Evaluating participant engagement in a preconception cohort study in relation to the Dobbs decision.

BACKGROUND: On June 24th, 2022, the United States (US) Supreme Court's ruling in Dobbs v. Jackson, et al. (hereafter, the Dobbs decision) removed federal-level protections for induced abortion, sparking concerns about reproductive rights and health privacy. Although other pregnancy outcomes (e.g. spontaneous abortion, ectopic pregnancy) are not explicit targets of post-Dobbs abortion bans, study participants may be worried about how their reproductive health data are used by researchers in the post-Dobbs era. OBJECTIVE: To evaluate the extent to which the Dobbs decision influenced participant's engagement in a preconception cohort study. METHODS: We leveraged data spanning 20 weeks before and after the Dobbs decision (4 February 2022, to 11 November 2022) from US participants in Pregnancy Study Online (PRESTO), an internet-based prospective preconception cohort study of couples attempting conception. We categorised participants' state-level abortion access by residential location: banned or restricted rights; limited access; and protected rights. We evaluated three participant engagement outcomes: follow-up questionnaire completion; report of a pregnancy; and clicking on the invitation link for a fertility-tracking app. We fit separate linear regression models and restricted cubic splines to compare outcome prevalence before and after the Dobbs decision by state-level abortion category. RESULTS: A total of 585 newly enrolled participants and 1247 already-enrolled participants received 2802 invitations to complete a follow-up questionnaire. In states with limited or protected abortion rights, we observed little change in participant engagement. In states with banned or restricted abortion rights, however, we observed a 27.12 percentage point reduction (95% confidence interval -43.68, -10.51) in the prevalence of clicking on the invitation link for the fertility-tracking app comparing the post- versus pre-Dobbs periods. CONCLUSIONS: There was some evidence of reduced participant engagement after the Dobbs decision in states with banned or restricted abortion rights, indicating potentially deleterious effects on the conduct of reproductive health studies.

Use of Chemical Hair Straighteners and Fecundability in a North American Preconception Cohort.

Chemical hair straighteners ("relaxers") are used by millions of North Americans, particularly women of color. Hair relaxers may contain endocrine-disrupting compounds, which can harm fertility. We evaluated the association between hair relaxer use and fecundability among 11,274 participants from Pregnancy Study Online (PRESTO), a North American preconception cohort study. During 2014-2022, participants completed a baseline questionnaire in which they reported their history of relaxer use and completed follow-up questionnaires every 8 weeks for 12 months or until pregnancy, whichever came first. We used multivariable-adjusted proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs). Relative to never use, fecundability was lower among current (FR = 0.81, 95% CI: 0.64, 1.03) and former (FR = 0.89, 95% CI: 0.81, 0.98) users of hair relaxers. FRs for first use of hair relaxers at ages <10, 10-19, and ≥20 years were 0.73 (95% CI: 0.55, 0.96), 0.93 (95% CI: 0.83, 1.04), and 0.85 (95% CI: 0.74, 0.98), respectively. Fecundability was lowest among those with longer durations of use (≥10 years vs. never: FR = 0.71, 95% CI: 0.54, 0.91) and more frequent use (≥5 times/year vs. never: FR = 0.82, 95% CI: 0.60, 1.11), but associations were nonmonotonic. In this preconception cohort study, use of chemical hair straighteners was associated with slightly reduced fecundability.

A prospective cohort study of preconception COVID-19 vaccination and miscarriage.

STUDY QUESTION: To what extent is preconception maternal or paternal coronavirus disease 2019 (COVID-19) vaccination associated with miscarriage incidence? SUMMARY ANSWER: COVID-19 vaccination in either partner at any time before conception is not associated with an increased rate of miscarriage. WHAT IS KNOWN ALREADY: Several observational studies have evaluated the safety of COVID-19 vaccination during pregnancy and found no association with miscarriage, though no study prospectively evaluated the risk of early miscarriage (gestational weeks [GW] <8) in relation to COVID-19 vaccination. Moreover, no study has evaluated the role of preconception vaccination in both male and female partners. STUDY DESIGN, SIZE, DURATION: An Internet-based, prospective preconception cohort study of couples residing in the USA and Canada. We analyzed data from 1815 female participants who conceived during December 2020-November 2022, including 1570 couples with data on male partner vaccination. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible female participants were aged 21-45 years and were trying to conceive without use of fertility treatment at enrollment. Female participants completed questionnaires at baseline, every 8 weeks until pregnancy, and during early and late pregnancy; they could also invite their male partners to complete a baseline questionnaire. We collected data on COVID-19 vaccination (brand and date of doses), history of SARS-CoV-2 infection (yes/no and date of positive test), potential confounders (demographic, reproductive, and lifestyle characteristics), and pregnancy status on all questionnaires. Vaccination status was categorized as never (0 doses before conception), ever (≥1 dose before conception), having a full primary sequence before conception, and completing the full primary sequence ≤3 months before conception. These categories were not mutually exclusive. Participants were followed up from their first positive pregnancy test until miscarriage or a censoring event (induced abortion, ectopic pregnancy, loss to follow-up, 20 weeks' gestation), whichever occurred first. We estimated incidence rate ratios (IRRs) for miscarriage and corresponding 95% CIs using Cox proportional hazards models with GW as the time scale. We used propensity score fine stratification weights to adjust for confounding. MAIN RESULTS AND THE ROLE OF CHANCE: Among 1815 eligible female participants, 75% had received at least one dose of a COVID-19 vaccine by the time of conception. Almost one-quarter of pregnancies resulted in miscarriage, and 75% of miscarriages occurred <8 weeks' gestation. The propensity score-weighted IRR comparing female participants who received at least one dose any time before conception versus those who had not been vaccinated was 0.85 (95% CI: 0.63, 1.14). COVID-19 vaccination was not associated with increased risk of either early miscarriage (GW: <8) or late miscarriage (GW: 8-19). There was no indication of an increased risk of miscarriage associated with male partner vaccination (IRR = 0.90; 95% CI: 0.56, 1.44). LIMITATIONS, REASONS FOR CAUTION: The present study relied on self-reported vaccination status and infection history. Thus, there may be some non-differential misclassification of exposure status. While misclassification of miscarriage is also possible, the preconception cohort design and high prevalence of home pregnancy testing in this cohort reduced the potential for under-ascertainment of miscarriage. As in all observational studies, residual or unmeasured confounding is possible. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to evaluate prospectively the relation between preconception COVID-19 vaccination in both partners and miscarriage, with more complete ascertainment of early miscarriages than earlier studies of vaccination. The findings are informative for individuals planning a pregnancy and their healthcare providers. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Health [R01-HD086742 (PI: L.A.W.); R01-HD105863S1 (PI: L.A.W. and M.L.E.)], the National Institute of Allergy and Infectious Diseases (R03-AI154544; PI: A.K.R.), and the National Science Foundation (NSF-1914792; PI: L.A.W.). The funders had no role in the study design, data collection, analysis and interpretation of data, writing of the report, or the decision to submit the paper for publication. L.A.W. is a fibroid consultant for AbbVie, Inc. She also receives in-kind donations from Swiss Precision Diagnostics (Clearblue home pregnancy tests) and Kindara.com (fertility apps). M.L.E. received consulting fees from Ro, Hannah, Dadi, VSeat, and Underdog, holds stock in Ro, Hannah, Dadi, and Underdog, is a past president of SSMR, and is a board member of SMRU. K.F.H. reports being an investigator on grants to her institution from UCB and Takeda, unrelated to this study. S.H.-D. reports being an investigator on grants to her institution from Takeda, unrelated to this study, and a methods consultant for UCB and Roche for unrelated drugs. The authors report no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER: N/A.

Periconceptional antibiotic use and spontaneous abortion: A prospective cohort study.

BACKGROUND: Many reproductive-aged North Americans use antibiotics in the weeks preceding conception or during early pregnancy. Antibiotic use may influence risk of spontaneous abortion (SAB) by disrupting the reproductive tract microbiome or treating harmful infections. However, this association has not been extensively studied. OBJECTIVE: To determine the extent to which periconceptional antibiotic use is associated with the risk of SAB. METHODS: We analysed data from an internet-based preconception cohort study of pregnancy planners. Eligible participants self-identified as female, were aged 21-45 years, resided in the USA or Canada, and conceived during 12 months of follow-up (n = 7890). Participants completed an enrolment questionnaire during June 2013-September 2021 and bimonthly follow-up questionnaires for up to 12 months or until a reported pregnancy, whichever came first. Pregnant participants completed questionnaires in early (~8-9 weeks) and late (~32 weeks) gestation. We assessed antibiotic use, including type (penicillins, nitrofurantoin, cephalosporins and macrolides) and indication for use, during the previous 4 weeks on preconception questionnaires. Participants reported pregnancies and SAB on follow-up and pregnancy questionnaires. We used Cox proportional hazards regression models with gestational weeks as the time scale to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between periconceptional antibiotic use and SAB, controlling for potential demographic, medical, and lifestyle confounders. RESULTS: Nineteen percent (n = 1537) of pregnancies ended in SAB. Participants reported periconceptional antibiotic use in 8% of pregnancies ending in SAB and 7% not ending in SAB. Periconceptional antibiotic use was not appreciably associated with SAB (adjusted HR 1.06, 95% CI 0.88, 1.28). We observed no strong associations between antibiotic type, indication for use, or recency of exposure and SAB risk. CONCLUSIONS: Periconceptional antibiotic use was not appreciably associated with SAB in this study. This association is likely complicated by antibiotic type and dosage, timing of conception, and the individual's overall health.

A Prospective Cohort Study of COVID-19 Vaccination, SARS-CoV-2 Infection, and Fertility.

Some reproductive-aged individuals remain unvaccinated against coronavirus disease 2019 (COVID-19) because of concerns about potential adverse effects on fertility. Using data from an internet-based preconception cohort study, we examined the associations of COVID-19 vaccination and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with fertility among couples trying to conceive spontaneously. We enrolled 2,126 self-identified female participants aged 21-45 year residing in the United States or Canada during December 2020-September 2021 and followed them through November 2021. Participants completed questionnaires every 8 weeks on sociodemographics, lifestyle, medical factors, and partner information. We fit proportional probabilities regression models to estimate associations between self-reported COVID-19 vaccination and SARS-CoV-2 infection in both partners with fecundability (i.e., the per-cycle probability of conception), adjusting for potential confounders. COVID-19 vaccination was not appreciably associated with fecundability in either partner (female fecundability ratio (FR) = 1.08, 95% confidence interval (CI): 0.95, 1.23; male FR = 0.95, 95% CI: 0.83, 1.10). Female SARS-CoV-2 infection was not strongly associated with fecundability (FR = 1.07, 95% CI: 0.87, 1.31). Male infection was associated with a transient reduction in fecundability (for infection within 60 days, FR = 0.82, 95% CI: 0.47, 1.45; for infection after 60 days, FR = 1.16, 95% CI: 0.92, 1.47). These findings indicate that male SARS-CoV-2 infection may be associated with a short-term decline in fertility and that COVID-19 vaccination does not impair fertility in either partner.

Predictive models of pregnancy based on data from a preconception cohort study.

STUDY QUESTION: Can we derive adequate models to predict the probability of conception among couples actively trying to conceive? SUMMARY ANSWER: Leveraging data collected from female participants in a North American preconception cohort study, we developed models to predict pregnancy with performance of ∼70% in the area under the receiver operating characteristic curve (AUC). WHAT IS KNOWN ALREADY: Earlier work has focused primarily on identifying individual risk factors for infertility. Several predictive models have been developed in subfertile populations, with relatively low discrimination (AUC: 59-64%). STUDY DESIGN, SIZE, DURATION: Study participants were female, aged 21-45 years, residents of the USA or Canada, not using fertility treatment, and actively trying to conceive at enrollment (2013-2019). Participants completed a baseline questionnaire at enrollment and follow-up questionnaires every 2 months for up to 12 months or until conception. We used data from 4133 participants with no more than one menstrual cycle of pregnancy attempt at study entry. PARTICIPANTS/MATERIALS, SETTING, METHODS: On the baseline questionnaire, participants reported data on sociodemographic factors, lifestyle and behavioral factors, diet quality, medical history and selected male partner characteristics. A total of 163 predictors were considered in this study. We implemented regularized logistic regression, support vector machines, neural networks and gradient boosted decision trees to derive models predicting the probability of pregnancy: (i) within fewer than 12 menstrual cycles of pregnancy attempt time (Model I), and (ii) within 6 menstrual cycles of pregnancy attempt time (Model II). Cox models were used to predict the probability of pregnancy within each menstrual cycle for up to 12 cycles of follow-up (Model III). We assessed model performance using the AUC and the weighted-F1 score for Models I and II, and the concordance index for Model III. MAIN RESULTS AND THE ROLE OF CHANCE: Model I and II AUCs were 70% and 66%, respectively, in parsimonious models, and the concordance index for Model III was 63%. The predictors that were positively associated with pregnancy in all models were: having previously breastfed an infant and using multivitamins or folic acid supplements. The predictors that were inversely associated with pregnancy in all models were: female age, female BMI and history of infertility. Among nulligravid women with no history of infertility, the most important predictors were: female age, female BMI, male BMI, use of a fertility app, attempt time at study entry and perceived stress. LIMITATIONS, REASONS FOR CAUTION: Reliance on self-reported predictor data could have introduced misclassification, which would likely be non-differential with respect to the pregnancy outcome given the prospective design. In addition, we cannot be certain that all relevant predictor variables were considered. Finally, though we validated the models using split-sample replication techniques, we did not conduct an external validation study. WIDER IMPLICATIONS OF THE FINDINGS: Given a wide range of predictor data, machine learning algorithms can be leveraged to analyze epidemiologic data and predict the probability of conception with discrimination that exceeds earlier work. STUDY FUNDING/COMPETING INTEREST(S): The research was partially supported by the U.S. National Science Foundation (under grants DMS-1664644, CNS-1645681 and IIS-1914792) and the National Institutes for Health (under grants R01 GM135930 and UL54 TR004130). In the last 3 years, L.A.W. has received in-kind donations for primary data collection in PRESTO from FertilityFriend.com, Kindara.com, Sandstone Diagnostics and Swiss Precision Diagnostics. L.A.W. also serves as a fibroid consultant to AbbVie, Inc. The other authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Air pollution and fecundability: Results from a Danish preconception cohort study.

BACKGROUND: Animal and epidemiologic studies indicate that air pollution may adversely affect fertility. Epidemiologic studies have been restricted largely to couples undergoing fertility treatment or have retrospectively ascertained time-to-pregnancy among pregnant women. OBJECTIVES: We examined the association between residential ambient air pollution and fecundability, the per-cycle probability of conception, in a large preconception cohort of Danish pregnancy planners. METHODS: During 2007-2018, we used the Internet to recruit and follow women who were trying to conceive without the use of fertility treatment. Participants completed an online baseline questionnaire eliciting socio-demographic characteristics, lifestyle factors, and medical and reproductive histories and follow-up questionnaires every 8 weeks to ascertain pregnancy status. We determined concentrations of ambient nitrogen oxides (NOx ), nitrogen dioxide (NO2 ), carbon monoxide (CO), ozone (O3 ), particulate matter <2.5 µm (PM2.5 ) and <10 µm (PM10 ), and sulphur dioxide (SO2 ) at each participant's residential address. We calculated average exposure during the year before baseline, during each menstrual cycle over follow-up and during the entire pregnancy attempt time. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs), adjusting for potential confounders and co-pollutants. The analysis was restricted to the 10,183 participants who were trying to conceive for <12 cycles at study entry whose addresses could be geocoded. RESULTS: During 12 months of follow-up, 73% of participants conceived. Higher concentrations of PM2.5 and PM10 were associated with small reductions in fecundability. For example, the FRs for a one interquartile range (IQR) increase in PM2.5 (IQR = 3.2 µg/m3 ) and PM10 (IQR = 5.3 µg/m3 ) during each menstrual cycle were 0.93 (95% CI: 0.87, 0.99) and 0.91 (95% CI: 0.84, 0.99), respectively. Other air pollutants were not appreciably associated with fecundability. CONCLUSIONS: In this preconception cohort study of Danish women, residential exposures to PM2.5 and PM10 were associated with reduced fecundability.

Protein-rich food intake and risk of spontaneous abortion: a prospective cohort study.

PURPOSE: Diet quality is increasingly recognized as important for human reproductive capacity. We studied the association between intake of protein-rich foods and risk of spontaneous abortion (SAB). METHODS: During 2013-2020, we recruited pregnancy planners from the United States and Canada (Pregnancy Study Online; PRESTO) and Denmark (SnartForaeldre.dk; SF). Participants completed a baseline questionnaire and a validated cohort-specific food frequency questionnaire. We estimated preconception intake of red meat, poultry, processed meat, seafood, eggs, plant-based proteins, and dairy from individual foods and mixed recipes. We included 4,246 PRESTO and 2,953 SF participants who reported a pregnancy during the study. Data on SAB were derived from questionnaires and population registries. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CI), representing the effect of substituting one type of protein-rich food for another. RESULTS: SAB risk was 23% in PRESTO and 16% in SF. In PRESTO, substitution of seafood with other protein-rich foods was associated with higher SAB risk [for example, the HR for replacing 100 g of seafood/week with 100 g of red meat was 1.10 (95% CI 1.00, 1.20)]. In contrast, in SF, substituting seafood with other protein-rich foods was associated with lower SAB risk [HR for replacing 100 g of seafood/week with 100 g of red meat was 0.89 (95% CI 0.82, 0.98)]. Other protein-rich food substitutions were not meaningfully associated with SAB risk. CONCLUSIONS: Preconception intake of protein-rich foods was largely unrelated to SAB risk, with the exception of seafood, which was associated with higher risk of SAB in Denmark, but a lower risk in North America.

Antibiotics and fecundability among female pregnancy planners: a prospective cohort study.

STUDY QUESTION: To what extent is female preconception antibiotic use associated with fecundability? SUMMARY ANSWER: Preconception antibiotic use overall was not appreciably associated with fecundability. WHAT IS KNOWN ALREADY: Antibiotics are commonly used by women and are generally thought to be safe for use during pregnancy. However, little is known about possible effects of antibiotic use on fecundability, the per-cycle probability of conception. Previous research on this question has been limited to occupational rather than therapeutic exposure. STUDY DESIGN, SIZE, DURATION: We analyzed data from an Internet-based preconception cohort study of 9524 female pregnancy planners aged 21-45 years residing in the USA and Canada who had been attempting to conceive for six or fewer cycles at study entry. Participants enrolled between June 2013 and September 2020 and completed baseline and bimonthly follow-up questionnaires for up to 12 months or until a reported pregnancy, whichever came first. The questions pertaining to antibiotic type and indication were added to the PRESTO questionnaires in March 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: We assessed antibiotic use in the previous 4 weeks at baseline and on each follow-up questionnaire. Participants provided the name of the specific antibiotic and the indication for use. Antibiotics were classified based on active ingredient (penicillins, macrolides, nitrofurantoin, nitroimidazole, cephalosporins, sulfonamides, quinolones, tetracyclines, lincosamides), and indications were classified by type of infection (respiratory, urinary tract, skin, vaginal, pelvic, and surgical). Participants reported pregnancy status on follow-up questionnaires. We used proportional probabilities regression to estimate fecundability ratios (FR), the per-cycle probability of conception comparing exposed with unexposed individuals, and 95% confidence intervals (CI), adjusting for sociodemographics, lifestyle factors, and reproductive history. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, women who used antibiotics in the past 4 weeks at baseline had similar fecundability to those who had not used antibiotics (FR: 0.98, 95% CI: 0.89-1.07). Sulfonamides and lincosamides were associated with slightly increased fecundability (FR: 1.39, 95% CI: 0.90-2.15, and FR: 1.58 95% CI: 0.96-2.60, respectively), while macrolides were associated with slightly reduced fecundability (FR: 0.70, 95% CI: 0.47-1.04). Analyses of the indication for antibiotic use suggest that there is likely some confounding by indication. LIMITATIONS, REASONS FOR CAUTION: Findings were imprecise for some antibiotic classes and indications for use owing to small numbers of antibiotic users in these categories. There are likely heterogeneous effects of different combinations of indications and treatments, which may be obscured in the overall null results, but cannot be further elucidated in this analysis. WIDER IMPLICATIONS OF THE FINDINGS: There is little evidence that use of most antibiotics is associated with reduced fecundability. Antibiotics and the infections they treat are likely associated with fecundability through differing mechanisms, resulting in their association with increased fecundability in some circumstances and decreased fecundability in others. STUDY FUNDING/COMPETING INTEREST(S): This study was supported through funds provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (R01-HD086742, R21-HD072326). L.A.W. has received in-kind donations from Swiss Precision Diagnostics, Sandstone Diagnostics, Fertility Friend, and Kindara for primary data collection in PRESTO. The other authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

Accuracy of self-reported birth outcomes relative to birth certificate data in an Internet-based prospective cohort study.

BACKGROUND: The accuracy of birth outcome data provided by Internet-based cohort study participants has not been well studied. METHODS: We compared self-reported data on birth characteristics in Pregnancy Study Online (PRESTO), an Internet-based prospective cohort study of North American pregnancy planners, with birth certificate data. At enrolment, participants were aged 21-45 years, attempting conception, and not using fertility treatment. Women completed online questionnaires during preconception, early and late pregnancy, and postpartum. We requested birth certificate data during 2014-2019 from seven health departments in states with the most participants. After restricting to singleton births, we assessed specificity, sensitivity, and agreement comparing self-reported data from postpartum questionnaires with birth certificate data for gestational age at delivery (GA) and birthweight (grams). Our primary measure of self-reported GA (weeks) was calculated as [280-(due date-birth date)]/7. We used log-binomial regression to assess predictors of agreement. RESULTS: We linked 85% (771/909) of women in selected states. Median age of women was 30 years (range: 21-42), 84% had ≥ 16 years of education, nearly 96% were married, 12% had household incomes <$50 000, 32% were parous, and 85% identified as non-Hispanic White. Median recall interval was 6 months. Among those with self-reported data, 89% reported the same GA as the birth certificate and 98% reported GA within 1 week of the birth certificate. Self-report of preterm birth (GA < 37 weeks) agreed with information from birth certificates for 100% of women; sensitivity was 100%, and specificity was 99%. Self-reported low birthweight (<2500 grams) agreed with birth certificates for 93% of women; sensitivity and specificity were 93% and ≥99%, respectively. Predictors of poorer agreement included higher parity and longer pregnancy attempt time for GA, and lower education and longer recall interval for birthweight. CONCLUSION: Self-reported data on GA and birthweight from an Internet-based cohort showed high accuracy compared with birth certificates.

Effect of a Home Pregnancy Test Intervention on Cohort Retention and Pregnancy Detection: A Randomized Trial.

We conducted a parallel, nonblinded randomized trial to assess whether offering home pregnancy tests (HPTs) to preconception cohort study participants influenced cohort retention or pregnancy detection. Pregnancy Study Online participants were female, aged 21-45 years, attempting pregnancy, and not using fertility treatment. At enrollment (2017-2018), 1,493 participants with 6 or fewer cycles of attempt time were randomly assigned with 50% probability to receive 12 Clearblue visual HPTs plus the standard protocol (n = 720) or the standard protocol alone (n = 773). Women completed bimonthly questionnaires for 12 months or until conception, whichever came first. In intent-to-treat analyses, retention (≥1 follow-up) was higher in the HPT arm (n = 598; 83%) than the standard protocol arm (n = 535 (69%); mean difference = 15%, 95% CI: 10, 19). Mean time at first pregnancy testing was identical in both arms (2 days before expected menses), as was mean gestational weeks at first positive pregnancy test (4 weeks). Conception was reported by 78% of women in the HPT arm and 75% in the standard protocol arm. Spontaneous abortion was reported by 21% in the HPT arm (mean gestational weeks = 7) and 21% in the standard protocol arm (mean gestational weeks = 6). Randomization of HPTs was associated with greater cohort retention but had little impact on incidence or timing of pregnancy detection.

Association Between Male Use of Pain Medication and Fecundability.

Administration of pain relievers has been associated with both lower and higher risks of adverse reproductive outcomes in animals. In the sole investigation of male pain-reliever use and human fertility carried out to date, Smarr et al. (Hum Reprod. 2016;31(9):2119-2127) found a 35% reduction in fecundability among males with urinary acetaminophen concentrations in the highest quartile (>73.5 ng/mL) versus the lowest (<5.4 ng/mL). We analyzed data from 1,956 males participating in Pregnancy Study Online, a preconception cohort study of North American couples enrolled between 2013 and 2019. Males and females completed baseline questionnaires on sociodemographic characteristics, lifestyle, medication use, and medical history; females completed bimonthly follow-up questionnaires for up to 12 months. We categorized pain medications by active ingredient (ibuprofen, acetaminophen, naproxen, aspirin) and cumulative monthly dose. We used proportional probabilities models to calculate fecundability ratios and 95% confidence intervals, adjusting for potential confounders. In the 4 weeks before baseline, 51.7% of males used pain medications. Adjusted fecundability ratios were 1.02 for ibuprofen (95% confidence interval (CI): 0.91, 1.13), 0.89 for acetaminophen (95% CI: 0.77, 1.03), 1.07 for naproxen (95% CI: 0.85, 1.35), and 1.05 for aspirin (95% CI: 0.81, 1.35), as compared with nonuse of each medication. In this study, male use of pain medications at low doses was not notably associated with fecundability.

Changes in Behavior with Increasing Pregnancy Attempt Time: A Prospective Cohort Study.

BACKGROUND: The extent to which couples change their behaviors with increasing pregnancy attempt time is not well documented. METHODS: We examined change in selected behaviors over pregnancy attempt time in a North American preconception cohort study. Eligible females were ages 21-45 years and not using fertility treatment. Participants completed baseline and bimonthly follow-up questionnaires for up to 12 months or until pregnancy. RESULTS: Among 3,339 females attempting pregnancy for 0-1 cycles at enrollment, 250 contributed 12 months of follow-up without conceiving. Comparing behaviors at 12 months versus baseline, weighted for loss-to-follow-up, we observed small-to-moderate reductions in mean caffeine intake (-19.5 mg/day, CI = -32.7, -6.37), alcohol intake (-0.85 drinks/week, CI = -1.28, -0.43), marijuana use (-3.89 percentage points, CI = -7.33, 0.46), and vigorous exercise (-0.68 hours/week, CI = -1.05, -0.31), and a large increase in activities to improve conception chances (e.g., ovulation testing) (21.7 percentage points, CI = 14.8, 28.6). There was little change in mean cigarette smoking (-0.27 percentage points, CI = -1.58, 1.04), perceived stress scale score (-0.04 units, CI = -0.77, 0.69), or other factors (e.g., sugar-sweetened soda intake, moderate exercise, intercourse frequency, and multivitamin use), but some heterogeneity within subgroups (e.g., 31% increased and 32% decreased their perceived stress scores by ≥2 units; 14% reduced their smoking but none increased their smoking by ≥5 cigarettes/day). CONCLUSIONS: Although many behaviors changed with increasing pregnancy attempt time, mean changes tended to be modest for most variables. The largest differences were observed for the use of caffeine, alcohol, and marijuana, and methods to improve conception chances.

At-home sperm testing for epidemiologic studies: Evaluation of the Trak male fertility testing system in an internet-based preconception cohort.

BACKGROUND: Semen quality assessment in population-based epidemiologic studies presents logistical and financial challenges due to reliance on centralised laboratory semen analysis. The Trak Male Fertility Testing System is an FDA-cleared and validated at-home test for sperm concentration and semen volume, with a research use only sperm motility test. Here we evaluate the Trak System's overall utility among men participating in Pregnancy Study Online (PRESTO), a web-based study of North American couples planning pregnancy. METHODS: US male participants aged ≥21 years with ≤6 months of pregnancy attempt time at study enrolment were invited to participate in the semen testing substudy after completing their baseline questionnaire. Consenting participants received a Trak Engine (battery-powered centrifuge) and two test kits. Participants shared their test results via smartphone images uploaded to online questionnaires. Data were then linked with covariate data from the baseline questionnaire. RESULTS: Of the 688 men invited to participate, 373 (54%) provided consent and 271 (73%) completed at least one semen test result. The distributions of semen volume, sperm concentration, motile sperm concentration, total sperm count, and total motile sperm count were similar to 2010 World Health Organization (WHO) semen parameter data of men in the general population. The overall usability score for the Trak System was 1.4 on a 5-point Likert scale (1 = Very Easy, 5 = Difficult), and 92% of participants believed they performed the test correctly and received an accurate result. Lastly, men with higher motile sperm count were more likely to report feeling "at ease" or "excited" following testing, while men with low motile sperm count were more likely to report feeling "concerned" or "frustrated." Overall, 91% of men reported they would like to test again. CONCLUSIONS: The Trak System provides a simple and potentially cost-effective means of measuring important semen parameters and may be useful in population-based epidemiologic fertility studies.

Association between job control and time to pregnancy in a preconception cohort.

OBJECTIVE: To evaluate associations between low job control (operationalized as job independence and freedom to make decisions) and time to pregnancy. Low job control, a form of workplace stress, is associated with adverse health outcomes ranging from cardiovascular disease to premature mortality; few studies have specifically examined its association with reproductive outcomes. DESIGN: We used data from Pregnancy Study Online, an internet-based preconception cohort study of couples trying to conceive in the United States and Canada. We estimated fecundability ratios (FRs) and 95% confidence intervals (CIs) via proportional probability regression models, adjusting for sociodemographic and behavioral characteristics. SETTING: Not applicable (Web-based study). PATIENTS: Participants self-identified as female, were aged 21-45 years, and reported ≤6 cycles of pregnancy attempt time at enrollment (2018-2022). EXPOSURE: We assessed job control by matching participants' baseline self-reported occupation and industry with standardized occupation codes from the National Institute for Occupational Safety and Health's Industry and Occupation Computerized Coding System, then linking codes to O∗NET job exposure scores for job independence and freedom to make decisions. MAIN OUTCOME MEASURE: Our main outcome measure was fecundability. Participants completed self-administered questionnaires at baseline and every 8 weeks for up to 12 months or until reported pregnancy, whichever occurred first. RESULTS: Among 3,110 participants, lower job independence was associated with reduced fecundability. Compared with the fourth (highest) quartile, corresponding to the most job independence, FRs (95% CI) for first (lowest), second, and third quartiles were 0.92 (0.82-1.04), 0.84 (0.74-0.95), and 0.99 (0.88, 1.11), respectively. Lower freedom to make decisions was associated with slightly reduced fecundability (first vs. fourth quartile: FR = 0.92; 95% CI: 0.80-1.05). CONCLUSION: Lower job control, a work-related stressor, may adversely influence time to pregnancy. Because job control is a condition of work (i.e., not modifiable by individuals), these findings may strengthen arguments for improving working conditions as a means of improving worker health, including fertility.

Predictive models of miscarriage on the basis of data from a preconception cohort study.

OBJECTIVE: To use self-reported preconception data to derive models that predict the risk of miscarriage. DESIGN: Prospective preconception cohort study. SETTING: Not applicable. PATIENTS: Study participants were female, aged 21-45 years, residents of the United States or Canada, and attempting spontaneous pregnancy at enrollment during 2013-2022. Participants were followed for up to 12 months of pregnancy attempts; those who conceived were followed through pregnancy and postpartum. We restricted analyses to participants who conceived during the study period. EXPOSURE: On baseline and follow-up questionnaires completed every 8 weeks until pregnancy, we collected self-reported data on sociodemographic factors, reproductive history, lifestyle, anthropometrics, diet, medical history, and male partner characteristics. We included 160 potential predictor variables in our models. MAIN OUTCOME MEASURES: The primary outcome was a miscarriage, defined as pregnancy loss before 20 weeks of gestation. We followed participants from their first positive pregnancy test until miscarriage or a censoring event (induced abortion, ectopic pregnancy, loss of follow-up, or 20 weeks of gestation), whichever occurred first. We fit both survival and static models using Cox proportional hazards models, logistic regression, support vector machines, gradient-boosted trees, and random forest algorithms. We evaluated model performance using the concordance index (survival models) and the weighted F1 score (static models). RESULTS: Among the 8,720 participants who conceived, 20.4% reported miscarriage. In multivariable models, the strongest predictors of miscarriage were female age, history of miscarriage, and male partner age. The weighted F1 score ranged from 73%-89% for static models and the concordance index ranged from 53%-56% for survival models, indicating better discrimination for the static models compared with the survival models (i.e., the ability of the model to discriminate between individuals with and without miscarriage). No appreciable differences were observed across strata of miscarriage history or among models restricted to ≥8 weeks of gestation. CONCLUSION: Our findings suggest that miscarriage is not easily predicted on the basis of preconception lifestyle characteristics and that advancing age and a history of miscarriage are the most important predictors of incident miscarriage.

A preconception cohort study of sugar-sweetened beverage consumption and semen quality.

BACKGROUND: Dietary factors, including high sugar intake, may have adverse effects on male reproduction. Studies of the association between sugar-sweetened beverage (SSB) intake and semen quality have reported inconsistent results. OBJECTIVE: We estimated the effects of SSB consumption on semen quality in a North American preconception cohort study. METHODS: We analyzed baseline data from 690 males (n = 1,247 samples) participating in Pregnancy Study Online (PRESTO) during 2015-2022. Participants aged ≥21 years completed a baseline questionnaire on which they reported information about intake of SSBs, including sodas, energy drinks, sports drinks, and fruit juices. After enrollment, we invited U.S. participants to a semen testing substudy, in which they collected and analyzed two samples using an at-home semen testing kit. We used linear regression models to estimate adjusted percent differences (%D) and 95% confidence intervals (CI) for associations of SSB intake with semen volume, sperm concentration, total sperm count (TSC), motility, and total motile sperm count (TMSC). We used modified Poisson regression models to estimate adjusted risk ratios (RRs) and 95% CIs for the association of SSB intake with World Health Organization semen parameter cut points. RESULTS: Relative to non-consumers of SSBs, those who consumed ≥7 SSBs/week had lower semen volume (%D = -6, 95% CI: -13, 0), sperm concentration (%D = -22, 95% CI: -38, 0), TSC (%D = -22, 95% CI: -38, -2), motility (%D = -4, 95% CI: -10, 2), and TMSC (%D = -25, 95% CI: -43, -2). High SSB consumers also had greater risks of low sperm concentration (≤16 million/mL; RR = 1.89, 95% CI: 1.11, 3.21), low TSC (≤39 million; RR = 1.75, 95% CI: 0.92, 3.33), low motility (≤42%; RR = 1.23, 95% CI: 0.87, 1.75) and low TMSC (≤21 million; RR = 1.95, 95% CI: 1.12, 3.38). Associations were stronger among participants with body mass index ≥ 25 kg/m2 . CONCLUSION: Greater SSB consumption was associated with reduced semen quality in a North American preconception cohort.

Risk of Miscarriage in Relation to Seasonal Influenza Vaccination Before or During Pregnancy.

OBJECTIVE: To evaluate the association between seasonal influenza vaccination and miscarriage using data from an ongoing, prospective cohort study. METHODS: We analyzed 2013-2022 data from PRESTO (Pregnancy Study Online), a prospective prepregnancy cohort study of female pregnancy planners and their male partners in the United States and Canada. Female participants completed a baseline questionnaire and then follow-up questionnaires every 8 weeks until pregnancy, during early and late pregnancy, and during the postpartum period. Vaccine information was self-reported on all questionnaires. Miscarriage was identified from self-reported information during follow-up. Male partners were invited to complete a baseline questionnaire only. We used Cox proportional hazard models to estimate the hazard ratio (HR) and 95% CI for the association between vaccination less than 3 months before pregnancy detection through the 19th week of pregnancy and miscarriage, with gestational weeks as the time scale. We modeled vaccination as a time-varying exposure and used propensity-score fine stratification to control for confounding from seasonal and female partner factors. RESULTS: Of 6,946 pregnancies, 23.3% of female partners reported exposure to influenza vaccine before or during pregnancy: 3.2% during pregnancy (gestational age 4-19 weeks) and 20.1% during the 3 months before pregnancy detection. The miscarriage rate was 16.2% in unvaccinated and 17.0% among vaccinated participants. Compared with no vaccine exposure, influenza vaccination was not associated with increased rate of miscarriage when administered before (HR 0.99, 95% CI 0.81-1.20) or during (HR 0.83, 95% CI 0.47-1.47) pregnancy. Of the 1,135 couples with male partner vaccination data available, 10.8% reported vaccination less than 3 months before pregnancy. The HR for the association between male partner vaccination and miscarriage was 1.17 (95% CI 0.73-1.90). CONCLUSION: Influenza vaccination before or during pregnancy was not associated with miscarriage.

A randomized trial of web-based fertility-tracking software and fecundability.

OBJECTIVE: To assess the effect of randomization to FertilityFriend.com, a mobile computing fertility-tracking app, on fecundability. DESIGN: Parallel non-blinded randomized controlled trial nested within the Pregnancy Study Online (PRESTO), a North American preconception cohort. PATIENT(S): Female participants aged 21 to 45 years attempting conception for ≤6 menstrual cycles at enrolment (2013-2019). INTERVENTION: Randomization (1:1) of 5532 participants to receive a premium Fertility Friend (FF) subscription. MAIN OUTCOME MEASURE(S): Fecundability (per-cycle probability of conception). Participants completed bimonthly follow-up questionnaires until pregnancy or a censoring event, whichever came first. We first performed an intent-to-treat analysis of the effect of FF randomization on fecundability. In secondary analyses, we used a per-protocol approach that accounted for adherence in each trial arm. In both analyses, we used proportional probabilities regression models to estimate fecundability ratios (FR) and 95% confidence intervals (CI) comparing those randomized vs. not randomized and applied inverse probability weights to account for loss-to-follow-up (intent-to-treat and per-protocol analyses) and adherence (per-protocol analyses only). RESULTS: Using life-table methods, 64% of the 2775 participants randomized to FF and 63% of the 2767 participants not randomized to FF conceived during 12 cycles; these respective percentages were each 70% among those with 0-1 cycles of attempt time at enrolment. Of those randomized to FF, 72% were defined as adherent (68% of observed menstrual cycles). In intent-to-treat analyses, there was no appreciable association overall (FR = 0.97; 95% CI, 0.90-1.04) or within strata of pregnancy attempt time at enrolment, age, education, or other characteristics. In per-protocol analyses, we observed little association overall (FR = 1.06; 95% CI, 0.99-1.14), but weak-to-moderate positive associations among participants who had longer attempt times at enrolment (FR = 1.15; 95% CI, 0.98-1.35 for 3-4 cycles; FR = 1.14; 95% CI, 0.87-1.48 for 5-6 cycles), were aged <25 years (FR = 1.29; 95% CI, 1.01-1.66), had ≤12 years of education (FR = 1.32; 95% CI, 0.92-1.89), or were non-users of hormonal contraception within 3 months before enrolment (FR = 1.10; 95% CI, 1.02-1.19). CONCLUSION: No appreciable associations were observed in intent-to-treat analyses. In secondary per-protocol analyses that accounted for adherence, randomization to FF was associated with slightly greater fecundability among selected subgroups of participants; however, these results are susceptible to unmeasured confounding.

Preconception contraceptive use and miscarriage: prospective cohort study.

Objectives: To evaluate the association between preconception contraceptive use and miscarriage. Design: Prospective cohort study. Setting: Residents of the United States of America or Canada, recruited from 2013 until the end of 2022. Participants: 13 460 female identified participants aged 21-45 years who were planning a pregnancy were included, of whom 8899 conceived. Participants reported data for contraceptive history, early pregnancy, miscarriage, and potential confounders during preconception and pregnancy. Main outcome measure: Miscarriage, defined as pregnancy loss before 20 weeks of gestation. Results: Preconception use of combined and progestin-only oral contraceptives, hormonal intrauterine devices, copper intrauterine devices, rings, implants, or natural methods was not associated with miscarriage compared with use of barrier methods. Participants who most recently used patch (incidence rate ratios 1.34 (95% confidence interval 0.81 to 2.21)) or injectable contraceptives (1.44 (0.99 to 2.12)) had higher rates of miscarriage compared with recent users of barrier methods, although results were imprecise due to the small numbers of participants who used patch and injectable contraceptives. Conclusions: Use of most contraceptives before conception was not appreciably associated with miscarriage rate. Individuals who used patch and injectable contraceptives had higher rates of miscarriage relative to users of barrier methods, although these results were imprecise and residual confounding was possible.