PregnancyFAZSTNCT01857310

Folic Acid and Zinc Supplementation Trial (FAZST)

A study testing 5 mg folic acid and 30 mg elemental zinc in people with Pregnancy and Live Birth, run by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at 4 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

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. Read more about this study

Who is it for?: Ages 18 to 45 yearsHealthy volunteers can take part
Conditions the study is for: Pregnancy, Live Birth, Spontaneous Abortion
What is being tested?: 5 mg folic acid and 30 mg elemental zinc
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 2,370 participants
Where: 4 sitesUnited States
Study dates: Jun 2013to Jun 2019
Phase: Interventional
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 45 years
All sexes
Healthy volunteers accepted
Adult

Couples Inclusion Criteria:

Heterosexual couples in a committed relationship with a female partner aged 18-45 years and male partner aged 18 years and older attempting to conceive and seeking assisted reproduction at participating fertility clinics.
Couples actively trying to conceive.
Couples who are planning ovulation induction (OI), natural fertility optimization methods, or intrauterine insemination (IUI) should be willing to be on the study dietary supplement for at least 3 weeks before starting the next assisted reproduction cycle.Women with regular periods may initiate their fertility therapy at the start of the woman's menstrual cycle following randomization if randomization occurred within the first 10 days of the cycle, but must wait one menstrual cycle if the visit occurred after day 10 of the cycle). For women with irregular periods or amenorrhea, the male must be on the study supplement for 3 weeks prior to initiation of any ovulation induction medication (e.g., clomid, letrozole, gonadotropins).

Couples Exclusion Criteria:

Female partner unwilling to participate (e.g., no abstraction of her assisted fertility treatment record or unwilling to complete baseline visit).
Couples using donor, cryopreserved sperm, or sperm obtained via microsurgical or percutaneous epididymal sperm aspiration.
Couples attempting to conceive with a gestational carrier (surrogate).
Positive urine pregnancy test at screening.

Male Inclusion Criteria:

Willing to provide semen samples according to the proposed schedule at baseline, 2, 4, and 6 months of follow-up.
Able to complete regular study questionnaires and daily journals aimed at capturing ejaculation, sexual intercourse and lifestyle factors considered to affect male fecundity (e.g., cigarette smoking, fever, high temperature environment and other environmental exposures) and other data collection instruments (e.g., physical activity, food frequency questionnaire, stress).

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.
Dihydrofolate reductase inhibitors: Trimethoprim, Triamterene, Bactrim, Iclaprim
Sulfonamides: Hydrochlorothiazide (HCTZ), Metolazone, Indapamide, Lasix, Bumex, Torsemide, Chlorthalidone, Acetazolamide, Mefruside, Xipamide
Sulfonylureas: Glipizide, Glyburide
Cox-2 inhibitors: Celecoxib
Others: Valproic acid, Probenecid, Sulfasalazine, Sumatriptan, Mafenide, Ethoxzolamide, Sulfiram, Zonisamide, Dorzolamide (optic), Dichlorphenamide, Fluorouracil, Capecitabine, Methotrexate
History of organ transplantation.
Physician diagnosed:
Current poorly controlled chronic diseases such as heart disease, diabetes mellitus, hypertension, cancer, inflammatory diseases, autoimmune, thyroid disease, endocrine dysfunction, liver disease, kidney disease, or HIV/AIDS or other immune-insufficient related illnesses.
Crohn's disease, celiac disease, ulcerative colitis, gastric bypass surgery, lap band surgery or history of intestinal surgery to remove a portion of small bowel. History of diseases/symptoms that require folic acid dietary supplementation, such as megaloblastic anemia, homocystinemia, and homocystinuria.
History of alcohol dependency disorder and/or other drug/substance dependency in the past 180 days.
History of psychoses or other mental conditions that would result in cognitive impairment and inability to participate in any part of this study including the informed consent process, as diagnosed by a physician within the past year.
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.

Trial locations and contacts

4 sites in 1 country.

United States4 sites

Northwestern University
Chicago, Illinois, 60611
University of Iowa
Iowa City, Iowa, 52242
Center for Reproductive Medicine
Minneapolis, Minnesota, 55407
University of Utah
Salt Lake City, Utah, 84132

Other trials in United States

About this study

Official title: Folic Acid and Zinc Supplementation Trial: A Multi-center, Double-blind, Block-randomized, Placebo-controlled Trial

To estimate the effect of folic acid and zinc dietary supplementation on semen quality parameters, including but not limited to concentration, motility, morphology, and sperm DNA integrity, relative to the placebo group.
To estimate the effect of folic acid and zinc dietary supplementation on fertility treatment outcomes [fertilization, embryo quality, implantation/human Chorionic Gonadotropin (hCG) confirmed pregnancy, clinical pregnancy, live birth], relative to the placebo group.
To estimate the association between semen quality parameters, sperm DNA integrity and fertility treatment outcomes (fertilization, embryo quality, clinical pregnancy, live birth) and to identify the best combination of semen quality parameters for prediction of clinical pregnancy and live birth.
To estimate the effect of folic acid and zinc dietary supplementation on fertilization rates among couples undergoing assisted reproductive technology procedures, relative to the placebo group.
To estimate the effect of folic acid and zinc dietary supplementation on embryonic quality among couples undergoing assisted reproductive technology procedures, relative to the placebo group.

Read the detailed description

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.

Conditions: Pregnancy, Live Birth, Spontaneous Abortion
Being tested: 5 mg folic acid and 30 mg elemental zinc, Placebo Comparator: Placebo
Keywords: Folic Acid, Zinc, Semen, In vitro fertilization, Assisted reproductive technology, Ovulation induction, Intrauterine insemination, Pregnancy, Live Birth, Abortion, spontaneous
Medical subject headings: Abortion, Spontaneous

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

5 mg folic acid and 30 mg elemental zincDietary supplement
Placebo Comparator: PlaceboDrug

Study groups in NCT01857310
Study group	Role	What they receive
Folic acid and zinc supplementation	Experimental	5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. Receives: Dietary Supplement: 5 mg folic acid and 30 mg elemental zinc
Placebo	Placebo comparator	Matching placebo, taken orally daily for 6 months. Receives: Drug: Placebo Comparator: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

Live Birth
Based on hospital delivery records
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 6 months
Total Motile Sperm Count
Calculated as semen volume (mL) * sperm concentration (10^6 spermatozoa/mL) * motility (% motile)
Measured: 6 months

Secondary outcomes (30)

Human Chorionic Gonadotropin (hCG) Detected Pregnancy (Implantation)
A quantitative hCG evaluation in serum > 5 milli-international units per milliliter (mIU/ml)
Measured: 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
Clinical Intrauterine Pregnancy
Visualized gestational sac in the uterus on ultrasound
Measured: 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.
Measured: 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.
Measured: hcG-detected pregnancy until 20 weeks of pregnancy
Preeclampsia or Gestational Hypertension
Abstracted from hospital records and medical charts
Measured: Delivery
Gestational Diabetes
Abstracted from hospital records and medical charts
Measured: Delivery
Cesarean Delivery
Abstracted from hospital records and medical charts
Measured: Delivery
Preterm Delivery
Abstracted from hospital records and medical charts
Measured: Delivery
Small for Gestational Age
Abstracted from hospital records and medical charts
Measured: Delivery
Gestational Age
Abstracted from hospital records and medical charts
Measured: Delivery
Birth Weight
Abstracted from hospital records and medical charts
Measured: Delivery
Stillbirth
Loss at or after 20 weeks gestation. Determined based on hospital records and medical chart abstraction.
Measured: Delivery
Neonatal Mortality
Abstracted from hospital records and medical charts
Measured: 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
Measured: 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
Measured: Delivery
Severe Maternal Morbidity
Abstracted from delivery record: including postpartum hemorrhage, anemia requiring transfusion, sepsis, seizure, HELLP syndrome or preeclampsia with pulmonary edema
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Up to 9 months of fertility treatment post-randomization
Number of Embryos Transferred Per Cycle
Among participants in the IVF stratum
Measured: Up to 9 months of fertility treatment post-randomization
Number of Embryos Cryopreserved Per Cycle
Among participants in the IVF stratum
Measured: Up to 9 months of fertility treatment post-randomization
Sperm Penetration Per Cycle, %
Among participants in the IVF stratum
Measured: Up to 9 months of fertility treatment post-randomization
Cells on Day 3 Per Embryo Per Cycle
Among participants in the IVF stratum
Measured: 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
Measured: Up to 9 months of fertility treatment post-randomization
Cells on Day 5 Per Embryo Per Cycle, Categorical
Among participants in the IVF stratum
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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
Measured: 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.
Measured: Up to 9 months of fertility treatment post-randomization

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Jun 2013Jun 2019

First posted20 May 2013 (estimated)
Study startJun 2013
Primary completionJun 2019
Study completionJun 2019

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (6)Papers the sponsor has linked to this study.
Other trials for PregnancyStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase N/A
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 2,370 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01857310
Sponsor's protocol ID: FAZST
Acronym: FAZST
Status last verified: Nov 2020
First submitted: 13 May 2013
Last updated: 19 Nov 2020
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

Russo LM, Pilsner JR, Canty TP, Perkins NJ, Mendola P, Schliep KC, Shaaban M, Hemmert RB, Singh A, Ring AM, Vanderslice JA, Peterson CM, Johnstone EB, Rabeya K, Nobles C. Critical Windows of Air Pollution Exposure During Spermatogenesis and Intrauterine Insemination Outcomes. Paediatr Perinat Epidemiol. 2026 Aug 4. doi: 10.1111/ppe.70185. Online ahead of print.
PubMed 42551848
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.
PubMed 41875434
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.
PubMed 39173703
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.
PubMed 36192231
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.
PubMed 34656303
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.
PubMed 31910279

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 19 Nov 2020. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Folic Acid and Zinc Supplementation Trial: A Multi-center, Double-blind, Block-randomized, Placebo-controlled Trial
ClinicalTrials.gov ID: NCT01857310
Acronym / sponsor ID: FAZST / FAZST
Conditions: Pregnancy, Live Birth, Spontaneous Abortion
Keywords: Folic Acid, Zinc, Semen, In vitro fertilization, Assisted reproductive technology, Ovulation induction, Intrauterine insemination, Pregnancy
Study type: Interventional
Recruitment status: Completed
Enrolment: 2,370 participants (actual)
Lead sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)US National Institutes of Health
Study start: Jun 2013 (actual)
Primary completion: Jun 2019 (actual)
Study completion: Jun 2019 (actual)
First posted: 20 May 2013 (estimated)
Results: Posted 19 Nov 2020

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

To estimate the effect of folic acid and zinc dietary supplementation on semen quality parameters, including but not limited to concentration, motility, morphology, and sperm DNA integrity, relative to the placebo group.
To estimate the effect of folic acid and zinc dietary supplementation on fertility treatment outcomes [fertilization, embryo quality, implantation/human Chorionic Gonadotropin (hCG) confirmed pregnancy, clinical pregnancy, live birth], relative to the placebo group.
To estimate the association between semen quality parameters, sperm DNA integrity and fertility treatment outcomes (fertilization, embryo quality, clinical pregnancy, live birth) and to identify the best combination of semen quality parameters for prediction of clinical pregnancy and live birth.
To estimate the effect of folic acid and zinc dietary supplementation on fertilization rates among couples undergoing assisted reproductive technology procedures, relative to the placebo group.
To estimate the effect of folic acid and zinc dietary supplementation on embryonic quality among couples undergoing assisted reproductive technology procedures, relative to the placebo group.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 2

Arm	Type	Receives
Folic acid and zinc supplementation	Experimental	Dietary Supplement: 5 mg folic acid and 30 mg elemental zinc5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months.
Placebo	Placebo comparator	Drug: Placebo Comparator: PlaceboMatching placebo, taken orally daily for 6 months.

Who may qualify

Ages: 18 to 45 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
5 mg folic acid and 30 mg elemental zinc	Dietary supplement	Folic acid and zinc supplementation
Placebo Comparator: Placebo	Drug	Placebo

Primary outcome

Live Birth
Time frame: At delivery
Based on hospital delivery records
Semen Volume
Time frame: 6 months
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.
Sperm Concentration
Time frame: 6 months
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.
Sperm Motility
Time frame: 6 months
% 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.
Sperm Morphology
Time frame: 6 months
% 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.
DNA Fragmentation Index
Time frame: 6 months
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.
Total Motile Sperm Count
Time frame: 6 months
Calculated as semen volume (mL) * sperm concentration (10^6 spermatozoa/mL) * motility (% motile)

30 secondary outcomes

Human Chorionic Gonadotropin (hCG) Detected Pregnancy (Implantation)
Time frame: 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
Clinical Intrauterine Pregnancy
Time frame: approximately 6.5 weeks gestation
Ectopic Pregnancy
Time frame: approximately 6.5 weeks gestation
Early Pregnancy Loss
Time frame: hcG-detected pregnancy until 20 weeks of pregnancy
Preeclampsia or Gestational Hypertension
Time frame: Delivery
Gestational Diabetes
Time frame: Delivery
Cesarean Delivery
Time frame: Delivery
Preterm Delivery
Time frame: Delivery
Small for Gestational Age
Time frame: Delivery
Gestational Age
Time frame: Delivery
Birth Weight
Time frame: Delivery
Stillbirth
Time frame: Delivery
Neonatal Mortality
Time frame: Delivery
Major Neonatal Complications
Time frame: Delivery
Structural Malformations
Time frame: Delivery
Severe Maternal Morbidity
Time frame: Delivery
Fertilization Rate Per Cycle, %
Time frame: Up to 9 months of fertility treatment post-randomization
Number of Good Quality Embryos on Day 5 Per Cycle
Time frame: Up to 9 months of fertility treatment post-randomization
Percentage of Good Quality Embryos on Day 5 Per Cycle
Time frame: Up to 9 months of fertility treatment post-randomization
Number of Embryos Transferred Per Cycle
Time frame: Up to 9 months of fertility treatment post-randomization
Number of Embryos Cryopreserved Per Cycle
Time frame: Up to 9 months of fertility treatment post-randomization
Sperm Penetration Per Cycle, %
Time frame: Up to 9 months of fertility treatment post-randomization
Cells on Day 3 Per Embryo Per Cycle
Time frame: Up to 9 months of fertility treatment post-randomization
Cells on Day 3 Per Embryo Per Cycle, Categorical
Time frame: Up to 9 months of fertility treatment post-randomization
Cells on Day 5 Per Embryo Per Cycle, Categorical
Time frame: Up to 9 months of fertility treatment post-randomization
Embryo Morphology on Day 3 Per Cycle, Categorical
Time frame: Up to 9 months of fertility treatment post-randomization
Embryo Morphology on Day 5 Per Cycle, Categorical
Time frame: Up to 9 months of fertility treatment post-randomization
Method of Fertilization Per Cycle
Time frame: Up to 9 months of fertility treatment post-randomization
Quality of Embryos Transferred Per Cycle, Categorical
Time frame: Up to 9 months of fertility treatment post-randomization
Chromosomal Complement of Embryo Per Cycle
Time frame: Up to 9 months of fertility treatment post-randomization

Results and safety

Results posted to the registry on 19 Nov 2020, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Folic Acid and Zinc Supplementation	1,185	1,185
Placebo	1,185	1,185

Primary outcome: Live Birth

Time frame: At delivery. Count of participants. Unit: Participants

Measure	Folic Acid and Zinc Supplementation n = 1185	Placebo n = 1185
Overall	404	416
IVF stratum	97	91
Other treatment onsite	264	277
Other treatment offsite	43	48

Folic Acid and Zinc Supplementation vs Placebo: Risk Difference (RD): -0.9 (95% CI -4.7 to 2.8)
Folic Acid and Zinc Supplementation vs Placebo: Risk Ratio (RR): 0.98 (95% CI 0.88 to 1.09)

Population analysed: Complete randomized cohort

Primary outcome: Semen Volume

Time frame: 6 months. Mean (Standard Deviation). Unit: mL

Measure	Folic Acid and Zinc Supplementation n = 794	Placebo n = 836
Overall	3.5 (1.7)	3.5 (1.8)
IVF stratum	3.5 (1.5)	3.5 (1.7)
Other treatment onsite	3.5 (1.7)	3.5 (1.8)
Other treatment offsite	3.5 (1.7)	3.4 (1.7)

Folic Acid and Zinc Supplementation vs Placebo: Mean Difference (Final Values): 0 (95% CI -0.2 to 0.2)
Folic Acid and Zinc Supplementation vs Placebo: Mean Difference (Final Values): 0 (95% CI -0.1 to 0.2)

Population analysed: 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.

Primary outcome: Sperm Concentration

Time frame: 6 months. Mean (Standard Deviation). Unit: 10^6 spermatozoa/mL

Measure	Folic Acid and Zinc Supplementation n = 794	Placebo n = 835
Overall	84.8 (85.2)	89.0 (85.0)
IVF stratum	81.8 (96.5)	76.1 (78.6)
Other treatment onsite	85.0 (83.1)	92.2 (84.8)
Other treatment offsite	87.2 (83.0)	87.7 (92.5)

Folic Acid and Zinc Supplementation vs Placebo: Mean Difference (Final Values): -4.3 (95.1% CI -12.5 to 3.9)
Folic Acid and Zinc Supplementation vs Placebo: Mean Difference (Final Values): -5.2 (95.1% CI -13.6 to 3.1)

Population analysed: 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.

Primary outcome: Sperm Motility

Time frame: 6 months. Mean (Standard Deviation). Unit: % motile

Measure	Folic Acid and Zinc Supplementation n = 794	Placebo n = 835
Overall	52.7 (21.2)	53.2 (20.1)
IVF stratum	51.7 (21.9)	51.7 (20.0)
Other treatment onsite	52.5 (21.1)	53.9 (19.5)
Other treatment offsite	55.0 (20.9)	51.5 (22.8)

Folic Acid and Zinc Supplementation vs Placebo: Mean Difference (Final Values): -0.5 (95.1% CI -2.5 to 1.5)
Folic Acid and Zinc Supplementation vs Placebo: Mean Difference (Final Values): -0.6 (95.1% CI -2.7 to 1.4)

30 secondary outcomes are reported in the full results.

Adverse events

Time frame: Adverse events were collected over the 6 month duration of the study.. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Folic Acid and Zinc Supplementation	7 of 1,185 (0.6%)	189 of 1,185 (15.9%)	0 of 1,185
Placebo	5 of 1,185 (0.4%)	162 of 1,185 (13.7%)	0 of 1,185

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 19 Nov 2020.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 42551848Russo LM, Pilsner JR, Canty TP, Perkins NJ, Mendola P, Schliep KC, Shaaban M, Hemmert RB, Singh A, Ring AM, Vanderslice JA, Peterson CM, Johnstone EB, Rabeya K, Nobles C. Critical Windows of Air Pollution Exposure During Spermatogenesis and Intrauterine Insemination Outcomes. Paediatr Perinat Epidemiol. 2026 Aug 4. doi: 10.1111/ppe.70185. Online ahead of print.
Derived from this study: PubMed 41875434Nobles 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.
Derived from this study: PubMed 39173703DiTosto 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.
Derived from this study: PubMed 36192231DeVilbiss 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.
Derived from this study: PubMed 34656303Jenkins 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.
Derived from this study: PubMed 31910279Schisterman 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.
The FAZST trial home pageLink provided by the sponsor.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Enrique F. Schisterman, PhD study director

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Sunni L. Mumford, PhD study director

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

C. Matthew Peterson, MD principal investigator

University of Utah

4 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Nov 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Yes. Results are posted in the registry (first posted 19 Nov 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Live Birth (time frame: At delivery). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01857310, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Nov 2020.