Trial Outcomes & Findings for Folic Acid and Zinc Supplementation Trial (FAZST) (NCT NCT01857310)

NCT ID: NCT01857310

Last Updated: 2020-11-19

Results Overview

Based on hospital delivery records

• Recruitment status: COMPLETED
• Study phase: NA
• Target enrollment: 2370 participants
• Primary outcome timeframe: At delivery
• Results posted on: 2020-11-19

Participant Flow

Only the male partners in couples attempting to conceive were enrolled and assigned to treatment arms.

Participant milestones

Measure	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	Placebo Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Primary Analysis: Live Birth STARTED	1185	1185
Primary Analysis: Live Birth COMPLETED	1185	1185
Primary Analysis: Live Birth NOT COMPLETED	0	0
Secondary Analysis: Semen Quality at 6m STARTED	1185	1185
Secondary Analysis: Semen Quality at 6m COMPLETED	870	903
Secondary Analysis: Semen Quality at 6m NOT COMPLETED	315	282

Reasons for withdrawal

Measure	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	Placebo Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Secondary Analysis: Semen Quality at 6m Lost to Follow-up	315	282

Baseline Characteristics

Male partners: 427 participants in the FA/Zn arm and 426 participants in the placebo arm did not provide this information.

Baseline characteristics by cohort

Measure	Folic Acid and Zinc Supplementation n=1185 Male-female couples 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=1185 Male-female couples Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo	Total n=2370 Male-female couples Total of all reporting groups
Male factor infertility diagnosis No	598 Participants n=758 Participants • Male partners: 427 participants in the FA/Zn arm and 426 participants in the placebo arm did not provide this information.	594 Participants n=759 Participants • Male partners: 427 participants in the FA/Zn arm and 426 participants in the placebo arm did not provide this information.	1192 Participants n=1517 Participants • Male partners: 427 participants in the FA/Zn arm and 426 participants in the placebo arm did not provide this information.
Age, Continuous	30.6 years STANDARD_DEVIATION 5.0 • n=1185 Participants • Female partners	30.8 years STANDARD_DEVIATION 5.2 • n=1185 Participants • Female partners	30.7 years STANDARD_DEVIATION 5.1 • n=2370 Participants • Female partners
Sex: Female, Male Female	1185 Participants n=2370 Participants	1185 Participants n=2370 Participants	2370 Participants n=4740 Participants
Sex: Female, Male Male	1185 Participants n=2370 Participants	1185 Participants n=2370 Participants	2370 Participants n=4740 Participants
Race/Ethnicity, Customized Non-Hispanic white	994 Participants n=1185 Participants • Female partners	962 Participants n=1185 Participants • Female partners	1956 Participants n=2370 Participants • Female partners
Race/Ethnicity, Customized Non-Hispanic black	22 Participants n=1185 Participants • Female partners	21 Participants n=1185 Participants • Female partners	43 Participants n=2370 Participants • Female partners
Race/Ethnicity, Customized Asian	61 Participants n=1185 Participants • Female partners	70 Participants n=1185 Participants • Female partners	131 Participants n=2370 Participants • Female partners
Race/Ethnicity, Customized Hispanic or Latino	52 Participants n=1185 Participants • Female partners	75 Participants n=1185 Participants • Female partners	127 Participants n=2370 Participants • Female partners
Race/Ethnicity, Customized Other racial/ethnic groups	51 Participants n=1185 Participants • Female partners	50 Participants n=1185 Participants • Female partners	101 Participants n=2370 Participants • Female partners
Race/Ethnicity, Customized Do not wish to provide	5 Participants n=1185 Participants • Female partners	7 Participants n=1185 Participants • Female partners	12 Participants n=2370 Participants • Female partners
Body mass index (BMI)	30.1 kg/m^2 STANDARD_DEVIATION 6.7 • n=1185 Participants • Male partners	29.6 kg/m^2 STANDARD_DEVIATION 6.7 • n=1185 Participants • Male partners	29.8 kg/m^2 STANDARD_DEVIATION 6.7 • n=2370 Participants • Male partners
Systolic blood pressure	126.8 mmHg STANDARD_DEVIATION 12.8 • n=1185 Participants • Male partners	126.5 mmHg STANDARD_DEVIATION 13.9 • n=1185 Participants • Male partners	126.7 mmHg STANDARD_DEVIATION 13.4 • n=2370 Participants • Male partners
Diastolic blood pressure	78.4 mmHg STANDARD_DEVIATION 10.8 • n=1185 Participants • Male partners	78.0 mmHg STANDARD_DEVIATION 10.9 • n=1185 Participants • Male partners	78.2 mmHg STANDARD_DEVIATION 10.9 • n=2370 Participants • Male partners
Education High school or less	198 Participants n=1185 Participants • Male partners	173 Participants n=1185 Participants • Male partners	371 Participants n=2370 Participants • Male partners
Education Some college	428 Participants n=1185 Participants • Male partners	386 Participants n=1185 Participants • Male partners	814 Participants n=2370 Participants • Male partners
Education Bachelor's degree	335 Participants n=1185 Participants • Male partners	389 Participants n=1185 Participants • Male partners	724 Participants n=2370 Participants • Male partners
Education Master's degree or higher	212 Participants n=1185 Participants • Male partners	220 Participants n=1185 Participants • Male partners	432 Participants n=2370 Participants • Male partners
Education Do not wish to provide	12 Participants n=1185 Participants • Male partners	17 Participants n=1185 Participants • Male partners	29 Participants n=2370 Participants • Male partners
Employment status Not employed	149 Participants n=1096 Participants • Male partners: 89 participants in the FA/Zn arm and 90 participants in the placebo arm did not provide this information.	148 Participants n=1095 Participants • Male partners: 89 participants in the FA/Zn arm and 90 participants in the placebo arm did not provide this information.	297 Participants n=2191 Participants • Male partners: 89 participants in the FA/Zn arm and 90 participants in the placebo arm did not provide this information.
Employment status Employed part-time	58 Participants n=1096 Participants • Male partners: 89 participants in the FA/Zn arm and 90 participants in the placebo arm did not provide this information.	53 Participants n=1095 Participants • Male partners: 89 participants in the FA/Zn arm and 90 participants in the placebo arm did not provide this information.	111 Participants n=2191 Participants • Male partners: 89 participants in the FA/Zn arm and 90 participants in the placebo arm did not provide this information.
Employment status Employed full-time	802 Participants n=1096 Participants • Male partners: 89 participants in the FA/Zn arm and 90 participants in the placebo arm did not provide this information.	798 Participants n=1095 Participants • Male partners: 89 participants in the FA/Zn arm and 90 participants in the placebo arm did not provide this information.	1600 Participants n=2191 Participants • Male partners: 89 participants in the FA/Zn arm and 90 participants in the placebo arm did not provide this information.
Employment status Full-time student	87 Participants n=1096 Participants • Male partners: 89 participants in the FA/Zn arm and 90 participants in the placebo arm did not provide this information.	96 Participants n=1095 Participants • Male partners: 89 participants in the FA/Zn arm and 90 participants in the placebo arm did not provide this information.	183 Participants n=2191 Participants • Male partners: 89 participants in the FA/Zn arm and 90 participants in the placebo arm did not provide this information.
Marital status Married/living with partner	1180 Male-female couples n=1185 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)	1179 Male-female couples n=1185 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)	2359 Male-female couples n=2370 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)
Marital status Single/other	4 Male-female couples n=1185 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)	4 Male-female couples n=1185 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)	8 Male-female couples n=2370 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)
Marital status Do not wish to provide	1 Male-female couples n=1185 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)	2 Male-female couples n=1185 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)	3 Male-female couples n=2370 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)
Annual household income <$40,000	176 Male-female couples n=1185 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)	157 Male-female couples n=1185 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)	333 Male-female couples n=2370 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)
Annual household income $40,000-$74,999	422 Male-female couples n=1185 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)	456 Male-female couples n=1185 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)	878 Male-female couples n=2370 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)
Annual household income $75,000-$99,999	261 Male-female couples n=1185 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)	232 Male-female couples n=1185 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)	493 Male-female couples n=2370 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)
Annual household income $100,000 and greater	252 Male-female couples n=1185 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)	278 Male-female couples n=1185 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)	530 Male-female couples n=2370 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)
Annual household income Do not wish to provide	74 Male-female couples n=1185 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)	62 Male-female couples n=1185 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)	136 Male-female couples n=2370 Male-female couples • Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)
Taking multivitamin within past 3 mo Yes	298 Participants n=751 Participants • Male partners: 434 participants in the FA/Zn arm and 433 participants in the placebo arm did not provide this information.	284 Participants n=752 Participants • Male partners: 434 participants in the FA/Zn arm and 433 participants in the placebo arm did not provide this information.	582 Participants n=1503 Participants • Male partners: 434 participants in the FA/Zn arm and 433 participants in the placebo arm did not provide this information.
Taking multivitamin within past 3 mo No	453 Participants n=751 Participants • Male partners: 434 participants in the FA/Zn arm and 433 participants in the placebo arm did not provide this information.	468 Participants n=752 Participants • Male partners: 434 participants in the FA/Zn arm and 433 participants in the placebo arm did not provide this information.	921 Participants n=1503 Participants • Male partners: 434 participants in the FA/Zn arm and 433 participants in the placebo arm did not provide this information.
Male factor infertility diagnosis Yes	160 Participants n=758 Participants • Male partners: 427 participants in the FA/Zn arm and 426 participants in the placebo arm did not provide this information.	165 Participants n=759 Participants • Male partners: 427 participants in the FA/Zn arm and 426 participants in the placebo arm did not provide this information.	325 Participants n=1517 Participants • Male partners: 427 participants in the FA/Zn arm and 426 participants in the placebo arm did not provide this information.
Male health insurance Yes	1108 Participants n=1173 Participants • Male partners: 12 participants in the FA/Zn arm and 14 participants in the placebo arm did not provide this information.	1117 Participants n=1171 Participants • Male partners: 12 participants in the FA/Zn arm and 14 participants in the placebo arm did not provide this information.	2225 Participants n=2344 Participants • Male partners: 12 participants in the FA/Zn arm and 14 participants in the placebo arm did not provide this information.
Male health insurance No	65 Participants n=1173 Participants • Male partners: 12 participants in the FA/Zn arm and 14 participants in the placebo arm did not provide this information.	54 Participants n=1171 Participants • Male partners: 12 participants in the FA/Zn arm and 14 participants in the placebo arm did not provide this information.	119 Participants n=2344 Participants • Male partners: 12 participants in the FA/Zn arm and 14 participants in the placebo arm did not provide this information.
Male infertility insurance Yes	297 Participants n=1106 Participants • Male partners: 79 participants in the FA/Zn arm and 69 participants in the placebo arm did not provide this information.	266 Participants n=1116 Participants • Male partners: 79 participants in the FA/Zn arm and 69 participants in the placebo arm did not provide this information.	563 Participants n=2222 Participants • Male partners: 79 participants in the FA/Zn arm and 69 participants in the placebo arm did not provide this information.
Male infertility insurance No	493 Participants n=1106 Participants • Male partners: 79 participants in the FA/Zn arm and 69 participants in the placebo arm did not provide this information.	495 Participants n=1116 Participants • Male partners: 79 participants in the FA/Zn arm and 69 participants in the placebo arm did not provide this information.	988 Participants n=2222 Participants • Male partners: 79 participants in the FA/Zn arm and 69 participants in the placebo arm did not provide this information.
Male infertility insurance Do not know	316 Participants n=1106 Participants • Male partners: 79 participants in the FA/Zn arm and 69 participants in the placebo arm did not provide this information.	355 Participants n=1116 Participants • Male partners: 79 participants in the FA/Zn arm and 69 participants in the placebo arm did not provide this information.	671 Participants n=2222 Participants • Male partners: 79 participants in the FA/Zn arm and 69 participants in the placebo arm did not provide this information.
Time trying to conceive	19 months n=1102 Male-female couples • 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.	18 months n=1105 Male-female couples • 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.	18 months n=2207 Male-female couples • 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.

PRIMARY outcome

Timeframe: At delivery

Population: Complete randomized cohort

Based on hospital delivery records

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=1185 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=1185 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Live Birth Other treatment onsite	264 Participants	277 Participants
Live Birth Overall	404 Participants	416 Participants
Live Birth IVF stratum	97 Participants	91 Participants
Live Birth Other treatment offsite	43 Participants	48 Participants

PRIMARY outcome

Timeframe: 6 months

Population: 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.

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.

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=794 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=836 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Semen Volume Other treatment onsite	3.5 mL Standard Deviation 1.7	3.5 mL Standard Deviation 1.8
Semen Volume Other treatment offsite	3.5 mL Standard Deviation 1.7	3.4 mL Standard Deviation 1.7
Semen Volume Overall	3.5 mL Standard Deviation 1.7	3.5 mL Standard Deviation 1.8
Semen Volume IVF stratum	3.5 mL Standard Deviation 1.5	3.5 mL Standard Deviation 1.7

PRIMARY outcome

Timeframe: 6 months

Population: 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.

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.

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=794 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=835 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Sperm Concentration Overall	84.8 10^6 spermatozoa/mL Standard Deviation 85.2	89.0 10^6 spermatozoa/mL Standard Deviation 85.0
Sperm Concentration IVF stratum	81.8 10^6 spermatozoa/mL Standard Deviation 96.5	76.1 10^6 spermatozoa/mL Standard Deviation 78.6
Sperm Concentration Other treatment onsite	85.0 10^6 spermatozoa/mL Standard Deviation 83.1	92.2 10^6 spermatozoa/mL Standard Deviation 84.8
Sperm Concentration Other treatment offsite	87.2 10^6 spermatozoa/mL Standard Deviation 83.0	87.7 10^6 spermatozoa/mL Standard Deviation 92.5

PRIMARY outcome

Timeframe: 6 months

Population: 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.

% 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.

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=794 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=835 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Sperm Motility Overall	52.7 % motile Standard Deviation 21.2	53.2 % motile Standard Deviation 20.1
Sperm Motility IVF stratum	51.7 % motile Standard Deviation 21.9	51.7 % motile Standard Deviation 20.0
Sperm Motility Other treatment onsite	52.5 % motile Standard Deviation 21.1	53.9 % motile Standard Deviation 19.5
Sperm Motility Other treatment offsite	55.0 % motile Standard Deviation 20.9	51.5 % motile Standard Deviation 22.8

PRIMARY outcome

Timeframe: 6 months

Population: 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.

% 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.

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=775 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=819 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Sperm Morphology Other treatment offsite	6.7 % normal Standard Deviation 4.9	5.6 % normal Standard Deviation 4.3
Sperm Morphology Other treatment onsite	5.6 % normal Standard Deviation 4.0	6.2 % normal Standard Deviation 4.9
Sperm Morphology IVF stratum	5.2 % normal Standard Deviation 4.3	5.4 % normal Standard Deviation 4.7
Sperm Morphology Overall	5.7 % normal Standard Deviation 4.2	6.0 % normal Standard Deviation 4.8

PRIMARY outcome

Timeframe: 6 months

Population: 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.

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.

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=750 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=781 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
DNA Fragmentation Index Overall	29.7 % breakage Standard Deviation 20.5	27.2 % breakage Standard Deviation 17.8
DNA Fragmentation Index IVF stratum	27.1 % breakage Standard Deviation 19.6	26.8 % breakage Standard Deviation 19.6
DNA Fragmentation Index Other treatment onsite	30.0 % breakage Standard Deviation 20.3	27.0 % breakage Standard Deviation 16.8
DNA Fragmentation Index Other treatment offsite	30.7 % breakage Standard Deviation 22.7	28.5 % breakage Standard Deviation 20.5

PRIMARY outcome

Timeframe: 6 months

Population: 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.

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

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=793 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=834 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Total Motile Sperm Count Overall	183 million motile sperm Standard Deviation 226	182 million motile sperm Standard Deviation 212
Total Motile Sperm Count IVF stratum	165 million motile sperm Standard Deviation 221	152 million motile sperm Standard Deviation 188
Total Motile Sperm Count Other treatment onsite	186 million motile sperm Standard Deviation 226	188 million motile sperm Standard Deviation 207
Total Motile Sperm Count Other treatment offsite	192 million motile sperm Standard Deviation 233	184 million motile sperm Standard Deviation 262

SECONDARY outcome

Timeframe: 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

A quantitative hCG evaluation in serum > 5 milli-international units per milliliter (mIU/ml)

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=1185 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=1185 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Human Chorionic Gonadotropin (hCG) Detected Pregnancy (Implantation)	479 Participants	490 Participants

SECONDARY outcome

Timeframe: approximately 6.5 weeks gestation

Visualized gestational sac in the uterus on ultrasound

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=1185 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=1185 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Clinical Intrauterine Pregnancy	449 Participants	462 Participants

SECONDARY outcome

Timeframe: approximately 6.5 weeks gestation

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.

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=1185 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=1185 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Ectopic Pregnancy	6 Participants	5 Participants

SECONDARY outcome

Timeframe: hcG-detected pregnancy until 20 weeks of pregnancy

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.

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=1185 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=1185 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Early Pregnancy Loss	137 Participants	150 Participants

SECONDARY outcome

Timeframe: Delivery

Abstracted from hospital records and medical charts

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=1185 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=1185 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Preeclampsia or Gestational Hypertension	47 Participants	51 Participants

SECONDARY outcome

Timeframe: Delivery

Abstracted from hospital records and medical charts

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=1185 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=1185 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Gestational Diabetes	26 Participants	34 Participants

SECONDARY outcome

Timeframe: Delivery

Abstracted from hospital records and medical charts

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=1185 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=1185 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Cesarean Delivery	143 Participants	129 Participants

SECONDARY outcome

Timeframe: Delivery

Abstracted from hospital records and medical charts

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=1185 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=1185 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Preterm Delivery	67 Participants	45 Participants

SECONDARY outcome

Timeframe: Delivery

Abstracted from hospital records and medical charts

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=1185 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=1185 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Small for Gestational Age	62 Participants	59 Participants

SECONDARY outcome

Timeframe: Delivery

Population: Among participants with live birth

Abstracted from hospital records and medical charts

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=404 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=416 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Gestational Age	38.6 weeks Standard Deviation 2.5	38.8 weeks Standard Deviation 2.2

SECONDARY outcome

Timeframe: Delivery

Population: Among participants with live birth

Abstracted from hospital records and medical charts

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=404 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=416 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Birth Weight	3062 grams Standard Deviation 731	3133 grams Standard Deviation 654

SECONDARY outcome

Timeframe: Delivery

Loss at or after 20 weeks gestation. Determined based on hospital records and medical chart abstraction.

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=1185 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=1185 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Stillbirth	1 Participants	4 Participants

SECONDARY outcome

Timeframe: Delivery

Abstracted from hospital records and medical charts

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=1185 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=1185 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Neonatal Mortality	3 Participants	2 Participants

SECONDARY outcome

Timeframe: Delivery

Abstracted from hospital records and medical charts: includes bronchopulmonary dysplasia, necrotizing enterocolitis, severe intraventricular hemorrhage, periventricular leukomalacia, and retinopathy of prematurity

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=1185 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=1185 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Major Neonatal Complications	2 Participants	1 Participants

SECONDARY outcome

Timeframe: Delivery

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

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=1185 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=1185 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Structural Malformations	15 Participants	14 Participants

SECONDARY outcome

Timeframe: Delivery

Abstracted from delivery record: including postpartum hemorrhage, anemia requiring transfusion, sepsis, seizure, HELLP syndrome or preeclampsia with pulmonary edema

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=1185 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=1185 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Severe Maternal Morbidity	15 Participants	10 Participants

SECONDARY outcome

Timeframe: Up to 9 months of fertility treatment post-randomization

Population: 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

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.

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=124 cycles 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=119 cycles Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Fertilization Rate Per Cycle, %	75.3 percent per cycle Standard Deviation 2.25	77.7 percent per cycle Standard Deviation 1.74

SECONDARY outcome

Timeframe: Up to 9 months of fertility treatment post-randomization

Population: 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

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.

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=72 cycles 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=74 cycles Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Number of Good Quality Embryos on Day 5 Per Cycle	2.66 embryos per cycle Standard Deviation 0.23	2.98 embryos per cycle Standard Deviation 0.21

SECONDARY outcome

Timeframe: Up to 9 months of fertility treatment post-randomization

Population: 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

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.

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=124 cycles 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=119 cycles Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Percentage of Good Quality Embryos on Day 5 Per Cycle	17.2 percent per cycle Standard Deviation 2.05	18.5 percent per cycle Standard Deviation 1.81

SECONDARY outcome

Timeframe: Up to 9 months of fertility treatment post-randomization

Population: 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

Among participants in the IVF stratum

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=147 cycles 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=152 cycles Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Number of Embryos Transferred Per Cycle	1.50 embryos per cycle Standard Deviation 0.06	1.51 embryos per cycle Standard Deviation 0.05

SECONDARY outcome

Timeframe: Up to 9 months of fertility treatment post-randomization

Population: 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

Among participants in the IVF stratum

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=92 cycles 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=116 cycles Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Number of Embryos Cryopreserved Per Cycle	4.22 embryos per cycle Standard Deviation 0.32	4.32 embryos per cycle Standard Deviation 0.31

SECONDARY outcome

Timeframe: Up to 9 months of fertility treatment post-randomization

Population: 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

Among participants in the IVF stratum

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=10 Participants 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=14 Participants Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Sperm Penetration Per Cycle, %	62.7 percent penetration Standard Deviation 13.0	74.8 percent penetration Standard Deviation 11.0

SECONDARY outcome

Timeframe: Up to 9 months of fertility treatment post-randomization

Population: 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

Among participants in the IVF stratum

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=117 cycles 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=114 cycles Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Cells on Day 3 Per Embryo Per Cycle	5.60 cells per embryo Standard Deviation 0.20	5.98 cells per embryo Standard Deviation 0.19

SECONDARY outcome

Timeframe: Up to 9 months of fertility treatment post-randomization

Population: 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

Number of cells per embryo among women in the IVF stratum

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=114 cycles 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=114 cycles Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Cells on Day 3 Per Embryo Per Cycle, Categorical Fewer than 4 cells	0.27 predicted probability	0.22 predicted probability
Cells on Day 3 Per Embryo Per Cycle, Categorical 4 cells or greater	0.73 predicted probability	0.78 predicted probability

SECONDARY outcome

Timeframe: Up to 9 months of fertility treatment post-randomization

Population: 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

Among participants in the IVF stratum

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=141 cycles 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=141 cycles Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Cells on Day 5 Per Embryo Per Cycle, Categorical Fewer than 8 cells	0.20 predicted probability	0.19 predicted probability
Cells on Day 5 Per Embryo Per Cycle, Categorical 8 cells or greater	0.80 predicted probability	0.81 predicted probability

SECONDARY outcome

Timeframe: Up to 9 months of fertility treatment post-randomization

Population: 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

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.

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=141 cycles 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=141 cycles Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Embryo Morphology on Day 3 Per Cycle, Categorical Excellent or good	0.66 predicted probability	0.68 predicted probability
Embryo Morphology on Day 3 Per Cycle, Categorical Fair or poor	0.34 predicted probability	0.32 predicted probability

SECONDARY outcome

Timeframe: Up to 9 months of fertility treatment post-randomization

Population: 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

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.

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=132 cycles 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=134 cycles Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Embryo Morphology on Day 5 Per Cycle, Categorical Excellent or good	0.28 predicted probability	0.35 predicted probability
Embryo Morphology on Day 5 Per Cycle, Categorical Fair or poor	0.72 predicted probability	0.65 predicted probability

SECONDARY outcome

Timeframe: Up to 9 months of fertility treatment post-randomization

Population: 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

Among participants in the in vitro fertilization (IVF) stratum: method of fertilization classified into intracytoplasmic sperm injection (ICSI) and other

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=145 cycles 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=157 cycles Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Method of Fertilization Per Cycle ICSI	0.74 predicted probability	0.79 predicted probability
Method of Fertilization Per Cycle Other	0.26 predicted probability	0.21 predicted probability

SECONDARY outcome

Timeframe: Up to 9 months of fertility treatment post-randomization

Population: 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

Among participants in the IVF stratum Embryonic grading based on Society for Assisted Reproductive Technologies (SART) morphology criteria

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=121 cycles 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=125 cycles Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Quality of Embryos Transferred Per Cycle, Categorical Excellent or good	0.75 predicted probability	0.73 predicted probability
Quality of Embryos Transferred Per Cycle, Categorical Fair or poor	0.25 predicted probability	0.27 predicted probability

SECONDARY outcome

Timeframe: Up to 9 months of fertility treatment post-randomization

Population: 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

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.

Outcome measures

Measure	Folic Acid and Zinc Supplementation n=5 cycles 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=17 cycles Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Chromosomal Complement of Embryo Per Cycle Abnormal	0.75 predicted probability	0.32 predicted probability
Chromosomal Complement of Embryo Per Cycle Normal	0.25 predicted probability	0.68 predicted probability

OTHER_PRE_SPECIFIED outcome

Timeframe: 4 or 6 months

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.

Outcome measures

Outcome data not reported

Adverse Events

Folic Acid and Zinc Supplementation

Serious events: 7 serious events

Other events: 189 other events

Deaths: 0 deaths

Placebo

Serious events: 5 serious events

Other events: 162 other events

Deaths: 0 deaths

Serious adverse events

Measure	Folic Acid and Zinc Supplementation n=1185 participants at risk 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=1185 participants at risk Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Cardiac disorders Myocardial infarction	0.00% 0/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.	0.08% 1/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.
Cardiac disorders Pericardial effusion	0.00% 0/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.	0.08% 1/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.
Gastrointestinal disorders Eosinophilic oesophagitis	0.08% 1/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.	0.00% 0/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.
General disorders Chest pain	0.08% 1/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.	0.00% 0/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.
Infections and infestations Appendicitis	0.00% 0/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.	0.08% 1/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.
Infections and infestations Clostridium difficile infection	0.08% 1/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.	0.00% 0/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.
Infections and infestations Staphylococcal infection	0.08% 1/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.	0.00% 0/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.
Injury, poisoning and procedural complications Gun shot wound	0.00% 0/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.	0.08% 1/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.
Musculoskeletal and connective tissue disorders Rhabdomyolysis	0.08% 1/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.	0.00% 0/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.08% 1/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.	0.00% 0/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.
Surgical and medical procedures Hospitalisation	0.08% 1/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.	0.00% 0/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.
Surgical and medical procedures Variococele repair	0.00% 0/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.	0.08% 1/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.

Other adverse events

Measure	Folic Acid and Zinc Supplementation n=1185 participants at risk 5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months. 5 mg folic acid and 30 mg elemental zinc	Placebo n=1185 participants at risk Matching placebo, taken orally daily for 6 months. Placebo Comparator: Placebo
Gastrointestinal disorders Abdominal discomfort or pain	5.6% 66/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.	3.4% 40/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.
General disorders Pyrexia	5.6% 66/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.	5.2% 62/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	4.8% 57/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.	5.1% 60/1185 • Adverse events were collected over the 6 month duration of the study. Adverse events were only collected from the male partners.

Additional Information

Dr. Enrique Schisterman

NICHD

Phone: 3014356893

Email: schistee@mail.nih.gov

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place