procedures | Systematic Assessment |
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| Pyrexia | General disorders | Systematic Assessment |
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| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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Not provided
Not provided
| D006571 | Heterocyclic Compounds |
| Asian |
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| Hispanic or Latino |
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| Other racial/ethnic groups |
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| Do not wish to provide |
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| Asian |
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| Hispanic or Latino |
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| Other racial/ethnic groups |
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| Do not wish to provide |
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| Bachelor's degree |
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| Master's degree or higher |
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| Do not wish to provide |
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| Employed full-time |
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| Full-time student |
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| Do not wish to provide |
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| $75,000-$99,999 |
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| $100,000 and greater |
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| Do not wish to provide |
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| Do not know |
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| IVF stratum |
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| Other treatment onsite |
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| Other treatment offsite |
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| The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Semen volume will be compared using two sided tests conducted at the 0.05 level. | Mean Difference (Final Values) | 0 | 2-Sided | 95 | -0.1 | 0.2 | Weighted for loss to follow-up and adjusted for infertility treatment stratum and study site. | Superiority |
| IVF stratum |
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| Other treatment onsite |
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| Other treatment offsite |
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| The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. The confidence interval for sperm concentration represents 95.1% coverage to properly account for the alpha spent in the interim analysis. | Mean Difference (Final Values) | -5.2 | 2-Sided | 95.1 | -13.6 | 3.1 | Weighted for loss to follow-up and adjusted for fertility treatment stratum and study site. | Superiority |
| IVF stratum |
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| Other treatment onsite |
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| Other treatment offsite |
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| The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. The confidence interval for sperm motility represents 95.1% coverage to properly account for the alpha spent in the interim analysis. | Mean Difference (Final Values) | -0.6 | 2-Sided | 95.1 | -2.7 | 1.4 | Weighted for loss to follow-up and adjusted for infertility treatment stratum and study site. | Superiority |
| IVF stratum |
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| Other treatment onsite |
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| Other treatment offsite |
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| The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. The confidence interval for sperm morphology represents 95.1% coverage to properly account for the alpha spent in the interim analysis. | Mean Difference (Final Values) | -0.4 | 2-Sided | 95.1 | -0.9 | 0 | Weighted for loss to follow-up and adjusted for infertility treatment stratum and study site. | Superiority |
| IVF stratum |
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| Other treatment onsite |
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| Other treatment offsite |
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| The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. DNA fragmentation will be compared using two sided tests conducted at the 0.05 level. | Mean Difference (Final Values) | 2.3 | 2-Sided | 95 | 0.3 | 4.3 | Weighted for loss to follow-up and adjusted for infertility treatment stratum and study site. | Superiority |
| IVF stratum |
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| Other treatment onsite |
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| Other treatment offsite |
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| The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Total motile sperm count will be compared using two sided tests conducted at the 0.05 level. | Mean Difference (Final Values) | 0.3 | 2-Sided | 95 | -20.9 | 21.4 | Weighted for loss to follow-up and adjusted for infertility treatment stratum and study site. | Superiority |
| The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. hCG detected pregnancy will be compared using two sided tests conducted at the 0.05 level. | Risk Ratio (RR) | 1.00 | 2-Sided | 95 | 0.91 | 1.09 | Adjusted for infertility treatment stratum and study site. | Superiority |
| The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Clinical intrauterine pregnancy will be compared using two sided tests conducted at the 0.05 level. | Risk Ratio (RR) | 0.98 | 2-Sided | 95 | 0.89 | 1.08 | Adjusted for infertility treatment stratum and study site. | Superiority |
| The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Ectopic pregnancy will be compared using two sided tests conducted at the 0.05 level. | Risk Ratio (RR) | 1.21 | 2-Sided | 95 | 0.37 | 3.97 | Adjusted for fertility treatment stratum and study site. | Superiority |
| The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Early pregnancy loss will be compared using two sided tests conducted at the 0.05 level. | Risk Ratio (RR) | 0.93 | 2-Sided | 95 | 0.75 | 1.15 | Adjusted for infertility treatment stratum and study site. | Superiority |
| The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Preeclampsia/gestational hypertension will be compared using two sided tests conducted at the 0.05 level. | Risk Ratio (RR) | 0.92 | 2-Sided | 95 | 0.63 | 1.36 | Adjusted for infertility treatment stratum and study site. | Superiority |
| The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Gestational diabetes will be compared using two sided tests conducted at the 0.05 level. | Risk Ratio (RR) | 0.77 | 2-Sided | 95 | 0.47 | 1.27 | Adjusted for infertility treatment stratum and study site. | Superiority |
| The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Cesarean delivery will be compared using two sided tests conducted at the 0.05 level. | Risk Ratio (RR) | 1.12 | 2-Sided | 95 | 0.89 | 1.39 | Adjusted for infertility treatment stratum and study site. | Superiority |
| The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Preterm delivery will be compared using two sided tests conducted at the 0.05 level. | Risk Ratio (RR) | 1.49 | 2-Sided | 95 | 1.04 | 2.16 | Adjusted for infertility treatment stratum and study site. | Superiority |
| The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Small for gestational age will be compared using two sided tests conducted at the 0.05 level. | Risk Ratio (RR) | 1.05 | 2-Sided | 95 | 0.75 | 1.49 | Adjusted for infertility treatment stratum and study site. | Superiority |
| The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Stillbirth will be compared using two sided tests conducted at the 0.05 level. | Risk Ratio (RR) | 0.25 | 2-Sided | 95 | 0.03 | 2.24 | Adjusted for infertility treatment stratum and study site. | Superiority |
| The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Neonatal mortality will be compared using two sided tests conducted at the 0.05 level. | Risk Ratio (RR) | 1.50 | 2-Sided | 95 | 0.25 | 8.95 | Adjusted for infertility treatment stratum and study site. | Superiority |
| The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Major neonatal complications will be compared using two sided tests conducted at the 0.05 level. | Risk Ratio (RR) | 1.99 | 2-Sided | 95 | 0.18 | 21.9 | Adjusted for infertility treatment stratum and study site. | Superiority |
| The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Structural malformations will be compared using two sided tests conducted at the 0.05 level. | Risk Ratio (RR) | 1.08 | 2-Sided | 95 | 0.53 | 2.21 | Adjusted for infertility treatment stratum and study site. | Superiority |
| The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Severe maternal morbidity will be compared using two sided tests conducted at the 0.05 level. | Risk Ratio (RR) | 1.50 | 2-Sided | 95 | 0.68 | 3.32 | Adjusted for infertility treatment stratum and study site. | Superiority |