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Folic Acid and Zinc Supplementation Trial (FAZST) (FAZST)

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ClinicalTrials.gov Identifier: NCT01857310
Recruitment Status : Completed
First Posted : May 20, 2013
Results First Posted : November 19, 2020
Last Update Posted : November 19, 2020
Sponsor:
Information provided by (Responsible Party):
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Pregnancy
Live Birth
Spontaneous Abortion
Interventions Dietary Supplement: 5 mg folic acid and 30 mg elemental zinc
Drug: Placebo Comparator: Placebo
Enrollment 2370
Recruitment Details  
Pre-assignment Details Only the male partners in couples attempting to conceive were enrolled and assigned to treatment arms.
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Period Title: Primary Analysis: Live Birth
Started 1185 [1] 1185 [1]
Completed 1185 [2] 1185 [2]
Not Completed 0 0
[1]
Male partner
[2]
Chart abstraction of whether live birth occurred
Period Title: Secondary Analysis: Semen Quality at 6m
Started 1185 [1] 1185 [1]
Completed 870 [2] 903 [2]
Not Completed 315 282
Reason Not Completed
Lost to Follow-up             315             282
[1]
Male partner
[2]
Completed 6-month study visit
Arm/Group Title Folic Acid and Zinc Supplementation Placebo Total
Hide Arm/Group Description

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Total of all reporting groups
Overall Number of Baseline Participants 2370 2370 4740
Overall Number of Units Analyzed
Type of Units Analyzed: Male-female couples
1185 1185 2370
Hide Baseline Analysis Population Description
Only male partners randomized to each folic acid/zinc (n = 1185) and placebo (n = 1185) arms
Age, Continuous   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 1185 participants 1185 participants 2370 participants
32.5  (5.7) 32.7  (6.0) 32.6  (5.9)
[1]
Measure Description: Male partner age, continuous
[2]
Measure Analysis Population Description: Male partners
Age, Continuous   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 1185 participants 1185 participants 2370 participants
30.6  (5.0) 30.8  (5.2) 30.7  (5.1)
[1]
Measure Description: Female partner age, continuous
[2]
Measure Analysis Population Description: Female partners
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2370 participants 2370 participants 4740 participants
Female
1185
  50.0%
1185
  50.0%
2370
  50.0%
Male
1185
  50.0%
1185
  50.0%
2370
  50.0%
Race/Ethnicity, Customized   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1185 participants 1185 participants 2370 participants
Non-Hispanic white
974
  82.2%
962
  81.2%
1936
  81.7%
Non-Hispanic black
21
   1.8%
34
   2.9%
55
   2.3%
Asian
43
   3.6%
46
   3.9%
89
   3.8%
Hispanic or Latino
70
   5.9%
68
   5.7%
138
   5.8%
Other racial/ethnic groups
74
   6.2%
68
   5.7%
142
   6.0%
Do not wish to provide
3
   0.3%
7
   0.6%
10
   0.4%
[1]
Measure Description: Male partner race/ethnicity, customized
[2]
Measure Analysis Population Description: Male partners
Race/Ethnicity, Customized   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1185 participants 1185 participants 2370 participants
Non-Hispanic white
994
  83.9%
962
  81.2%
1956
  82.5%
Non-Hispanic black
22
   1.9%
21
   1.8%
43
   1.8%
Asian
61
   5.1%
70
   5.9%
131
   5.5%
Hispanic or Latino
52
   4.4%
75
   6.3%
127
   5.4%
Other racial/ethnic groups
51
   4.3%
50
   4.2%
101
   4.3%
Do not wish to provide
5
   0.4%
7
   0.6%
12
   0.5%
[1]
Measure Description: Female partner race/ethnicity, customized
[2]
Measure Analysis Population Description: Female partners
Body mass index (BMI)   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 1185 participants 1185 participants 2370 participants
30.1  (6.7) 29.6  (6.7) 29.8  (6.7)
[1]
Measure Description: Male partner body mass index
[2]
Measure Analysis Population Description: Male partners
Systolic blood pressure   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  mmHg
Number Analyzed 1185 participants 1185 participants 2370 participants
126.8  (12.8) 126.5  (13.9) 126.7  (13.4)
[1]
Measure Description: Male partner systolic blood pressure
[2]
Measure Analysis Population Description: Male partners
Diastolic blood pressure   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  mmHg
Number Analyzed 1185 participants 1185 participants 2370 participants
78.4  (10.8) 78.0  (10.9) 78.2  (10.9)
[1]
Measure Description: Male partner diastolic blood pressure
[2]
Measure Analysis Population Description: Male partners
Education   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1185 participants 1185 participants 2370 participants
High school or less
198
  16.7%
173
  14.6%
371
  15.7%
Some college
428
  36.1%
386
  32.6%
814
  34.3%
Bachelor's degree
335
  28.3%
389
  32.8%
724
  30.5%
Master's degree or higher
212
  17.9%
220
  18.6%
432
  18.2%
Do not wish to provide
12
   1.0%
17
   1.4%
29
   1.2%
[1]
Measure Description: Male partner education
[2]
Measure Analysis Population Description: Male partners
Employment status   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1096 participants 1095 participants 2191 participants
Not employed
149
  13.6%
148
  13.5%
297
  13.6%
Employed part-time
58
   5.3%
53
   4.8%
111
   5.1%
Employed full-time
802
  73.2%
798
  72.9%
1600
  73.0%
Full-time student
87
   7.9%
96
   8.8%
183
   8.4%
[1]
Measure Description: Male partner employment status
[2]
Measure Analysis Population Description: Male partners: 89 participants in the FA/Zn arm and 90 participants in the placebo arm did not provide this information.
Marital status   [1] 
Count of Units
Unit of measure:  Male-female couples
Number Analyzed 1185 Male-female couples [2]  1185 Male-female couples [2]  2370 Male-female couples [3] 
Married/living with partner
1180
  99.6%
1179
  99.5%
2359
  99.5%
Single/other
4
   0.3%
4
   0.3%
8
   0.3%
Do not wish to provide
1
   0.1%
2
   0.2%
3
   0.1%
[1]
Measure Analysis Population Description: Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)
[2]
1185 participants
[3]
2370 participants
Annual household income   [1] 
Count of Units
Unit of measure:  Male-female couples
Number Analyzed 1185 Male-female couples [2]  1185 Male-female couples [2]  2370 Male-female couples [3] 
<$40,000
176
  14.9%
157
  13.2%
333
  14.1%
$40,000-$74,999
422
  35.6%
456
  38.5%
878
  37.0%
$75,000-$99,999
261
  22.0%
232
  19.6%
493
  20.8%
$100,000 and greater
252
  21.3%
278
  23.5%
530
  22.4%
Do not wish to provide
74
   6.2%
62
   5.2%
136
   5.7%
[1]
Measure Analysis Population Description: Measure assessed among each of 2370 male-female couples (n=1185 active and 1185 placebo)
[2]
1185 participants
[3]
2370 participants
Taking multivitamin within past 3 mo   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 751 participants 752 participants 1503 participants
Yes
298
  39.7%
284
  37.8%
582
  38.7%
No
453
  60.3%
468
  62.2%
921
  61.3%
[1]
Measure Description: Male partner taking multivitamin within past 3 mo
[2]
Measure Analysis Population Description: 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   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 758 participants 759 participants 1517 participants
No
598
  78.9%
594
  78.3%
1192
  78.6%
Yes
160
  21.1%
165
  21.7%
325
  21.4%
[1]
Measure Description: Baseline male factor infertility diagnosis includes low sperm count, low sperm motility, abnormal morphology, poor DNA fragmentation, testicular failure, and other.
[2]
Measure Analysis Population Description: Male partners: 427 participants in the FA/Zn arm and 426 participants in the placebo arm did not provide this information.
Male health insurance   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1173 participants 1171 participants 2344 participants
Yes
1108
  94.5%
1117
  95.4%
2225
  94.9%
No
65
   5.5%
54
   4.6%
119
   5.1%
[1]
Measure Analysis Population Description: Male partners: 12 participants in the FA/Zn arm and 14 participants in the placebo arm did not provide this information.
Male infertility insurance   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1106 participants 1116 participants 2222 participants
Yes
297
  26.9%
266
  23.8%
563
  25.3%
No
493
  44.6%
495
  44.4%
988
  44.5%
Do not know
316
  28.6%
355
  31.8%
671
  30.2%
[1]
Measure Analysis Population Description: 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   [1] 
Median (Inter-Quartile Range)
Unit of measure:  Months
Number Analyzed 1102 Male-female couples [2]  1105 Male-female couples [3]  2207 Male-female couples [4] 
19
(12 to 36)
18
(12 to 36)
18
(12 to 36)
[1]
Measure Analysis Population Description: 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.
[2]
1102 participants
[3]
1105 participants
[4]
2207 participants
1.Primary Outcome
Title Live Birth
Hide Description Based on hospital delivery records
Time Frame At delivery
Hide Outcome Measure Data
Hide Analysis Population Description
Complete randomized cohort
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 1185 1185
Measure Type: Count of Participants
Unit of Measure: Participants
Overall Number Analyzed 1185 participants 1185 participants
404
  34.1%
416
  35.1%
IVF stratum Number Analyzed 185 participants 188 participants
97
  52.4%
91
  48.4%
Other treatment onsite Number Analyzed 831 participants 827 participants
264
  31.8%
277
  33.5%
Other treatment offsite Number Analyzed 169 participants 170 participants
43
  25.4%
48
  28.2%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Live birth will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -0.9
Confidence Interval (2-Sided) 95%
-4.7 to 2.8
Estimation Comments Adjusted for infertility treatment stratum and study site
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Live birth will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.98
Confidence Interval (2-Sided) 95%
0.88 to 1.09
Estimation Comments Adjusted for infertility treatment stratum and study site
2.Primary Outcome
Title Semen Volume
Hide Description 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.
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 794 836
Mean (Standard Deviation)
Unit of Measure: mL
Overall Number Analyzed 794 participants 836 participants
3.5  (1.7) 3.5  (1.8)
IVF stratum Number Analyzed 124 participants 135 participants
3.5  (1.5) 3.5  (1.7)
Other treatment onsite Number Analyzed 566 participants 590 participants
3.5  (1.7) 3.5  (1.8)
Other treatment offsite Number Analyzed 104 participants 110 participants
3.5  (1.7) 3.4  (1.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Semen volume will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0
Confidence Interval (2-Sided) 95%
-0.2 to 0.2
Estimation Comments Adjusted for infertility treatment stratum and study site.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Semen volume will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0
Confidence Interval (2-Sided) 95%
-0.1 to 0.2
Estimation Comments Weighted for loss to follow-up and adjusted for infertility treatment stratum and study site.
3.Primary Outcome
Title Sperm Concentration
Hide Description 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.
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 794 835
Mean (Standard Deviation)
Unit of Measure: 10^6 spermatozoa/mL
Overall Number Analyzed 794 participants 835 participants
84.8  (85.2) 89.0  (85.0)
IVF stratum Number Analyzed 124 participants 135 participants
81.8  (96.5) 76.1  (78.6)
Other treatment onsite Number Analyzed 566 participants 590 participants
85.0  (83.1) 92.2  (84.8)
Other treatment offsite Number Analyzed 104 participants 110 participants
87.2  (83.0) 87.7  (92.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. The confidence interval for sperm concentration represents 95.1% coverage to properly account for the alpha spent in the interim analysis.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -4.3
Confidence Interval (2-Sided) 95.1%
-12.5 to 3.9
Estimation Comments Adjusted for infertility treatment stratum and study site.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. The confidence interval for sperm concentration represents 95.1% coverage to properly account for the alpha spent in the interim analysis.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -5.2
Confidence Interval (2-Sided) 95.1%
-13.6 to 3.1
Estimation Comments Weighted for loss to follow-up and adjusted for fertility treatment stratum and study site.
4.Primary Outcome
Title Sperm Motility
Hide Description % 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.
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 794 835
Mean (Standard Deviation)
Unit of Measure: % motile
Overall Number Analyzed 794 participants 835 participants
52.7  (21.2) 53.2  (20.1)
IVF stratum Number Analyzed 124 participants 135 participants
51.7  (21.9) 51.7  (20.0)
Other treatment onsite Number Analyzed 566 participants 590 participants
52.5  (21.1) 53.9  (19.5)
Other treatment offsite Number Analyzed 104 participants 110 participants
55.0  (20.9) 51.5  (22.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. The confidence interval for sperm motility represents 95.1% coverage to properly account for the alpha spent in the interim analysis.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.5
Confidence Interval (2-Sided) 95.1%
-2.5 to 1.5
Estimation Comments Adjusted for infertility treatment stratum and study site.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. The confidence interval for sperm motility represents 95.1% coverage to properly account for the alpha spent in the interim analysis.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.6
Confidence Interval (2-Sided) 95.1%
-2.7 to 1.4
Estimation Comments Weighted for loss to follow-up and adjusted for infertility treatment stratum and study site.
5.Primary Outcome
Title Sperm Morphology
Hide Description % 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.
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 775 819
Mean (Standard Deviation)
Unit of Measure: % normal
Overall Number Analyzed 775 participants 819 participants
5.7  (4.2) 6.0  (4.8)
IVF stratum Number Analyzed 124 participants 135 participants
5.2  (4.3) 5.4  (4.7)
Other treatment onsite Number Analyzed 566 participants 590 participants
5.6  (4.0) 6.2  (4.9)
Other treatment offsite Number Analyzed 104 participants 110 participants
6.7  (4.9) 5.6  (4.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. The confidence interval for sperm morphology represents 95.1% coverage to properly account for the alpha spent in the interim analysis.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.4
Confidence Interval (2-Sided) 95.1%
-0.8 to 0.1
Estimation Comments Adjusted for infertility treatment stratum and study site.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. The confidence interval for sperm morphology represents 95.1% coverage to properly account for the alpha spent in the interim analysis.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.4
Confidence Interval (2-Sided) 95.1%
-0.9 to 0
Estimation Comments Weighted for loss to follow-up and adjusted for infertility treatment stratum and study site.
6.Primary Outcome
Title DNA Fragmentation Index
Hide Description 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.
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 750 781
Mean (Standard Deviation)
Unit of Measure: % breakage
Overall Number Analyzed 750 participants 781 participants
29.7  (20.5) 27.2  (17.8)
IVF stratum Number Analyzed 124 participants 135 participants
27.1  (19.6) 26.8  (19.6)
Other treatment onsite Number Analyzed 566 participants 590 participants
30.0  (20.3) 27.0  (16.8)
Other treatment offsite Number Analyzed 104 participants 110 participants
30.7  (22.7) 28.5  (20.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. DNA fragmentation will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2.4
Confidence Interval (2-Sided) 95%
0.5 to 4.4
Estimation Comments Adjusted for infertility treatment stratum and study site.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. DNA fragmentation will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2.3
Confidence Interval (2-Sided) 95%
0.3 to 4.3
Estimation Comments Weighted for loss to follow-up and adjusted for infertility treatment stratum and study site.
7.Primary Outcome
Title Total Motile Sperm Count
Hide Description Calculated as semen volume (mL) * sperm concentration (10^6 spermatozoa/mL) * motility (% motile)
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 793 834
Mean (Standard Deviation)
Unit of Measure: million motile sperm
Overall Number Analyzed 793 participants 834 participants
183  (226) 182  (212)
IVF stratum Number Analyzed 124 participants 135 participants
165  (221) 152  (188)
Other treatment onsite Number Analyzed 566 participants 590 participants
186  (226) 188  (207)
Other treatment offsite Number Analyzed 104 participants 110 participants
192  (233) 184  (262)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Total motile sperm count will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.4
Confidence Interval (2-Sided) 95%
-19.7 to 22.5
Estimation Comments Adjusted for infertility treatment stratum and study site.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Total motile sperm count will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.3
Confidence Interval (2-Sided) 95%
-20.9 to 21.4
Estimation Comments Weighted for loss to follow-up and adjusted for infertility treatment stratum and study site.
8.Secondary Outcome
Title Human Chorionic Gonadotropin (hCG) Detected Pregnancy (Implantation)
Hide Description A quantitative hCG evaluation in serum > 5 milli-international units per milliliter (mIU/ml)
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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 1185 1185
Measure Type: Count of Participants
Unit of Measure: Participants
479
  40.4%
490
  41.4%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. hCG detected pregnancy will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -0.9
Confidence Interval (2-Sided) 95%
-4.7 to 3.0
Estimation Comments Adjusted for infertility treatment stratum and study site.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. hCG detected pregnancy will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.00
Confidence Interval (2-Sided) 95%
0.91 to 1.09
Estimation Comments Adjusted for infertility treatment stratum and study site.
9.Secondary Outcome
Title Clinical Intrauterine Pregnancy
Hide Description Visualized gestational sac in the uterus on ultrasound
Time Frame approximately 6.5 weeks gestation
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 1185 1185
Measure Type: Count of Participants
Unit of Measure: Participants
449
  37.9%
462
  39.0%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Clinical intrauterine pregnancy will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -1.0
Confidence Interval (2-Sided) 95%
-4.9 to 2.8
Estimation Comments Adjusted for infertility treatment stratum and study site.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Clinical intrauterine pregnancy will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.98
Confidence Interval (2-Sided) 95%
0.89 to 1.08
Estimation Comments Adjusted for infertility treatment stratum and study site.
10.Secondary Outcome
Title Ectopic Pregnancy
Hide Description 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.
Time Frame approximately 6.5 weeks gestation
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 1185 1185
Measure Type: Count of Participants
Unit of Measure: Participants
6
   0.5%
5
   0.4%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Ectopic pregnancy will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.1
Confidence Interval (2-Sided) 95%
-0.5 to 0.6
Estimation Comments Adjusted for infertility treatment stratum and study site.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Ectopic pregnancy will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.21
Confidence Interval (2-Sided) 95%
0.37 to 3.97
Estimation Comments Adjusted for fertility treatment stratum and study site.
11.Secondary Outcome
Title Early Pregnancy Loss
Hide Description 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.
Time Frame hcG-detected pregnancy until 20 weeks of pregnancy
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 1185 1185
Measure Type: Count of Participants
Unit of Measure: Participants
137
  11.6%
150
  12.7%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Early pregnancy loss will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -1.1
Confidence Interval (2-Sided) 95%
-3.7 to 1.5
Estimation Comments Adjusted for infertility treatment stratum and study site.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Early pregnancy loss will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.93
Confidence Interval (2-Sided) 95%
0.75 to 1.15
Estimation Comments Adjusted for infertility treatment stratum and study site.
12.Secondary Outcome
Title Preeclampsia or Gestational Hypertension
Hide Description Abstracted from hospital records and medical charts
Time Frame Delivery
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 1185 1185
Measure Type: Count of Participants
Unit of Measure: Participants
47
   4.0%
51
   4.3%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Preeclampsia/gestational hypertension will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -0.3
Confidence Interval (2-Sided) 95%
-1.9 to 1.3
Estimation Comments Adjusted for infertility treatment stratum and study site.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Preeclampsia/gestational hypertension will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.92
Confidence Interval (2-Sided) 95%
0.63 to 1.36
Estimation Comments Adjusted for infertility treatment stratum and study site.
13.Secondary Outcome
Title Gestational Diabetes
Hide Description Abstracted from hospital records and medical charts
Time Frame Delivery
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 1185 1185
Measure Type: Count of Participants
Unit of Measure: Participants
26
   2.2%
34
   2.9%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Gestational diabetes will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -0.7
Confidence Interval (2-Sided) 95%
-1.9 to 0.6
Estimation Comments Adjusted for infertility treatment stratum and study site.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Gestational diabetes will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.77
Confidence Interval (2-Sided) 95%
0.47 to 1.27
Estimation Comments Adjusted for infertility treatment stratum and study site.
14.Secondary Outcome
Title Cesarean Delivery
Hide Description Abstracted from hospital records and medical charts
Time Frame Delivery
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 1185 1185
Measure Type: Count of Participants
Unit of Measure: Participants
143
  12.1%
129
  10.9%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Cesarean delivery will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 1.2
Confidence Interval (2-Sided) 95%
-1.4 to 3.8
Estimation Comments Adjusted for infertility treatment stratum and study site.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Cesarean delivery will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.12
Confidence Interval (2-Sided) 95%
0.89 to 1.39
Estimation Comments Adjusted for infertility treatment stratum and study site.
15.Secondary Outcome
Title Preterm Delivery
Hide Description Abstracted from hospital records and medical charts
Time Frame Delivery
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 1185 1185
Measure Type: Count of Participants
Unit of Measure: Participants
67
   5.7%
45
   3.8%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Preterm delivery will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 1.9
Confidence Interval (2-Sided) 95%
0.2 to 3.6
Estimation Comments Adjusted for infertility treatment stratum and study site.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Preterm delivery will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.49
Confidence Interval (2-Sided) 95%
1.04 to 2.16
Estimation Comments Adjusted for infertility treatment stratum and study site.
16.Secondary Outcome
Title Small for Gestational Age
Hide Description Abstracted from hospital records and medical charts
Time Frame Delivery
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 1185 1185
Measure Type: Count of Participants
Unit of Measure: Participants
62
   5.2%
59
   5.0%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Small for gestational age will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.3
Confidence Interval (2-Sided) 95%
-1.5 to 2.0
Estimation Comments Adjusted for infertility treatment stratum and study site.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Small for gestational age will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.05
Confidence Interval (2-Sided) 95%
0.75 to 1.49
Estimation Comments Adjusted for infertility treatment stratum and study site.
17.Secondary Outcome
Title Gestational Age
Hide Description Abstracted from hospital records and medical charts
Time Frame Delivery
Hide Outcome Measure Data
Hide Analysis Population Description
Among participants with live birth
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 404 416
Mean (Standard Deviation)
Unit of Measure: weeks
38.6  (2.5) 38.8  (2.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Gestational age will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -0.2
Confidence Interval (2-Sided) 95%
-0.5 to 0.1
Estimation Comments Adjusted for infertility treatment stratum and study site.
18.Secondary Outcome
Title Birth Weight
Hide Description Abstracted from hospital records and medical charts
Time Frame Delivery
Hide Outcome Measure Data
Hide Analysis Population Description
Among participants with live birth
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 404 416
Mean (Standard Deviation)
Unit of Measure: grams
3062  (731) 3133  (654)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Birth weight will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -64.7
Confidence Interval (2-Sided) 95%
-156 to 26.4
Estimation Comments Adjusted for infertility treatment stratum and study site.
19.Secondary Outcome
Title Stillbirth
Hide Description Loss at or after 20 weeks gestation. Determined based on hospital records and medical chart abstraction.
Time Frame Delivery
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 1185 1185
Measure Type: Count of Participants
Unit of Measure: Participants
1
   0.1%
4
   0.3%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Stillbirth will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -0.2
Confidence Interval (2-Sided) 95%
-0.6 to 0.1
Estimation Comments Adjusted for infertility treatment stratum and study site.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Stillbirth will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.25
Confidence Interval (2-Sided) 95%
0.03 to 2.24
Estimation Comments Adjusted for infertility treatment stratum and study site.
20.Secondary Outcome
Title Neonatal Mortality
Hide Description Abstracted from hospital records and medical charts
Time Frame Delivery
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 1185 1185
Measure Type: Count of Participants
Unit of Measure: Participants
3
   0.3%
2
   0.2%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Neonatal mortality will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.1
Confidence Interval (2-Sided) 95%
-0.3 to 0.5
Estimation Comments Adjusted for infertility treatment stratum and study site.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Neonatal mortality will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.50
Confidence Interval (2-Sided) 95%
0.25 to 8.95
Estimation Comments Adjusted for infertility treatment stratum and study site.
21.Secondary Outcome
Title Major Neonatal Complications
Hide Description Abstracted from hospital records and medical charts: includes bronchopulmonary dysplasia, necrotizing enterocolitis, severe intraventricular hemorrhage, periventricular leukomalacia, and retinopathy of prematurity
Time Frame Delivery
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 1185 1185
Measure Type: Count of Participants
Unit of Measure: Participants
2
   0.2%
1
   0.1%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Major neonatal complications will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.1
Confidence Interval (2-Sided) 95%
-0.2 to 0.4
Estimation Comments Adjusted for infertility treatment stratum and study site.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Major neonatal complications will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.99
Confidence Interval (2-Sided) 95%
0.18 to 21.9
Estimation Comments Adjusted for infertility treatment stratum and study site.
22.Secondary Outcome
Title Structural Malformations
Hide Description 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
Time Frame Delivery
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 1185 1185
Measure Type: Count of Participants
Unit of Measure: Participants
15
   1.3%
14
   1.2%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Structural malformations will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.1
Confidence Interval (2-Sided) 95%
-0.8 to 1.0
Estimation Comments Adjusted for infertility treatment stratum and study site.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Structural malformations will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.08
Confidence Interval (2-Sided) 95%
0.53 to 2.21
Estimation Comments Adjusted for infertility treatment stratum and study site.
23.Secondary Outcome
Title Severe Maternal Morbidity
Hide Description Abstracted from delivery record: including postpartum hemorrhage, anemia requiring transfusion, sepsis, seizure, HELLP syndrome or preeclampsia with pulmonary edema
Time Frame Delivery
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 1185 1185
Measure Type: Count of Participants
Unit of Measure: Participants
15
   1.3%
10
   0.8%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Severe maternal morbidity will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.4
Confidence Interval (2-Sided) 95%
-0.4 to 1.3
Estimation Comments Adjusted for infertility treatment stratum and study site.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Severe maternal morbidity will be compared using two sided tests conducted at the 0.05 level.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.50
Confidence Interval (2-Sided) 95%
0.68 to 3.32
Estimation Comments Adjusted for infertility treatment stratum and study site.
24.Secondary Outcome
Title Fertilization Rate Per Cycle, %
Hide Description 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.
Time Frame Up to 9 months of fertility treatment post-randomization
Hide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 107 107
Overall Number of Units Analyzed
Type of Units Analyzed: Cycles
124 119
Mean (Standard Deviation)
Unit of Measure: percent per cycle
75.3  (2.25) 77.7  (1.74)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Fertilization rate will be compared using generalized estimating equations accounting for multiple cycles per couple.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.34
Confidence Interval (2-Sided) 95%
-7.90 to 3.23
Estimation Comments [Not Specified]
25.Secondary Outcome
Title Number of Good Quality Embryos on Day 5 Per Cycle
Hide Description 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.
Time Frame Up to 9 months of fertility treatment post-randomization
Hide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 68 71
Overall Number of Units Analyzed
Type of Units Analyzed: Cycles
72 74
Mean (Standard Deviation)
Unit of Measure: embryos per cycle
2.66  (0.23) 2.98  (0.21)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Number of good quality embryos will be compared using Poisson regression with generalized estimating equations accounting for multiple cycles per couple.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.11
Confidence Interval (2-Sided) 95%
-0.33 to 0.11
Estimation Comments [Not Specified]
26.Secondary Outcome
Title Percentage of Good Quality Embryos on Day 5 Per Cycle
Hide Description 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.
Time Frame Up to 9 months of fertility treatment post-randomization
Hide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 107 107
Overall Number of Units Analyzed
Type of Units Analyzed: Cycles
124 119
Mean (Standard Deviation)
Unit of Measure: percent per cycle
17.2  (2.05) 18.5  (1.81)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Proportion of good quality embryos on day 5 will be compared using generalized estimating equations accounting for multiple cycles per couple.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.31
Confidence Interval (2-Sided) 95%
-6.66 to 4.05
Estimation Comments [Not Specified]
27.Secondary Outcome
Title Number of Embryos Transferred Per Cycle
Hide Description Among participants in the IVF stratum
Time Frame Up to 9 months of fertility treatment post-randomization
Hide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 117 126
Overall Number of Units Analyzed
Type of Units Analyzed: Cycles
147 152
Mean (Standard Deviation)
Unit of Measure: embryos per cycle
1.50  (0.06) 1.51  (0.05)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Number of embryos transferred will be compared using Poisson regression with generalized estimating equations accounting for multiple cycles per couple.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.01
Confidence Interval (2-Sided) 95%
-0.11 to 0.10
Estimation Comments [Not Specified]
28.Secondary Outcome
Title Number of Embryos Cryopreserved Per Cycle
Hide Description Among participants in the IVF stratum
Time Frame Up to 9 months of fertility treatment post-randomization
Hide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 84 100
Overall Number of Units Analyzed
Type of Units Analyzed: Cycles
92 116
Mean (Standard Deviation)
Unit of Measure: embryos per cycle
4.22  (0.32) 4.32  (0.31)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Number of embryos cryopreserved will be compared using Poisson regression with generalized estimating equations accounting for multiple cycles per couple.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.02
Confidence Interval (2-Sided) 95%
-0.23 to 0.18
Estimation Comments [Not Specified]
29.Secondary Outcome
Title Sperm Penetration Per Cycle, %
Hide Description Among participants in the IVF stratum
Time Frame Up to 9 months of fertility treatment post-randomization
Hide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 10 14
Mean (Standard Deviation)
Unit of Measure: percent penetration
62.7  (13.0) 74.8  (11.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Sperm penetration percentage will be compared using generalized estimating equations accounting for multiple cycles per couple.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -12.1
Confidence Interval (2-Sided) 95%
-45.4 to 21.2
Estimation Comments [Not Specified]
30.Secondary Outcome
Title Cells on Day 3 Per Embryo Per Cycle
Hide Description Among participants in the IVF stratum
Time Frame Up to 9 months of fertility treatment post-randomization
Hide Outcome Measure Data
Hide Analysis Population Description

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

Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 99 99
Overall Number of Units Analyzed
Type of Units Analyzed: Cycles
117 114
Mean (Standard Deviation)
Unit of Measure: cells per embryo
5.60  (0.20) 5.98  (0.19)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Number of cells on day 3 will be compared with Poisson regression using generalized estimating equations accounting for multiple embryos per cycle and multiple cycles per couple.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.07
Confidence Interval (2-Sided) 95%
-0.16 to 0.03
Estimation Comments [Not Specified]
31.Secondary Outcome
Title Cells on Day 3 Per Embryo Per Cycle, Categorical
Hide Description Number of cells per embryo among women in the IVF stratum
Time Frame Up to 9 months of fertility treatment post-randomization
Hide Outcome Measure Data
Hide Analysis Population Description

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

Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 99 99
Overall Number of Units Analyzed
Type of Units Analyzed: Cycles
114 114
Measure Type: Number
Unit of Measure: predicted probability
Fewer than 4 cells 0.27 0.22
4 cells or greater 0.73 0.78
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Number of cells on day 3 will be compared using generalized estimating equations accounting for multiple embryos per cycle and multiple cycles per couple.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.19
Confidence Interval (2-Sided) 95%
0.88 to 1.61
Estimation Comments Fewer than 4 cells
32.Secondary Outcome
Title Cells on Day 5 Per Embryo Per Cycle, Categorical
Hide Description Among participants in the IVF stratum
Time Frame Up to 9 months of fertility treatment post-randomization
Hide Outcome Measure Data
Hide Analysis Population Description

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

Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 119 121
Overall Number of Units Analyzed
Type of Units Analyzed: Cycles
141 141
Measure Type: Number
Unit of Measure: predicted probability
Fewer than 8 cells 0.20 0.19
8 cells or greater 0.80 0.81
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Number of cells on day 5 will be compared using generalized estimating equations accounting for multiple embryos per cycle and multiple cycles per couple.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.05
Confidence Interval (2-Sided) 95%
0.77 to 1.43
Estimation Comments Fewer than 8 cells
33.Secondary Outcome
Title Embryo Morphology on Day 3 Per Cycle, Categorical
Hide Description

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.

Time Frame Up to 9 months of fertility treatment post-randomization
Hide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 97 98
Overall Number of Units Analyzed
Type of Units Analyzed: Cycles
141 141
Measure Type: Number
Unit of Measure: predicted probability
Excellent or good 0.66 0.68
Fair or poor 0.34 0.32
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Embryo morphology on day 3 will be compared using generalized estimating equations accounting for multiple embryos per cycle and multiple cycles per couple.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.98
Confidence Interval (2-Sided) 95%
0.87 to 1.09
Estimation Comments Excellent or good morphology
34.Secondary Outcome
Title Embryo Morphology on Day 5 Per Cycle, Categorical
Hide Description 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.
Time Frame Up to 9 months of fertility treatment post-randomization
Hide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 114 116
Overall Number of Units Analyzed
Type of Units Analyzed: Cycles
132 134
Measure Type: Number
Unit of Measure: predicted probability
Excellent or good 0.28 0.35
Fair or poor 0.72 0.65
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Embryo morphology on day 5 will be compared using generalized estimating equations accounting for multiple embryos per cycle and multiple cycles per couple.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.82
Confidence Interval (2-Sided) 95%
0.63 to 1.06
Estimation Comments Excellent or good morphology
35.Secondary Outcome
Title Method of Fertilization Per Cycle
Hide Description Among participants in the in vitro fertilization (IVF) stratum: method of fertilization classified into intracytoplasmic sperm injection (ICSI) and other
Time Frame Up to 9 months of fertility treatment post-randomization
Hide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 122 130
Overall Number of Units Analyzed
Type of Units Analyzed: Cycles
145 157
Measure Type: Number
Unit of Measure: predicted probability
ICSI 0.74 0.79
Other 0.26 0.21
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Method of fertilization will be compared using generalized estimating equations accounting for multiple embryos per cycle and multiple cycles per couple.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.93
Confidence Interval (2-Sided) 95%
0.80 to 1.09
Estimation Comments ICSI
36.Secondary Outcome
Title Quality of Embryos Transferred Per Cycle, Categorical
Hide Description Among participants in the IVF stratum Embryonic grading based on Society for Assisted Reproductive Technologies (SART) morphology criteria
Time Frame Up to 9 months of fertility treatment post-randomization
Hide Outcome Measure Data
Hide Analysis Population Description
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
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
Hide Arm/Group Description:

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

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 103 105
Overall Number of Units Analyzed
Type of Units Analyzed: Cycles
121 125
Measure Type: Number
Unit of Measure: predicted probability
Excellent or good 0.75 0.73
Fair or poor 0.25 0.27
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Quality of embryos transferred will be compared using generalized estimating equations accounting for multiple embryos per cycle and multiple cycles per couple.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.03
Confidence Interval (2-Sided) 95%
0.88 to 1.21
Estimation Comments Excellent or good quality
37.Secondary Outcome
Title Chromosomal Complement of Embryo Per Cycle
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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.

Time Frame Up to 9 months of fertility treatment post-randomization
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Hide Analysis Population Description
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
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
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5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months.

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

Overall Number of Participants Analyzed 3 11
Overall Number of Units Analyzed
Type of Units Analyzed: Cycles
5 17
Measure Type: Number
Unit of Measure: predicted probability
Abnormal 0.75 0.32
Normal 0.25 0.68
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Folic Acid and Zinc Supplementation, Placebo
Comments The primary analysis plan is based on an "intention-to-treat" (ITT) approach comparing the two treatment arms based on the randomized assignment. The common null hypothesis states that the effect of folic acid/zinc on the outcomes is null compared to the placebo. Chromosomal complement will be compared using generalized estimating equations accounting for multiple cycles per couple.
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 2.35
Confidence Interval (2-Sided) 95%
0.74 to 7.43
Estimation Comments Abnormal
38.Other Pre-specified Outcome
Title Reproductive Hormones and Other Measured Biomarkers
Hide Description 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.
Time Frame 4 or 6 months
Outcome Measure Data Not Reported
Time Frame Adverse events were collected over the 6 month duration of the study.
Adverse Event Reporting Description Adverse events were only collected from the male partners.
 
Arm/Group Title Folic Acid and Zinc Supplementation Placebo
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5 mg folic acid and 30 mg elemental zinc, taken orally, daily for 6 months.

5 mg folic acid and 30 mg elemental zinc

Matching placebo, taken orally daily for 6 months.

Placebo Comparator: Placebo

All-Cause Mortality
Folic Acid and Zinc Supplementation Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/1185 (0.00%)   0/1185 (0.00%) 
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Folic Acid and Zinc Supplementation Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   7/1185 (0.59%)   5/1185 (0.42%) 
Cardiac disorders     
Myocardial infarction   0/1185 (0.00%)  1/1185 (0.08%) 
Pericardial effusion   0/1185 (0.00%)  1/1185 (0.08%) 
Gastrointestinal disorders     
Eosinophilic oesophagitis   1/1185 (0.08%)  0/1185 (0.00%) 
General disorders     
Chest pain   1/1185 (0.08%)  0/1185 (0.00%) 
Infections and infestations     
Appendicitis   0/1185 (0.00%)  1/1185 (0.08%) 
Clostridium difficile infection   1/1185 (0.08%)  0/1185 (0.00%) 
Staphylococcal infection   1/1185 (0.08%)  0/1185 (0.00%) 
Injury, poisoning and procedural complications     
Gun shot wound   0/1185 (0.00%)  1/1185 (0.08%) 
Musculoskeletal and connective tissue disorders     
Rhabdomyolysis   1/1185 (0.08%)  0/1185 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Respiratory failure   1/1185 (0.08%)  0/1185 (0.00%) 
Surgical and medical procedures     
Hospitalisation   1/1185 (0.08%)  0/1185 (0.00%) 
Variococele repair   0/1185 (0.00%)  1/1185 (0.08%) 
Indicates events were collected by systematic assessment
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Frequency Threshold for Reporting Other Adverse Events 5%
Folic Acid and Zinc Supplementation Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   189/1185 (15.95%)   162/1185 (13.67%) 
Gastrointestinal disorders     
Abdominal discomfort or pain   66/1185 (5.57%)  40/1185 (3.38%) 
General disorders     
Pyrexia   66/1185 (5.57%)  62/1185 (5.23%) 
Respiratory, thoracic and mediastinal disorders     
Oropharyngeal pain   57/1185 (4.81%)  60/1185 (5.06%) 
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
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Name/Title: Dr. Enrique Schisterman
Organization: NICHD
Phone: 3014356893
EMail: schistee@mail.nih.gov
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Responsible Party: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier: NCT01857310    
Other Study ID Numbers: FAZST
First Submitted: May 13, 2013
First Posted: May 20, 2013
Results First Submitted: August 30, 2020
Results First Posted: November 19, 2020
Last Update Posted: November 19, 2020