Folic Acid and Zinc Supplementation Trial (FAZST)

NCT01857310 | Completed Results DMC

• 1 other identifier: FAZST
• Study Type: interventional
• Target: 2,370
• Locations: 1 country
• Sites: 4

Brief 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. The following study objectives underlie successful attainment of the overarching research goal:

1. 1.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.
2. 2.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.
3. 3.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.
4. 4.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.
5. 5.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.

Conditions

Pregnancy; Live Birth; Spontaneous Abortion

Keywords

Folic Acid; Zinc; Semen; In vitro fertilization; Assisted reproductive technology; Ovulation induction; Intrauterine insemination; Pregnancy; Live Birth; Abortion, spontaneous

Outcome Measures

Primary Outcomes (7)

• 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.

  6 months

• Total Motile Sperm Count

  Calculated as semen volume (mL) \* sperm concentration (10\^6 spermatozoa/mL) \* motility (% motile)

  6 months

Secondary Outcomes (30)

• Human Chorionic Gonadotropin (hCG) Detected Pregnancy (Implantation)

  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

  approximately 6.5 weeks gestation

• Ectopic Pregnancy

  approximately 6.5 weeks gestation

• Early Pregnancy Loss

  hcG-detected pregnancy until 20 weeks of pregnancy

• Preeclampsia or Gestational Hypertension

  Delivery

Other Outcomes (1)

• Reproductive Hormones and Other Measured Biomarkers

  4 or 6 months

Study Arms (2)

Folic acid and zinc supplementation

EXPERIMENTAL

5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months.

Dietary Supplement: 5 mg folic acid and 30 mg elemental zinc

Placebo

PLACEBO COMPARATOR

Matching placebo, taken orally daily for 6 months.

Drug: Placebo Comparator: Placebo

Interventions

5 mg folic acid and 30 mg elemental zinc DIETARY_SUPPLEMENT

Folic acid and zinc supplementation

Placebo Comparator: Placebo DRUG

Placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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).

You may not qualify if:

• 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.
• 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).
• 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

Sponsors & Collaborators

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

Study Sites (4)

Northwestern University

Chicago, Illinois, 60611, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

Center for Reproductive Medicine

Minneapolis, Minnesota, 55407, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

Related Publications (4)

• 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.

  PMID: 39173703 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.

  PMID: 36192231 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.

  PMID: 34656303 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.

  PMID: 31910279 DERIVED

Related Links

• The FAZST trial home page

MeSH Terms

Conditions

Abortion, Spontaneous

Interventions

Folic Acid

Condition Hierarchy (Ancestors)

Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Enrique Schisterman
• Organization: NICHD

schistee@mail.nih.gov

3014356893

Study Officials

• 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

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 13, 2013
• First Posted: May 20, 2013
• Study Start: June 1, 2013
• Primary Completion: June 1, 2019
• Study Completion: June 1, 2019
• Last Updated: November 19, 2020
• Results First Posted: November 19, 2020

Record last verified: 2020-11

Locations

US (4)