3 articles need to answer these questions: What are the elements of the study design, and why the authors made the choices they did? Identify the importance of this study and what it adds to the knowl

May 30, 2020 Study Design A Prospective Cohort Study to Evaluate the Impact of Diet, Exercise, and Lifestyle on Fertility: Design and Baseline Characteristics Sunni L. Mumford∗ , Erica Johnstone, Keewan Kim, Mudsar Ahmad, Shanna Salmon, Karen Summers, Kayla Chaney, Ginny Ryan, James M. Hotaling, Alexandra C. Purdue-Smithe, Zhen Chen, and Traci Clemons ∗ Correspondence to Dr. Sunni L. Mumford, Epidemiology Branch, Division of Intramural Population Health Research,Eunice Kennedy ShriverNational Institute of Child Health and Human Development, National Institutes of Health, 6710B Rockledge Drive, MSC 7004, Bethesda, MD 20892 (e-mail: [email protected]).

Initially submitted July 7, 2019; accepted for publication April 24, 2020. Diet, lifestyle, and psychosocial factors might inf luence fertility for men and women, although evidence is mixed, and couple-based approaches are needed for assessing associations with reproductive outcomes. The Impact of Diet, Exercise, and Lifestyle (IDEAL) on Fertility Study is a prospective cohort with contemporaneous detailed follow-up of female partners of men enrolled in the Folic Acid and Zinc Supplementation Trial studying couples seeking infertility treatment (2016–2019). Follow-up of men continued for 6 months, while female partners were followed for 9 months while attempting pregnancy and throughout any resulting pregnancy (up to 18 months).

Longitudinal data on diet, physical activity (including measurement via wearable device), sleep, and stress were captured at multiple study visits during this follow-up. A subset of women (IDEALplus) also completed daily journals and a body fat assessment via dual-energy x-ray absorptiometry. IDEAL enrolled 920 women, and IDEALPlus enrolled 218. We demonstrated the ability to enroll women in a prospective cohort study contemporaneous to a partner-enrolled randomized trial. In combination with data collected on male partners, IDEAL data facilitates a couple-based approach to understanding associations between lifestyle factors and infertility treatment outcomes. We describe in detail the study design, recruitment, data collection, lessons learned, and baseline characteristics.

diet; fertility; infertility treatment; lifestyle; pregnancy Abbreviations: DXA, dual-energy x-ray absorptiometry; FAZST, Folic Acid and Zinc Supplementation Trial; IDEAL, Impact of Diet, Exercise, and Lifestyle; IVF, in vitro fertilization; SD, standard deviation.

Infertility affects approximately 16% of couples in the United States (1,2). It is estimated that roughly one-third of infertility is caused by male disorders, one-third by female disorders, and one-third by combined male and female disorders (3). Many of the urological and/or gynecolog- ical disorders that lead to infertility are idiopathic, and unexplained infertility comprises a significant proportion of cases. At the same time, many of the potential identifiable “causes” of infertility, including oligo-ovulation, unilateral tubal obstruction, and suboptimal semen parameters, are not absolute blocks to pregnancy, and thus in many couples, multiple factors are likely at play. Psychosocial stressors, diet, and other potentially modifiable lifestyle factors inboth men and women have been shown to influence the hypothalamic pituitary gonadal axis, reproductive hormone concentrations, anovulation (4–8), inflammation (9–14), and other endocrine and metabolic pathways critical for reproduction (15), and could therefore have important downstream impacts on fertility (16–28). A couple-based definition of infertility highlights the importance of a couple-based approach to assessing lifestyle factors and re- productive success. Associations between lifestyle and psy- chosocial factors and ovulation, conception, implantation, and embryonic and fetal development remain largely un- explored, but they offer potential low-cost strategies to improve fertility. As yet, few well-conducted prospective 1254Am J Epidemiol.2020;189(11):1254–1265 Design of the IDEAL Fertility Study1255 studies have evaluated how these couple-level and individual factors might influence fertility in couples conceiving spon- taneously, as well as in those seeking infertility treatment.

In order to address these important research questions, we designed a prospective cohort study called Impact of Diet, Exercise, and Lifestyle (IDEAL) on Fertility by expanding follow-up of female partners of male participants in the Folic Acid and Zinc Supplementation Trial (FAZST). The FAZST trial is a multisite double-blind block-randomized placebo-controlled clinical trial to evaluate the effect of fo lic acid and zinc sulfate supplementation on semen quality and infertility treatment outcomes among male partners of couples seeking infertility treatment (29). The design of IDEAL allows for the analysis of preconception measures as well as longitudinal measures across critical sensitive windows of development throughout pregnancy, with the ability to combine data on both male and female partners for a couple-based approach. Furthermore, in this cohort of women recruited prior to conception, IDEAL is also able to evaluate associations between lifestyle factors and early pregnancy losses that are often not captured in studies that recruit pregnant women given that more than half of preg- nancy losses occur prior to 9 weeks of gestation (30). IDEAL study participants have presented seeking fertility treatment and, as such, are encouraged to test for pregnancy at the time of a missed period, and undergo serum pregnancy testing at this time, thus allowing for capture of very early pregnancy losses. The purpose of this paper is to describe the design of the IDEAL study, including recruitment and methodol- ogy, lessons learned, and baseline characteristics of enrolled participants.

METHODS Study objectives The primary aim of the IDEAL study is to evaluate the impact of dietary and other potentially modifiable lifestyle factors on prospectively measured pregnancy outcomes among couples seeking infertility treatment, including live birth, pregnancy, pregnancy loss, and specific pregnancy complications. Specific aims include the evaluation of preg- nancy-related outcomes in relation to: 1) dietary intake (par- ticularly dietary fiber, fat, phytoestrogens, caffeine, and vitamin D intake); 2) diet patterns (e.g., Mediterranean diet and low-carbohydrate diet); 3) adiposity and fat distribution (measured by dual-energy x-ray absorptiometry (DXA)) and the metabolic influences of adiposity, including leptin, insulin resistance, lipids, and inflammation; and 4) other lifestyle factors, such as physical activity, sleep, and psycho- social stress.

Study design and target population IDEAL is a prospective cohort study of the female part- ners in couples attempting to conceive and seeking infertility treatment. Women were recruited from couples whose male partners were enrolled in FAZST (29). Randomization was stratified by site and intended infertility treatment (in vitro fertilization (IVF), non-IVF/study site, and non-IVF/outsideclinic). Follow-up of men continued for 6 months, while fe- male partners were followed for 9 months while attempting to conceive and throughout any resulting pregnancy (up to 18 months). The IDEAL study specifically includes detailed follow-up through questionnaires, biospecimen collection, and activity monitoring during this time for a subset of female partners of FAZST participants, including up to 2 visits during infertility treatment and up to 3 pregnancy visits if they conceived.

This study was funded by the Intramural Research Pro- gram of theEunice Kennedy ShriverNational Institute of Child Health and Development and conducted at the Uni- versity of Utah and the University of Iowa. Institutional review board approval was obtained at each site and at the data coordinating center. All participants provided written informed consent. The FAZST trial was registered with clinicaltrials.gov(NCT01857310). The IDEAL study was overseen by an independent Data Safety and Monitoring Board, also responsible for the FAZST trial, that regularly reviewed the safety of all study participants, as well as data quality and timeliness, participant recruitment, accrual, and retention. Eligibility criteria Eligible participants included heterosexual couples (fe- male partner 18–45 years old and male partner aged 18 years or older) in a committed relationship, actively attempt- ing to conceive, and seeking infertility treatment. Specific eligibility criteria for the male partners have been detailed previously (29). Only female partners of male participants enrolled in FAZST at the University of Utah and the Uni- versity of Iowa were eligible for inclusion in IDEAL. In addition, women had to be willing to complete the additional questionnaires and biospecimen collection (Figure 1). Fur- ther eligibility for IDEALplus was based on willingness to undergo a DXA scan and to complete daily journals, and male partner willingness to undergo a DXA scan. Recruit- ment for FAZST started on June 3, 2013, with recruitment for IDEAL and IDEALplus starting on February 26, 2016.

Based on these criteria, 920 women were enrolled in IDEAL and 218 in IDEALplus (note that after the recruitment goal for IDEALplus was met, the enrollment for this portion was closed).

Baseline study visit The baseline enrollment visit was coordinated to occur at the same time as the FAZST enrollment visit. Data col- lection for female partners in FAZST at baseline consisted of a basic questionnaire regarding diet, physical activity, medication use, and reproductive history, as well as blood and urine collection and measurement of blood pressure and pulse. The baseline study visit for IDEAL included a questionnaire assessing pelvic pain and sexual health, as well as saliva collection. Participants were provided with a wrist-based fitness tracker (Fitbit Charge HR; Fitbit Inc., San Francisco, California) to track daily physical activity, heart rate, and sleep for 9 months while attempting to conceive, and throughout any resulting pregnancy (up to 18 months). Am J Epidemiol.2020;189(11):1254–1265 1256Mumford et al.

Figure 1.Recruitment and eligibility criteria for the Impact of Diet, Exercise, and Lifestyle (IDEAL) on Fertility Study, Folic Acid and Zinc Supplementation Trial (FAZST), and IDEALplus, United States, 2016–2019. CBAVD, congenital bilateral absence of the vas deferens; DXA, dual-energy x-ray absorptiometry; HIV/AIDS, human immunodeficiency virus/acquired immune deficiency syndrome.

Participants were instructed on how to use the fitness tracker and to sync their data to a smart phone application. The sub- set of women enrolled in IDEALplus received a DXA scan to assess body fat composition, as did their male partners. All women completed a urine pregnancy test at their baseline visit to confirm nonpregnant status. Women scheduled for DXA scans separate from their baseline visit were provided an additional urine pregnancy test to confirm nonpregnant status on the day of their scheduled DXA scan. DXA scans were conducted within 1 week of the baseline visit. Women in IDEALplus were also given access to an online journal to complete daily entries assessing dietary intake, sleep patterns, medication use, physical activity, and stress.

Follow-up visits As part of their participation in FAZST, female par- ticipants completed brief monthly online questionnaires regarding their pregnancy status and progress of infertilitytreatments during the 9 month follow-up period and through- out any pregnancy conceived during that window. Medical record abstraction by trained staff assessed infertility testing and treatments, prenatal care, obstetrical and neonatal out- comes using inpatient hospital records, and outpatient clinic records.

As part of the IDEAL protocol, participants also com- pleted up to 2 follow-up at-home data-collection visits while attempting to conceive, at months 2 and 4 after enrollment, that included online questionnaires and at-home biospeci- men collections (Figure 2). Specifically, participants com- pleted online questionnaires regarding dietary intake via the Automated Self-Administered 24-Hour Dietary Assess- ment (ASA24) (31) as well as other questionnaires, includ- ing the International Physical Activity Questionnaire (32), Pittsburgh Sleep Quality Index (33), Berlin Questionnaire for sleep apnea (34), the Perceived Stress Scale (35), and the Center for Epidemiologic Studies Depression Scale (36), to assess physical activity, sleep, stress, and depression. Am J Epidemiol.2020;189(11):1254–1265 Design of the IDEAL Fertility Study1257 Figure 2.

Data collection according to study visit in the Impact of Diet, Exercise, and Lifestyle (IDEAL) on Fertility Study, United States, 2016–2019.

DXA, dual-energy x-ray absorptiometry; FFQ, food frequency questionnaire. Circled plus sign indicates IDEALplus study components. Am J Epidemiol.2020;189(11):1254–1265 1258Mumford et al.

Ta b l e 1.Baseline Characteristics of Participants in the Impact of Diet, Exercise, and Lifestyle on Fertility Study, IDEALplus, and Folic Acid and Zinc Supplementation Trial, United States, 2016–2019 IDEAL (n= 920)IDEALplus (n=218)FAZST Non-IDEAL (n= 1,450)FA Z S T (n= 2,370) Characteristic No. % No. % No. % No. % Age, years a 30.7 (5.2) 30.3 (5.0) 30.7 (5.0) 30.7 (5.1) BMI a,b 29.2 (8.4) 28.7 (27.4) 28.0 (8.0) 28.5 (8.2) Randomization strata IVF 118 12.8 26 11.9 255 17.6 373 15.7 Non-IVF study site 701 76.2 153 70.2 957 66.0 1,658 70.0 Non-IVF outside clinic 101 11.0 39 17.9 238 16.4 339 14.3 Race/ethnicity White 765 83.2 184 84.4 1,191 82.1 1956 82.5 Black 12 1.3 4 1.8 31 2.1 43 1.8 Asian 41 4.5 9 4.1 90 6.2 131 5.5 Hispanic/Latino 52 5.7 11 5.0 75 5.2 127 5.4 Other race/ethnic groups 45 4.9 9 4.1 56 3.9 101 4.3 Do not wish to provide 5 0.5 1 0.5 7 0.5 12 0.5 Education High school or less 126 13.7 22 10.1 149 10.3 275 11.6 Some college 307 33.4 87 39.9 480 33.1 787 33.2 Bachelor’s degree 320 34.8 77 35.3 529 36.5 849 35.8 Master’s degree or higher 158 17.2 31 14.2 268 18.5 426 18.0 Do not wish to provide 9 1.0 1 0.5 24 1.7 33 1.4 Annual income, $ <40,000 118 12.8 29 13.3 215 14.8 333 14.1 40,000–74,999 325 35.3 83 38.1 552 38.1 877 37.0 75,000–99,999 198 21.5 44 20.2 297 20.5 495 20.9 ≥100,000 219 23.8 45 20.6 311 21.4 530 22.4 Do not wish to provide 60 6.5 17 7.8 75 5.2 135 5.7 Health insurance No 23 2.5 6 2.8 46 3.2 69 2.9 Yes 894 97.2 212 97.2 1,384 95.4 2,278 96.1 Do not wish to provide 3 0.3 0 0.0 20 1.4 23 1.0 Insurance cover infertility treatment No 378 41.1 97 44.5 636 43.9 1,014 42.8 Yes 287 31.2 59 27.1 395 27.2 682 28.8 Don’t know/do not wish to provide 229 24.9 56 25.7 353 24.3 582 24.6 Missing 26 2.8 6 2.8 66 4.6 92 3.9 Smoking Smoking in the past 3 months Never 798 86.7 198 90.8 1,257 86.7 2055 86.7 Rarely (1–4 times per month) 29 3.2 4 1.8 31 2.1 60 2.5 Sometimes (2–6 times per week) 11 1.2 1 0.5 10 0.7 21 0.9 Daily 20 2.2 4 1.8 28 1.9 48 2.0 Missing 62 6.7 11 5.0 124 8.6 186 7.8 Table continues Am J Epidemiol.2020;189(11):1254–1265 Design of the IDEAL Fertility Study1259 Ta b l e 1.Continued IDEAL (n= 920)IDEALplus (n=218)FAZST Non-IDEAL (n= 1,450)FA Z S T (n= 2,370) Characteristic No. % No. % No. % No. % Alcohol consumption in past 3 months Never 474 51.5 137 62.8 798 55.0 1,272 53.7 Rarely (1–4 times per month) 308 33.5 56 25.7 373 25.7 681 28.7 Sometimes (2–6 times per week) 72 7.8 12 5.5 150 10.3 222 9.4 Daily 4 0.4 2 0.9 4 0.3 8 0.3 Missing 62 6.7 11 5.0 125 8.6 187 7.9 Partner randomization arm Active 460 50.0 116 53.2 725 50.0 1,185 50.0 Placebo 460 50.0 102 46.8 725 50.0 1,185 50.0 Abbreviations: BMI, body mass index; FAZST, Folic Acid and Zinc Supplementation Trial; IDEAL, Impact of Diet, Exercise, and Lifestyle; IVF, in vitro fertilization.

aValues are expressed as mean (standard deviation).bWeight (kg)/height (m) 2. Participants were asked to collect a saliva sample at months 2 and 4, and toenails at month 4, to be returned to the clinic at the male partner’s visits. For couples undergoing IVF, serum was collected at the time of oocyte retrieval, as was follicular fluid and granulosa cells pooled from multiple follicles.

Participants who became pregnant during the 9-month follow-up period had 3 additional pregnancy follow-up clinic visits (1 per trimester) that included questionnaires, biospecimen collection, anthropometric measurements, and vital signs. All biospecimens were stored at−80 ◦C. The first trimester visit was scheduled at 6–8 weeks’ gestational age, the second trimester visit at 18–22 weeks’ gestational age, and the third trimester visit at 30–36 weeks’ gestational age. Throughout follow-up, participants were asked about daily fitness tracker use to ensure appropriate syncing and recording of information. Outcome measures The primary outcome of interest in the IDEAL study was live birth. Secondary outcomes included human chori- onic gonadotropin–recognized pregnancy, clinical intrauter- ine pregnancy, ectopic pregnancy, early pregnancy loss, spe- cific pregnancy complications (including cesarean delivery, preeclampsia, gestational diabetes, preterm birth, and infant being small for gestational age), and early embryonic devel- opment parameters among couples using assisted reproduc- tive technologies such as in IVF (29).

RESULTS From February 26, 2016, to December 30, 2017, a total of 920 women were enrolled in the IDEAL Study, withthe last third-trimester visit completed on January 31, 2019.

This represents 39% (920/2,370) of all female partners of FAZST participants and 97% (920/948) of those eligible for enrollment at the Utah and Iowa sites during the IDEAL recruitment period. From these 920, 218 women were addi- tionally enrolled in IDEALplus (24% of women enrolled in the IDEAL Study). Of those enrolled, 394 became pregnant over follow-up (360 with one pregnancy and 34 with two pregnancies), with 311 live births, 114 pregnancy losses, and 3 with unknown pregnancy outcome (Web Figure 1, available athttps://academic.oup.com/aje).

Baseline characteristics of IDEAL participants (n= 920), all female partners of FAZST participants (n= 2,370), female partners not included in the IDEAL Study (n= 1,450), and women enrolled in IDEALplus (n= 218) are summa- rized inTa b l e 1. The average age and body mass index of women enrolled in IDEAL were similar to female partners of FAZST participants overall (age: in IDEAL, 30.7 (standard deviation (SD), 5.2) years vs., in FAZST, 30.7 (SD, 5.1) years; body mass index: in IDEAL, 29.2 (SD, 8.4) vs., in FAZST, 28.5 (SD, 8.2)), although the average body mass index was slightly higher when compared with female partners not enrolled in IDEAL (IDEAL, 29.2 (SD, 8.4) vs., in non-IDEAL, 28.0 (SD, 8.0)). Most couples enrolled in IDEAL were planning non-IVF treatments at a study site upon enrollment, although a lower proportion of couples enrolled in IDEAL were planning to undergo IVF as compared with all couples in FAZST (12.8% vs. 15.7%). Women enrolled in IDEAL and IDEALplus tended to have a higher annual income and were more likely to have health insurance and insurance coverage for infertility treatment compared with female partners of FAZST participants not enrolled in IDEAL. Furthermore, women in IDEALplus were more likely never smokers and never drinkers compared with women enrolled in IDEAL Am J Epidemiol.2020;189(11):1254–1265 1260Mumford et al. Ta b l e 2 .Biospecimen Collections and Questionnaire Completions in the Impact of Diet, Exercise, and Lifestyle on Fertility Study, United States, 2016–2019 Infertility Treatment Pregnancy Follow-up Baseline (n= 920) a Month 2 (n= 828)Month 4 (n= 734)Oocyte Retrieval (IVF) b (n= 107)First Trimester (n= 302)Second Trimester (n= 290)Third Trimester (n= 267) Collection Component No. % No. % No. % No. % No. % No. % No. % Biospecimen collection Blood 773 84 44 41 205 68 176 61 154 57 Urine 918 99242 80 211 73 191 71 Saliva 874 95 649 78 573 78 243 80 214 74 192 71 Toenail 616 84 Follicular f luid60 56 Cord blood Placenta Questionnaires Lifestyle 815 89 738 89 631 86 259 86 198 68 177 66 ASA24 611 74 467 64 258 85 223 77 Anthropometry assessment Anthropometry 918 99254 84 218 75 193 71 DXA scan c 173 80 Abbreviations: ASA24, Automated Self-Administered 24-Hour Dietary Assessment; DXA, dual-energy x-ray absorptiometry; IVF, in vitro fertilization.aExpectedn. Denominators at each time point for calculation of % completion are based on the number of women expected to complete a given visit; some women withdrewfrom study participation, became pregnant during follow-up and switched to the pregnancy track, or had a pregnancy loss (and were not expected at subsequent pregnancy questionnaires and returned to infertility treatment follow-up). Of 920 women enrolled, 103 became pregnant, 5 withdrew, and 16 had a pregnancy loss before the month-2 visit (n= 828 expected at month 2); of 828 expected at month 2, 122 became pregnant, 6 withdrew, and 34 had a pregnancy loss before the month-4 visit (n= 734 expected at month 4); of 734 expected at month 4, 203 became pregnant, 5 withdrew, and 64 had a pregnancy loss through the end of follow-up. A total of 428 pregnancies were observed (from 394 women); of these, 101 were early pregnancy losses and 25 withdrew prior to the first trimester visit (n= 302 expected at first-trimester visit); of 302 expected at the first trimester, 12 experienced a loss during the second trimester (n= 290 expected at second-trimester visit); of 290 expected at the second trimester, 1 had a late loss, 1 withdrew, and 21 delivered preterm prior to their third-trimester visit (n= 267 expected at third-trimester visit). See Web Figure 2 for a detailed timeline. bNexpected = 107.cNexpected = 218. Am J Epidemiol.2020;189(11):1254–1265 Design of the IDEAL Fertility Study1261 Ta b l e 3 .Completion of Monthly Questionnaires in the Impact of Diet, Exercise, and Lifestyle on Fertility Study, IDEALplus, and Folic Acid and Zinc Supplementation Trial, United States, 2016–2019 IDEAL IDEALplus FAZST Non-IDEAL FAZST (n= 920) (n=218) (n= 1,450) (n= 2,370) Month Average Days of CompletionNo.

Complete% CompleteAverage Days of CompletionNo.

Complete% CompleteAverage Days of CompletionNo.

Complete% CompleteAverage Days of CompletionNo.

Complete% Complete 1 4.0 734 80 6.2 163 75 4.3 953 66 4.1 1,688 71 2 4.0 707 77 6.8 157 72 4.2 908 63 4.0 1,615 68 3 4.4 613 67 7.5 141 65 4.4 813 56 4.4 1,428 60 4 4.8 632 69 7.0 130 60 4.0 810 56 4.3 1,445 61 5 4.7 532 58 6.8 109 50 4.5 712 49 4.5 1,248 53 6 3.8 548 60 7.2 108 50 4.0 706 49 3.9 1,257 53 7 4.7 485 53 7.6 90 41 3.7 592 41 4.1 1,080 46 8 4.1 433 47 6.8 78 36 4.0 494 34 4.0 934 39 9 6.0 257 28 7.6 41 19 4.1 375 26 4.8 632 27 Overall 4.4 4,941 60 7.0 1,017 52 4.1 6,363 49 4.2 11,327 53 Abbreviations: FAZST, Folic Acid and Zinc Supplementation Trial; IDEAL, Impact of Diet, Exercise, and Lifestyle. or FAZST overall. Male partners of those women enrolled in the IDEAL study were similarly randomized to folic acid and zinc supplement (treatment group) or placebo. Although slightly more male partners of IDEALplus participants were randomized to treatment group compared with placebo group (53% vs. 47%), the difference was not substantial (P= 0.18).

Participants in the IDEAL study provided questionnaire data and biospecimens multiple times throughout follow up and pregnancy and were largely compliant with the study protocol, with 89% completing data collection at month 2 and 86% at month 4 (Ta b l e 2). Overall, women had higher completion rates for questionnaire components of the pro- tocol than for biospecimen collection, although the rate of questionnaire completion dropped substantially as preg- nancy progressed (86%, 68%, and 66% at first, second, and third trimester, respectively) for those with a resulting pregnancy.

Monthly questionnaires designed to follow infertility treat- ment and pregnancy status were completed as part of FAZST participation. Overall, women enrolled in the IDEAL and IDEALplus studies were more likely to complete the month- ly questionnaires compared with female partners of FAZST participants not enrolled in IDEAL, although completion rates for these also declined over time and the average days of completion were similar (Ta b l e 3). The average days of completion was somewhat longer for women enrolled in IDEALplus.

Overall, 94% of women had some Fitbit information available over follow-up (Ta b l e 4). Notably, 78% of women had over 3 months of data synced, and only 6% of women did not participate in the Fitbit component of the study.

The median number of days of activity synced was 184 (25th percentile: 124; 75th percentile: 255); with a median number of hours per day with heart rate information of 23.5 (25th percentile: 18.25; 75th percentile: 24). The median number of preconception days of activity was 141 (25th percentile: 66; 75th percentile: 188) including women who did not become pregnant over follow-up and the time prior to pregnancy among those that conceived. The median number of days of activity synced during pregnancy was 172 (25th percentile: 66; 75th percentile: 244). Women who either did not use the Fitbit or had more than 3 months of data were more likely to be older and have higher education, and were less likely to smoke or drink alcohol (Ta b l e 4). No differences in compliance were noted by stratum, body mass index, race, or insurance coverage.

DISCUSSION Dietary and lifestyle factors offer the potential for low- cost interventions to improve fertility, although well- designed prospective studies are needed to better understand associations with fertility and pregnancy outcomes. The IDEAL study was designed to answer these important questions by expanding follow-up of the female partners of FAZST participants to include more detailed questionnaire, biospecimen, and wearable fitness tracking data on the female partners. The IDEAL study results demonstrate the ability to recruit a large number of female partners for an Am J Epidemiol.2020;189(11):1254–1265 1262Mumford et al.

Ta b l e 4 .Baseline Characteristics of Participants in the Impact of Diet, Exercise, and Lifestyle on Fertility Study According to Compliance With Wrist-Based Fitness Tracker aBased on Number of Months With Synced Data Available, United States, 2016–2019 No Data (n= 52)<1 Month (n= 43)1–3 Months (n= 109)≥3 Months (n=716) Characteristic No. % No. % No. % No. %PValue Age, years b 32.8 (6.7) 28.1 (4.6) 29.2 (4.9) 30.9 (5.0)<0.0001 BMI b,c 28.0 (7.3) 31.3 (9.6) 29.9 (8.5) 29.1 (8.4) 0.21 Randomization strata0.16 IVF 12 23.1 5 11.6 14 12.8 87 12.2 Non-IVF study site 35 67.3 30 69.8 80 73.4 556 77.7 Non-IVF outside clinic 5 9.6 8 18.6 15 13.8 73 10.2 Race/ethnicity0.67 White 43 82.7 34 79.1 88 80.7 600 83.8 B l a c k 1 1. 9 1 2 . 3 2 1. 8 8 1. 1 Asian 4 7.7 1 2.3 3 2.8 33 4.6 Hispanic/Latino 1 1.9 3 7.0 8 7.3 40 5.6 Other race/ethnic groups 2 3.8 3 7.0 7 6.4 33 4.6 Do not wish to provide 1 1.9 1 2.3 1 0.9 2 0.3 Education0.0005 High school or less 8 15.4 8 18.6 25 22.9 85 11.9 Some college 18 34.6 18 41.9 44 40.4 227 31.7 Bachelor’s degree 16 30.8 12 27.9 27 24.8 265 37.0 Master’s degree or higher 8 15.4 3 7.0 13 11.9 134 18.7 Do not wish to provide 2 3.8 2 4.7 0 0 5 0.7 Annual income, $0.19 <40,000 8 15.4 6 14.0 17 15.6 87 12.2 40,000—74,999 17 32.7 15 34.9 47 43.1 246 34.4 75,000—99,999 6 11.5 9 20.9 16 14.7 167 23.3 ≥100,000 16 30.8 8 18.6 20 18.3 175 24.4 Do not wish to provide 5 9.6 5 11.6 9 8.3 41 5.7 Health insurance0.23 No 3 5.8 1 2.3 4 3.7 15 2.1 Yes 48 92.3 42 97.7 105 96.3 699 97.6 Do not wish to provide 1 1.9 0 0 0 0 2 0.3 Insurance cover infertility treatment0.38 No 22 42.3 22 51.2 47 43.1 287 40.1 Yes 16 30.8 9 20.9 35 32.1 227 31.7 Don’t know/do not wish to provide 10 19.2 11 25.6 23 21.1 185 25.8 Missing 4 7.7 1 2.3 4 3.7 17 2.4 Smoking Smoking in the past 3 months<0.0001 Never 39 75.0 22 51.2 80 73.4 657 91.8 Rarely (1–4 times per month) 2 3.8 3 7.0 6 5.5 18 2.5 Sometimes (2–6 times per week) 0 0 2 4.7 1 0.9 8 1.1 Daily 0 0 2 4.7 4 3.7 14 2.0 Missing 11 21.2 14 32.6 18 16.5 19 2.7 Table continues Am J Epidemiol.2020;189(11):1254–1265 Design of the IDEAL Fertility Study1263 Ta b l e 4 .Continued No Data (n= 52)<1 Month (n= 43)1–3 Months (n= 109)≥3 Months (n=716) Characteristic No. % No. % No. % No. %PValue Ever smoked≥100 cigarettes<0.0001 No 38 73.1 23 53.5 82 75.2 608 84.9 Yes 3 5.8 5 11.6 9 8.3 89 12.4 Missing 11 21.2 15 34.9 18 16.5 19 2.7 Alcohol consumption in past 3 months<0.0001 Never 26 50.0 15 34.9 46 42.2 387 54.1 Rarely (1–4 times per month) 10 19.2 13 30.2 37 33.9 248 34.6 Sometimes (2–6 times per week) 5 9.6 1 2.3 8 7.3 58 8.1 Daily 0 0 0 0 0 0 4 0.6 Missing 11 21.2 14 32.6 18 16.5 19 2.7 Partner randomization arm0.38 Active 20 38.5 22 51.2 57 52.3 361 50.4 Placebo 32 61.5 21 48.8 52 47.7 355 49.6 Abbreviations: BMI, body mass index; IVF, in vitro fertilization.aFitbit Charge HR; Fitbit Inc., San Francisco, California.bValues are expressed as mean (standard deviation).cWeight (kg)/height (m) 2. intensive study during infertility treatment (Figure 3)and provide a rich data source that can be linked to data on the male partners in FAZST for a couple-based approach to understanding lifestyle influences on infertility.

The design of the IDEAL study allows for the analysis of preconception samples as well as longitudinal measure- ments across critical windows of development throughout pregnancy. Furthermore, because this cohort of women was recruited prior to conception and in the infertility clinic setting, the IDEAL study is positioned to capture the timing of key pregnancy-related events such as fertilization (in the setting of IVF), implantation, clinical pregnancy recogni- tion, early pregnancy loss, and gestational age. Considering the stress and disruption of daily-life activities that infertility treatment imposes upon couples, this study was designed to be comprehensive while minimizing burden. At-home ques- tionnaires and biospecimen collection were implemented during infertility treatment to allow for schedule flexibility preferred by participants. Indeed, higher compliance was observed for the at-home questionnaires than for compo- nents that required a clinic visit. Compliance also improved with frequent reminders and the availability of staff support for completion of any outstanding items when they came into the clinic. Further, structuring study visits to align with clinical appointments, particularly during pregnancy, as well as offering flexible hours for visits improved retention and study visit completion. Despite these efforts, monthly questionnaire compliance was low, perhaps due to the par- ticular sensitivity of the questions to confirm pregnancyand infertility treatment status during this stressful time for participants. Importantly, we had planned for detailed chart abstraction from the outset of the FAZST trial so that impor- tant outcomes, such as pregnancy, loss, and live birth, would be captured regardless of the self-report. The low response rates were observed prior to the initiation of IDEAL and so additional tools to improve staff tracking of pregnancies were implemented in IDEAL to ensure that pregnancies were reported in a timely manner so that the IDEAL preg- nancy visits could be scheduled accordingly. Specifically, real-time tracking of electronic medical records to determine pregnancy and infertility treatment status proved to be a useful strategy because compliance with monthly question- naires was low despite these improvements.

The IDEAL study included innovative approaches for data collection, including a comprehensive assessment of body fat (using DXA combined with detailed anthropo- metric measurements), time-varying dietary questionnaires, and sleep and physical activity assessments using Fitbit.

Fitbits offer a noninvasive approach to prospectively collect detailed data on physical activity and sleep, and we found that participants in the study were highly compliant with the study protocol, with over 75% of women providing daily data for at least 3 months during follow-up. Staff noted that frequent reminders for syncing were needed. Compliance with wearing the fitness trackers was related to certain demo- graphic characteristics, including age, education, smoking, and alcohol intake. Interestingly, we observed similar pat- terns among those with high compliance as those who did Am J Epidemiol.2020;189(11):1254–1265 1264Mumford et al.

not wear the fitness trackers. To our knowledge, this is the first large-scale trial to use Fitbit or an equivalent tracker to obtain real-time data on a large cohort of women trying to conceive that demonstrates feasibility of having participants wear the tracker over a relatively long period of follow-up time.

This study provided a unique opportunity during critical periconception windows to explore the patterns of lifestyle factors and how these factors are associated with pregnancy outcomes. Although the results will be generalizable only to women seeking infertility treatment, these findings will provide much-needed evidence to inform clinical recom- mendations on low-cost strategies to optimize fecundability in an environment where infertility treatments are typically expensive and rarely covered by insurance.

Figure 3.Lessons learned during the design and recruitment of the Impact of Diet, Exercise, and Lifestyle (IDEAL) on Fertility Study, United States, 2016–2019.

ACKNOWLEDGMENTS Author affiliations: Epidemiology Branch, Division of Intramural Population Health Research,Eunice Kennedy ShriverNational Institute of Child Health and Human Development, Bethesda, Maryland (Sunni L. Mumford, Keewan Kim, Alexandra C. Purdue-Smithe); Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah (Erica Johnstone, Mudsar Ahmad, Shanna Salmon); Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, Iowa City, Iowa (Karen Summers, Ginny Ryan); The Emmes Company LLC, Rockville, Maryland (Kayla Chaney, Traci Clemons); Department of Surgery (Urology), Center for Reconstructive Urology and Men’s Health, University of Utah School of Medicine, Salt Lake City, Utah(James M. Hotaling); Department of Obstetrics and Gynecology, Center for Reconstructive Urology and Men’s Health, University of Utah School of Medicine, Salt Lake City, Utah (James M. Hotaling); and Biostatistics and Bioinformatics Branch, Division of Intramural Population Health Research,Eunice Kennedy ShriverNational Institute of Child Health and Human Development, Bethesda, Maryland (Zhen Chen).

This research was supported by the Intramural Research Program of theEunice Kennedy ShriverNational Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (contracts HHSN275201500001C, HHSN275201300026I/ HHSN27500008, and HHSN275201300026I/ HHSN27500018).

We thank all of the Folic Acid and Zinc Supplementation Trial and Impact of Diet, Exercise, and Lifestyle investigators, fellows, and staff who devoted their time and energy to the success of these studies, and the Data Safety and Monitoring Board members for ongoing oversight, constant support, and advice throughout the trial.

J.M.H. reports equity in early stage startups (streamDX, Nanonc, Andro360), grants from Endo Pharmaceuticals, and grants from Boston Scientific, that are unrelated to this work. The other authors report no conflicts. REFERENCES 1. Evers JL. Female subfertility.Lancet. 2002;360(9327):

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