Evaluating associations of bisphenol and phthalate exposure with time to pregnancy and subfecundity in a New York City pregnancy cohort.

It is important to understand the impact of consumer chemical exposure and fecundity, a couple's measure of probability of successful conception, given approximately 15% of couples experience infertility. Prior research has generally found null associations between bisphenol and phthalate exposure and fecundability, measured via time to pregnancy (TTP). However, this research has not been updated with current chemical exposures and have often lacked diversity in their study populations. We evaluated the associations between common bisphenol and phthalate chemical exposure groups and TTP as well as subfecundity (TTP>12 months) in the New York University Children's Health Study, a diverse pregnancy cohort from 2016 onward. Using first-trimester spot-urine samples to measure chemical exposure and self-reported TTP from first-trimester questionnaires, we observed a significant adverse association between total bisphenol exposure and certain phthalate groups on TTP and odds of subfecundity. Furthermore, in a mixtures analysis to explore the joint effects of the chemical groups on the outcomes, we found evidence of a potential interaction between total bisphenol exposure and low-molecular weight phthalates on TTP. Future research should continue to update our knowledge regarding the complex and potentially interacting effects of these chemicals on reproductive health.

Telomere length in relation to fecundability and use of assisted reproductive technologies: the Norwegian Mother, Father, and Child Cohort Study.

In women, shorter telomeres have been reported to be associated with conditions such as endometriosis and polycystic ovary syndrome, whereas other studies have reported the opposite. In men, studies mostly report associations between shorter telomeres and sperm quality. To our knowledge, no studies have thus far investigated the associations between TL and fecundability or the use of ART. This study is based on the Norwegian Mother, Father, and Child Cohort (MoBa) Study and uses data from the Medical Birth Registry of Norway (MBRN). We included women (24,645 with genotype data and 1,054 with TL measurements) and men (18,339 with genotype data and 965 with TL measurements) participating between 1998 and 2008. We investigated the associations between leukocyte TL and fecundability, infertility, and the use of ART. We also repeated the analyses using instrumental variables for TL, including genetic risk scores for TL and genetically predicted TL. Approximately 11% of couples had experienced infertility and 4% had used ART. TL was not associated with fecundability among women (fecundability ratio [FR], 0.98; 95% confidence interval [CI], 0.92-1.04) or men (FR, 0.99; CI, 0.93-1.06), nor with infertility among women (odds ratio [OR], 1.03; CI, 0.85-1.24) or men (OR, 1.05; CI, 0.87-1.28). We observed an increased likelihood of using ART with increasing TL among men (OR, 1.22; CI, 1.03-1.46), but not among women (OR, 1.10; CI, 0.92-1.31). No significant associations were observed using the instrumental variables. Our results indicate that TL is a poor biomarker of fecundability, infertility and use of ART in MoBa. Additional studies are required to replicate the association observed between TL and ART in men.

Cervical intraepithelial neoplasia and fecundability: a prospective cohort study.

STUDY QUESTION: Is cervical intraepithelial neoplasia (CIN) associated with reduced fecundability, defined as the probability of conceiving per menstrual cycle? SUMMARY ANSWER: Overall, we observed no meaningful association between CIN and fecundability, regardless of surgical status, although a recent diagnosis of moderate or severe CIN might be associated with slightly reduced fecundability for 2 years after diagnosis. WHAT IS KNOWN ALREADY: About 15% of couples experience infertility. Few studies have examined the influence of CIN on fertility, and the results have been inconsistent. No study has investigated the association between fecundability and pathologist-reported CIN diagnoses, particularly with respect to the recency of the specific CIN diagnoses. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 9586 women trying to conceive. The women were enrolled from 1 June 2007 to 3 February 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women were invited to complete a baseline questionnaire and bimonthly follow-up questionnaires for up to 12 months or until pregnancy occurred. Data on cervical cytologies and biopsies were retrieved from The National Pathology Registry (DNPR), which holds records of all cervical specimens examined in Denmark. Women were categorized based on their most severe diagnosis of CIN: no lesion, other cervical changes, mild CIN (CIN1), or moderate/severe CIN (CIN2+) with or without surgery. To investigate the association between CIN and fecundability, we computed fecundability ratios (FR) and 95% confidence intervals (CI) using a proportional probabilities regression model. We adjusted for age at study entry, partner age, body mass index, smoking status, timing of intercourse, parity, education, number of sexual partners, and household income. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with no lesion, the adjusted FRs (95% CI) for the association between CIN and fecundability were: other cervical lesions, 0.97 (0.91-1.04); CIN1, 1.04 (0.96-1.13); CIN2+ no surgery, 1.00 (0.82-1.22); and CIN2+ with surgery 0.99 (0.89-1.10). The FRs (95% CI) for a recent diagnosis (<2 years) of CIN were 0.98 (0.86-1.11) for other cervical lesions; 1.13 (0.99-1.29) for CIN1; 0.89 (0.62-1.26) for CIN2+ no surgery and 0.91 (0.75-1.10) for CIN2+ with surgery compared with the no lesion group. LIMITATIONS, REASONS FOR CAUTION: In the analyses, we adjusted for several covariates related to the women. However, we had little information on the male partners which could lead to unmeasured confounding as fecundability is a couple-based measure of fertility. Furthermore, a CIN diagnosis may not be constant as it may regress or progress spontaneously; therefore, it is possible that we have misclassified some women, especially women categorized as having normal cells or CIN1. WIDER IMPLICATIONS OF THE FINDINGS: Our results contribute important knowledge to women who are concerned about their future fertility after receiving a CIN diagnosis. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by The Danish Cancer Society (R167-A11036-17-S2). The overall cohorts were funded by the National Institute of Child Health and Human Development (R01-HD086742 and R03-HD094117). The authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Early or late menarche is associated with reduced fecundability in the Norwegian Mother, Father and Child Cohort Study.

STUDY QUESTION: Is age at menarche associated with fecundability? SUMMARY ANSWER: Both early (<11 years) and late (>15 years) menarche is associated with decreased fecundability. WHAT IS KNOWN ALREADY: Previous studies on age at menarche and fecundability have been inconclusive. Women with early or late menarche are at increased risks of gynaecological and autoimmune diseases that may affect their ability to conceive. STUDY DESIGN, SIZE, DURATION: We conducted a retrospective cohort study including 67 613 pregnant women, participating in the Norwegian Mother, Father and Child Cohort Study between 1999 and 2008, with self-reported information on age at menarche and time to pregnancy. We included planned pregnancies that were conceived either naturally or with the help of assisted reproductive technologies. PARTICIPANTS/MATERIALS, SETTING, METHODS: We calculated fecundability ratios (FRs) with 95% CIs representing the cycle-specific probability of conception by categories of age at menarche. FRs were adjusted for participants' pre-pregnancy body mass index, highest completed or ongoing education level, and age at initiation of trying to conceive. MAIN RESULTS AND THE ROLE OF CHANCE: We observed a 7% lower probability of conceiving during any given menstrual cycle up to 12 cycles in women with early or late menarche. Among women with menarche >15 years, the adjusted FR was 0.93 (95% CI: 0.90-0.97), and among women with menarche <11 years, the adjusted FR was 0.93 (95% CI: 0.89-0.99), when compared to women with menarche between 12 and 14 years. LIMITATIONS, REASONS FOR CAUTION: The study-population consisted of women pregnant in their second trimester, excluding those with persistent infertility. Recall of age at menarche and time to pregnancy may be inaccurate. WIDER IMPLICATIONS OF THE FINDINGS: Both early (<11 years) and late (>15 years) menarche was associated with decreased fecundability. Women experiencing early menarche or late menarche may be counselled accordingly. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Norwegian Institute of Public Health, Oslo, Norway, and by Telemark Hospital Trust, Porsgrunn, Norway and was partly supported by the Research Council of Norway through its centres of excellence funding scheme (project number 262700) and the Research Council of Norway (project no. 320656). The project was co-funded by the European Union (ERC, BIOSFER, 101071773). Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them. M.C.M. has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 947684). The authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Gravidity modifies the associations of age and spousal age difference with couple's fecundability: a large cohort study from China.

STUDY QUESTION: Do couple's age ranges for optimal fecundability, and the associations with fecundability of couple's age combinations and age differences differ with gravidity? SUMMARY ANSWER: The couple's age range of optimal fecundability and age combinations differed with gravidity, and gravidity might modify the associations of age and spousal age difference with couple's fecundability. WHAT IS KNOWN ALREADY: Age is one of the strongest determinants of fecundability, but the existing studies have certain limitations in study population, couple's extreme age combinations and age differences, and have not explored whether the association between age and fecundability differs with gravidity. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study. 5 407 499 general reproductive-aged couples (not diagnosed with infertility) participated in the National Free Pre-conception Check-up Projects during 2015-2017. They were followed up for pregnancy outcomes through telephone interviews every 3 months until they became pregnant or were followed up for 1 year. PARTICIPANTS/MATERIALS, SETTING, METHODS: The main outcome was time to pregnancy, and the fecundability odds ratios and 95% CIs were estimated using the Cox models for discrete survival time. The associations of age and spousal age difference with fecundability were evaluated by restricted cubic splines. MAIN RESULTS AND THE ROLE OF CHANCE: In this large cohort of general reproductive-aged population, the age of optimal fecundability of multigravida couples was older than that of nulligravida couples, but their subsequent fecundability declined more sharply with age. The decline in female fecundability was more pronounced with age, with fecundability dropping by ∼30% in both nulligravida and multigravida couples whose female partners aged ≥35 years. In the nulligravida group, the fecundability of couples who were both ≤24 years with the same age was the highest, which decreased steadily with the increase of spousal age difference, and younger male partners did not seem to contribute to improving couple's fecundability. In the multigravida group, couples with female partners aged 25-34 years and a spousal age difference of -5 to 5 years showed higher fecundability, and the effect of spousal age difference on couple's fecundability became suddenly apparent when female partners aged around 40 years. Young male partners were unable to change the decisive effect of female partner's age over 40 years on couple's reduced fecundability, regardless of gravidity. LIMITATIONS, REASONS FOR CAUTION: Lacking the time for couples to attempt pregnancy before enrollment, and some couples might suspend pregnancy plans during follow-up because of certain emergencies, which would misestimate the fecundability. Due to the lack of information on sperm quality and sexual frequency of couples, we could not adjust for these factors. Moreover, due to population characteristics, the extrapolation of our results required caution. WIDER IMPLICATIONS OF THE FINDINGS: The couple's age range of optimal fecundability, age combinations, and spousal age difference on fecundability varied with gravidity. Female age-related decline in fecundability was more dominant in couple's fecundability. Targeted fertility guidance should be provided to couples with different age combinations and gravidities. STUDY FUNDING/COMPETING INTEREST(S): This research received funding from the Project of National Research Institute for Family Planning (Grant No. 2018NRIFPJ03), the National Key Research and Development Program of China (Grant No. 2016YFC1000307), and the National Human Genetic Resources Sharing Service Platform (Grant No. 2005DKA21300), People's Republic of China. The funders had no role in study design, analysis, decision to publish, or preparation of the manuscript. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

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.

The association between the maternal pre-pregnancy platelet count and fecundability in mainland China: a population-based cohort study.

BACKGROUND: Currently, awareness about platelet count (PC) and its consequences for perinatal outcome have increased, but there is little reliable evidence on fecundability. METHODS: Based on the National Free Pre-conception Check-up Projects supported by the Chinese government, 5,524,886 couples met the inclusion criteria were included in this cohort study. Cox regression models were adopted to estimate fecundability ratios (FRs) and their 95% confidence intervals for pre-pregnancy PC quintiles. Restricted cubic splines were used to flexibly model and visualize the relationship of PC with FRs. Microsoft SQL server and R software were used for data management and analysis. RESULTS: The median of pre-pregnancy PC among women was 221.00×109/L. The first (<177.00 ×109/L) and second quintile (177.00-207.99 ×109/L) of PC showed slightly increased fecundability (Q1: adjusted FR 1.05, 95% CI 1.04-1.06; Q2: adjusted FR 1.04, 95% CI 1.03-1.05), while higher quintals (Q4: 236.00-271.99 ×109/L; Q5: ≥272.00 ×109/L) were related to reduction of fecundability, when compared with the third quintile of PC (208.00-235.99 ×109/L) (Q4: adjusted FR 0.96, 95% CI 0.95-0.97; Q5: adjusted FR 0.88, 95% CI 0.87-0.89). In the first quintiles (<177.00×109/L), only 20.93% women had PC below 129.94×109/L. An inverse-U shape association was consistently observed among women such that the lower PC of normal range (<118.03×109/L) and higher PC (>223.06×109/L) were associated with the risk of reduced female fecundability (P for non-linearity < 0.01). CONCLUSION: PC is associated with female fecundability. Further classification of PC levels may deepen our understanding of the early warnings and significance of female fecundability.

The relationship between cesarean delivery and fecundability: a population-based cohort study.

BACKGROUND: Previous studies have found that women who undergo cesarean delivery have fewer pregnancies. Cesarean delivery is also more common among women with lower fecundability. The potential role of cesarean delivery in reduced fecundability is not known. OBJECTIVE: This study aimed to assess the bidirectional relationship between cesarean delivery and fecundability. STUDY DESIGN: This was a prospective cohort study based on data from the Norwegian Mother, Father, and Child Cohort study linked with the Medical Birth Registry of Norway. We estimated the fecundability ratio (per cycle probability of pregnancy) and relative risk of infertility (time to pregnancy ≥12 months) by mode of delivery in the previous delivery among 42,379 women. For the reverse association, we estimated the relative risk of having a cesarean delivery by fecundability (the number of cycles women needed to conceive) among 74,024 women. RESULTS: The proportion of women with infertility was 7.3% (2707/37,226) among women with a previous vaginal delivery and 9.9% (508/5153) among women with a previous cesarean delivery, yielding an adjusted relative risk of 1.21 (95% confidence interval, 1.10-1.33). Women with a previous cesarean delivery also had a lower fecundability ratio (0.90; 95% confidence interval, 0.88-0.93) than women with a previous vaginal delivery. When assessing the reverse association between fecundability and cesarean delivery, we found that women who did not conceive within 12 or more cycles had a higher risk for cesarean delivery (adjusted relative risk, 1.57; 95% confidence interval, 1.48-1.66) than women who conceived within the first 2 cycles. The associations remained after controlling for sociodemographic and clinical risk factors and were observed across parity groups. CONCLUSION: Among women with more than 1 child, those who had a previous cesarean delivery subsequently had a lower fecundability ratio and an increased infertility risk than those who had a vaginal delivery. However, women who needed a longer time to conceive were also more prone to be delivered by cesarean delivery, indicating a bidirectional relationship between cesarean delivery and fecundability. This could suggest a common underlying explanatory mechanism and that the surgical procedure itself may not or only partly directly influence fecundability.

A prospective preconception cohort study of the association between Mycoplasma genitalium and fecundability in Kenyan women trying to conceive.

STUDY QUESTION: Is Mycoplasma genitalium-infection associated with reduced fecundability? SUMMARY ANSWER: Preconception M. genitalium-infection was associated with 27% lower fecundability though confidence intervals were wide, and the association between M. genitalium and fecundability may be dependent on concurrent bacterial vaginosis (BV). WHAT IS KNOWN ALREADY: M. genitalium has been associated with cervicitis, pelvic inflammatory disease, infertility, and preterm birth, but the extent to which M. genitalium is causally related to adverse reproductive sequelae in women is debated. STUDY DESIGN, SIZE, DURATION: Kenyan women enrolled in a prospective preconception cohort provided vaginal fluid specimens and underwent monthly pregnancy testing. Stored samples from 407 women who had been trying to conceive for ≤6 months were tested for M. genitalium using a nucleic acid amplification test. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on first day of last menstrual period, sexual behavior, pregnancy status, and vaginal specimens were collected at monthly preconception visits. The association between M. genitalium detected at the visit prior to each pregnancy test and fecundability was estimated using discrete time proportional probabilities models. Secondary analyses explored the influence of concurrent BV on the association between M. genitalium and fecundability. MAIN RESULTS AND THE ROLE OF CHANCE: The 407 participants experienced 1220 menstrual cycles and 213 pregnancies. The prevalence of M. genitalium at enrollment was 7.7%. After adjustment for age, frequency of condomless sex in the last 4 weeks, and study site, M. genitalium was associated with a 27% lower fecundability, but confidence intervals were wide (adjusted fecundability ratio (aFR) 0.73, 95% CI 0.44, 1.23). In secondary analyses, when compared to cycles without M. genitalium or BV at the visit prior, women with both M. genitalium and BV at the visit prior had a 51% lower fecundability (aFR = 0.49, 95% CI 0.22, 1.09) whereas there was no association of M. genitalium alone (aFR = 0.98 (95% CI 0.54, 1.76)), and a smaller reduction in fecundability for women with BV only (aFR = 0.80 (95% CI 0.60, 1.07)). LIMITATIONS, REASONS FOR CAUTION: Results should be interpreted cautiously given the relatively low prevalence of M. genitalium and wide confidence intervals. WIDER IMPLICATIONS OF THE FINDINGS: In this cohort of Kenyan women trying to conceive, the association between M. genitalium and fecundability was influenced by concurrent BV status, suggesting there may be a synergistic effect of M. genitalium and BV on fecundability. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a National Institutes of Health grant (NICHD R01 HD087346-RSM). R.S.M. received additional support for mentoring (NICHD K24 HD88229). E.M.L. was supported by pre- and post-doctoral fellowships (NIAID T32 AI07140, NICHD F32 HD100202). Data collection and management were completed using REDCap electronic data capture tools hosted at the University of Washington's Institute of Translational Health Science supported by grants from NCATS/NIH (UL1 TR002319). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. R.S.M. receives research funding, paid to the University of Washington, from Hologic Corporation and consulting fees from Lupin Pharmaceuticals. L.E.M. receives research funding and material for research studies, paid to the University of Washington, from Hologic Corporation and Nabriva Therapeutics, travel support from Hologic, and consulting fees from Health Advances. E.M.L.'s contributions to this study primarily occurred while affiliated with the University of Washington; at the time of submission, E.M.L. was an employee of and holds stock or stock grants for AbbVie, Inc. The other authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Vitamin D Status in Women with a History of Infertility and Decreased Fecundability: A Population-Based Study.

BACKGROUND: Infertility and fecundability problems have been linked with lower 25-hydroxyvitamin D (25(OH)D) concentrations, but studies conducted with small, heterogenous or selected populations have shown inconsistent results. METHODS: This study included women at age 31 from prospective population-based Northern Finland Birth Cohort 1966. Serum 25(OH)D concentrations were evaluated between women with or without previous infertility examinations or treatments (infertility group, n = 375, reference group, n = 2051) and time to pregnancy (TTP) of over 12 months (decreased fecundability group, n = 338) with a wide range of confounders. Furthermore, 25(OH)D concentrations were also compared among reproductive outcomes. RESULTS: The mean 25(OH)D concentration was lower and 25(OH)D < 30 nmol/L was more frequent in women with a history of infertility compared to reference group. Moreover, 25(OH)D > 75 nmol/L was more frequent in the reference group. The mean 25(OH)D concentration was lower in women who had had multiple miscarriages. Both history of infertility (ß = -2.7, 95% confidence interval (CI) -4.6, -0.7) and decreased fecundability associated with lower 25(OH)D concentration (ß = -4.1, 95% CI -7.4, -0.8) after adjustments. In conclusion, this population-based study demonstrated that previous infertility and decreased fecundability were associated with lower 25(OH)D.

Association of male fatty acid intake with fecundability among couples planning pregnancy.

STUDY QUESTION: To what extent is male fatty acid intake associated with fecundability among couples planning pregnancy? SUMMARY ANSWER: We observed weak positive associations of male dietary intakes of total and saturated fatty acids with fecundability; no other fatty acid subtypes were appreciably associated with fecundability. WHAT IS KNOWN ALREADY: Male fatty acid intake has been associated with semen quality in previous studies. However, little is known about the extent to which male fatty acid intake is associated with fecundability among couples attempting spontaneous conception. STUDY DESIGN, SIZE, DURATION: We conducted an internet-based preconception prospective cohort study of 697 couples who enrolled during 2015-2022. During 12 cycles of observation, 53 couples (7.6%) were lost to follow-up. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were residents of the USA or Canada, aged 21-45 years, and not using fertility treatment at enrollment. At baseline, male participants completed a food frequency questionnaire from which we estimated intakes of total fat and fatty acid subtypes. We ascertained time to pregnancy using questionnaires completed every 8 weeks by female participants until conception or up to 12 months. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% CIs for the associations of fat intakes with fecundability, adjusting for male and female partner characteristics. We used the multivariate nutrient density method to account for energy intake, allowing for interpretation of results as fat intake replacing carbohydrate intake. We conducted several sensitivity analyses to assess the potential for confounding, selection bias, and reverse causation. MAIN RESULTS AND THE ROLE OF CHANCE: Among 697 couples, we observed 465 pregnancies during 2970 menstrual cycles of follow-up. The cumulative incidence of pregnancy during 12 cycles of follow-up after accounting for censoring was 76%. Intakes of total and saturated fatty acids were weakly, positively associated with fecundability. Fully adjusted FRs for quartiles of total fat intake were 1.32 (95% CI 1.01-1.71), 1.16 (95% CI 0.88-1.51), and 1.43 (95% CI 1.09-1.88) for the second, third, and fourth vs the first quartile, respectively. Fully adjusted FRs for saturated fatty acid intake were 1.21 (95% CI 0.94-1.55), 1.16 (95% CI 0.89-1.51), and 1.23 (95% CI 0.94-1.62) for the second, third, and fourth vs the first quartile, respectively. Intakes of monounsaturated, polyunsaturated, trans-, omega-3, and omega-6 fatty acids were not strongly associated with fecundability. Results were similar after adjustment for the female partner's intakes of trans- and omega-3 fats. LIMITATIONS, REASONS FOR CAUTION: Dietary intakes estimated from the food frequency questionnaire may be subject to non-differential misclassification, which is expected to bias results toward the null in the extreme categories when exposures are modeled as quartiles. There may be residual confounding by unmeasured dietary, lifestyle, or environmental factors. Sample size was limited, especially in subgroup analyses. WIDER IMPLICATIONS OF THE FINDINGS: Our results do not support a strong causal effect of male fatty acid intakes on fecundability among couples attempting to conceive spontaneously. The weak positive associations we observed between male dietary fat intakes and fecundability may reflect a combination of causal associations, measurement error, chance, and residual confounding. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the National Institutes of Health, grant numbers R01HD086742 and R01HD105863. In the last 3 years, PRESTO has received in-kind donations from Swiss Precision Diagnostics (home pregnancy tests) and Kindara.com (fertility app). L.A.W. is a consultant for AbbVie, Inc. M.L.E. is an advisor to Sandstone, Ro, Underdog, Dadi, Hannah, Doveras, and VSeat. The other authors have no competing interests to report. TRIAL REGISTRATION NUMBER: N/A.

Impact of Physical Activity and Sedentary Behavior on Spontaneous Female and Male Fertility: A Systematic Review.

BACKGROUND: Before pregnancy is recognized, ovulation, fertilization, and implantation must all occur. Physical activity and sedentary behavior may impact pregnancy success by altering each or all of these processes. The aim of this review was to review the association between physical activity and sedentary behavior with spontaneous female and male fertility. METHOD: PubMed/MEDLINE, Web of Science, CINAHL, SPORTDiscus, and Embase were searched from inception to August 9, 2021. Eligible studies included randomized controlled trials or observational studies, published in English, describing an association between physical activity or sedentary behavior (exposures) and spontaneous fertility (outcome) among women or men. RESULTS: Thirty-four studies from 31 unique populations were included in this review (12 cross-sectional studies, 10 cohort studies, 6 case-control studies, 5 randomized controlled trials, and one case-cohort study). Of the 25 studies among women, the majority identified mixed results (n = 11) or no association (n = 9) between physical activity and female fertility. Seven studies reported on female fertility and sedentary behavior, and 2 found sedentary behavior was associated with decreased female fertility. Of the 11 studies among men, most of the studies (n = 6) found that physical activity was associated with increased male fertility. Two of the studies reported on male fertility and sedentary behavior, and neither identified an association. CONCLUSIONS: The association between spontaneous fertility and physical activity in both men and women remains unclear, and the association with sedentary behavior remains largely unexplored.

Preconception use of antibiotics and fecundability: a Danish prospective cohort study.

OBJECTIVE: To assess the association between preconception antibiotic use and fecundability, the per menstrual cycle probability of conception. DESIGN: SnartForaeldre.dk, a Danish prospective cohort study of women trying to conceive (2007-2020). SETTING: Not applicable. SUBJECT(S): 9462 female participants, median age 29 years at enrollment. EXPOSURE: Antibiotic use was defined by filled prescriptions retrieved from the Danish National Prescription Registry, using Anatomical Therapeutic Chemical codes, and modeled as time-varying (menstrual cycle-varying) exposure. MAIN OUTCOME MEASURE(S): Pregnancy status was reported on female follow-up questionnaires every 8 weeks for up to 12 months or until conception. Fecundability ratios (FR) and 95% confidence intervals (CI) were computed using proportional probabilities regression models, with adjustment for age, partner age, education, smoking, folic acid supplementation, body mass index, parity, cycle regularity, timing of intercourse, and sexually transmitted infections. RESULT(S): During all cycles of observation, the percentage of participants filing at least 1 antibiotic prescription was 11.9%; 8.6% had a prescription for penicillins, 2.1% for sulfonamides, and 1.8% for macrolides. Based on life-table methods, 86.5% of participants conceived within 12 cycles of follow-up. Recent preconception antibiotic use was associated with reduced fecundability (≥1 prescription vs. none: adjusted FR = 0.86; 95% CI, 0.76-0.99). For participants using penicillins, sulfonamides, or macrolides, the adjusted FRs were 0.97 (95% CI, 0.83-1.12), 0.68 (95% CI, 0.47-0.98), and 0.59 (95% CI, 0.37-0.93), respectively. CONCLUSION(S): Preconception use of antibiotics, specifically sulfonamides and macrolides, was associated with decreased fecundability compared with no use. The observed associations may be explained plausibly by confounding by indication, as we lacked data on indications for the prescribed antibiotics. Consequently, we cannot separate the effect of the medication from the effect of the underlying infection.

Socioeconomic status and fecundability in a Danish preconception cohort.

STUDY QUESTION: To what extent is socioeconomic status (SES), as measured by educational attainment and household income, associated with fecundability in a cohort of Danish couples trying to conceive? SUMMARY ANSWER: In this preconception cohort, lower educational attainment and lower household income were associated with lower fecundability after adjusting for potential confounders. WHAT IS KNOWN ALREADY: Approximately 15% of couples are affected by infertility. Socioeconomic disparities in health are well established. However, little is known about socioeconomic disparity and its relation to fertility. STUDY DESIGN, SIZE, DURATION: This is a cohort study of Danish females aged 18-49 years who were trying to conceive between 2007 and 2021. Information was collected via baseline and bi-monthly follow-up questionnaires for 12 months or until reported pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 10 475 participants contributed 38 629 menstrual cycles and 6554 pregnancies during a maximum of 12 cycles of follow-up. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% CIs. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with upper tertiary education (highest level), fecundability was substantially lower for primary and secondary school (FR: 0.73, 95% CI: 0.62-0.85), upper secondary school (FR: 0.89, 95% CI: 0.79-1.00), vocational education (FR: 0.81, 95% CI: 0.75-0.89), and lower tertiary education (FR: 0.87, 95% CI: 0.80-0.95), but not for middle tertiary education (FR: 0.98, 95% CI: 0.93-1.03). Compared with a monthly household income of >65 000 DKK, fecundability was lower for household income <25 000 DKK (FR: 0.78, 95% CI: 0.72-0.85), 25 000-39 000 DKK (FR: 0.88, 95% CI: 0.82-0.94), and 40 000-65 000 DKK (FR: 0.94, 95% CI: 0.88-0.99). The results did not change appreciably after adjustment for potential confounders. LIMITATIONS, REASONS FOR CAUTION: We used educational attainment and household income as indicators of SES. However, SES is a complex concept, and these indicators may not reflect all aspects of SES. The study recruited couples planning to conceive, including the full spectrum of fertility from less fertile to highly fertile individuals. Our results may generalize to most couples who are trying to conceive. WIDER IMPLICATIONS OF THE FINDINGS: Our results are consistent with the literature indicating well-documented inequities in health across socioeconomic groups. The associations for income were surprisingly strong considering the Danish welfare state. These results indicate that the redistributive welfare system in Denmark does not suffice to eradicate inequities in reproductive health. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, and the National Institute of Child Health and Human Development (RO1-HD086742, R21-HD050264, and R01-HD060680). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Chronotype and sleep duration interact to influence time to pregnancy: Results from a New York City cohort.

STUDY OBJECTIVE: To study associations between nighttime sleep characteristics and time to pregnancy. METHODS: Pregnant people age ≥18 years and<18 weeks' gestation were recruited from 3 New York University Grossman School of Medicine affiliated hospitals in Manhattan and Brooklyn (n = 1428) and enrolled into the New York University Children's Health and Environment Study. Participants in the first trimester of pregnancy were asked to recall their time to pregnancy and their sleep characteristics in the 3 months before conception. RESULTS: Participants who reported sleeping<7 hours per night tended to have shorter time to pregnancy than those who slept 7-9 hours per night (adjusted fecundability odds ratio = 1.16, 95% confidence interval: 0.94, 1.41). Participants with a sleep midpoint of 4 AM or later tended to have longer time to pregnancy compared with those with earlier sleep midpoints (before 4 AM) (adjusted fecundability odds ratio = 0.88, 95% confidence interval: 0.74, 1.04). When stratified by sleep midpoint, sleeping<7 hours was significantly associated with shorter time to pregnancy only among those whose sleep midpoint was before 4 AM (adjusted fecundability odds ratio = 1.33, 95% confidence interval: 1.07, 1.67). CONCLUSIONS: The association of sleep duration with time to pregnancy was modified by chronotype, suggesting that both biological and behavioral aspects of sleep may influence fecundability.

Exposure to perfluoroalkyl substances and women's fertility outcomes in a Singaporean population-based preconception cohort.

OBJECTIVES: Experimental models have demonstrated a link between exposure to perfluoroalkyl substances (PFAS) and decreased fertility and fecundability; however, human studies are scarce. We assessed the associations between preconception plasma PFAS concentrations and fertility outcomes in women. METHODS: In a case-control study nested within the population-based Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO), we measured PFAS in plasma collected in 2015-2017 from 382 women of reproductive age trying to conceive. Using Cox proportional hazards regression (fecundability ratios [FRs]) and logistic regression (odds ratios [ORs]) models, we assessed the associations of individual PFAS with time-to-pregnancy (TTP), and the likelihoods of clinical pregnancy and live birth, respectively, over one year of follow-up, adjusting for analytical batch, age, education, ethnicity, and parity. We used Bayesian weighted quantile sum (BWQS) regression to assess the associations of the PFAS mixture with fertility outcomes. RESULTS: We found a 5-10 % reduction in fecundability per quartile increase of exposure to individual PFAS (FRs [95 % CIs] for clinical pregnancy = 0.90 [0.82, 0.98] for PFDA; 0.88 [0.79, 0.99] for PFOS; 0.95 [0.86, 1.06] for PFOA; 0.92 [0.84, 1.00] for PFHpA). We observed similar decreased odds of clinical pregnancy (ORs [95 % CIs] = 0.74 [0.56, 0.98] for PFDA; 0.76 [0.53, 1.09] for PFOS; 0.83 [0.59, 1.17] for PFOA; 0.92 [0.70, 1.22] for PFHpA) and live birth per quartile increases of individual PFAS and the PFAS mixture (ORs [95 % CIs] = 0.61 [0.37, 1.02] for clinical pregnancy, and 0.66 [0.40, 1.07] for live birth). Within the PFAS mixture, PFDA followed by PFOS, PFOA, and PFHpA were the biggest contributors to these associations. We found no evidence of association for PFHxS, PFNA, and PFHpS and the fertility outcomes examined. CONCLUSIONS: Higher PFAS exposures may be associated with decreased fertility in women. The potential impact of ubiquitous PFAS exposures on infertility mechanisms requires further investigation.

Time-to-conception and clinical pregnancy rate with a myo-inositol, probiotics, and micronutrient supplement: secondary outcomes of the NiPPeR randomized trial.

OBJECTIVE: To determine whether a combined myo-inositol, probiotics and micronutrient nutritional supplement impacts time-to-natural-conception and clinical pregnancy rates. DESIGN: Secondary outcomes of a double-blind randomized controlled trial. SETTING: Community recruitment. PATIENTS: Women aged 18 to 38 years planning to conceive in the United Kingdom, Singapore, and New Zealand, excluding those with diabetes mellitus or receiving fertility treatment. INTERVENTION: A standard (control) supplement (folic acid, iron, calcium, iodine, ß-carotene), compared with an intervention additionally containing myo-inositol, probiotics, and other micronutrients (vitamins B2, B6, B12, D, zinc). MAIN OUTCOME MEASURES: Number of days between randomization and estimated date of natural conception of a clinical pregnancy, as well as cumulative pregnancy rates at 3, 6, and 12 months. RESULTS: Of 1729 women randomized, 1437 (83%; intervention, n=736; control, n=701) provided data. Kaplan-Meier curves of conception were similar between intervention and control groups; the time at which 20% achieved natural conception was 90.5 days (95% confidence interval: 80.7, 103.5) in the intervention group compared with 92.0 days (76.0, 105.1) in the control group. Cox's proportional hazard ratios (HRs) comparing intervention against control for cumulative achievement of pregnancy (adjusted for site, ethnicity, age, body mass index, and gravidity) were similar at 3, 6, and 12 months. Among both study groups combined, overall time-to-conception lengthened with higher preconception body mass index, and was longer in non-White than in White women. Among women who were overweight the intervention shortened time-to-conception compared with control regardless of ethnicity (12-month HR=1.47 [1.07, 2.02], P=.016; 20% conceived by 84.5 vs. 117.0 days) and improved it to that comparable to nonoverweight/nonobese women (20% conceived by 82.1 days). In contrast, among women with obesity, time-to-conception was lengthened with intervention compared with control (12-month HR=0.69 [0.47, 1.00]; P=.053; 20% conceived by 132.7 vs. 108.5 days); an effect predominantly observed in non-White women with obesity. CONCLUSIONS: Time-to-natural-conception and clinical pregnancy rates within a year were overall similar in women receiving the intervention supplement compared with control. Overweight women had a longer time-to-conception but there was suggestion that the supplement may shorten their time-to-conception to that comparable to the nonoverweight/nonobese women. Further studies are required to confirm this. CLINICAL TRIAL REGISTRATION NUMBER: clinicaltrials.gov (NCT02509988).

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.

Indoor and outdoor air pollution and couple fecundability: a systematic review.

BACKGROUND: Air pollution is both a sensory blight and a threat to human health. Inhaled environmental pollutants can be naturally occurring or human-made, and include traffic-related air pollution (TRAP), ozone, particulate matter (PM) and volatile organic compounds, among other substances, including those from secondhand smoking. Studies of air pollution on reproductive and endocrine systems have reported associations of TRAP, secondhand smoke (SHS), organic solvents and biomass fueled-cooking with adverse birth outcomes. While some evidence suggests that air pollution contributes to infertility, the extant literature is mixed, and varying effects of pollutants have been reported. OBJECTIVE AND RATIONALE: Although some reviews have studied the association between common outdoor air pollutants and time to pregnancy (TTP), there are no comprehensive reviews that also include exposure to indoor inhaled pollutants, such as airborne occupational toxicants and SHS. The current systematic review summarizes the strength of evidence for associations of outdoor air pollution, SHS and indoor inhaled air pollution with couple fecundability and identifies gaps and limitations in the literature to inform policy decisions and future research. SEARCH METHODS: We performed an electronic search of six databases for original research articles in English published since 1990 on TTP or fecundability and a number of chemicals in the context of air pollution, inhalation and aerosolization. Standardized forms for screening, data extraction and study quality were developed using DistillerSR software and completed in duplicate. We used the Newcastle-Ottawa Scale to assess risk of bias and devised additional quality metrics based on specific methodological features of both air pollution and fecundability studies. OUTCOMES: The search returned 5200 articles, 4994 of which were excluded at the level of title and abstract screening. After full-text screening, 35 papers remained for data extraction and synthesis. An additional 3 papers were identified independently that fit criteria, and 5 papers involving multiple routes of exposure were removed, yielding 33 articles from 28 studies for analysis. There were 8 papers that examined outdoor air quality, while 6 papers examined SHS exposure and 19 papers examined indoor air quality. The results indicated an association between outdoor air pollution and reduced fecundability, including TRAP and specifically nitrogen oxides and PM with a diameter of ≤2.5 µm, as well as exposure to SHS and formaldehyde. However, exposure windows differed greatly between studies as did the method of exposure assessment. There was little evidence that exposure to volatile solvents is associated with reduced fecundability. WIDER IMPLICATIONS: The evidence suggests that exposure to outdoor air pollutants, SHS and some occupational inhaled pollutants may reduce fecundability. Future studies of SHS should use indoor air monitors and biomarkers to improve exposure assessment. Air monitors that capture real-time exposure can provide valuable insight about the role of indoor air pollution and are helpful in assessing the short-term acute effects of pollutants on TTP.

Preconception sleep duration, sleep timing, and shift work in association with fecundability and live birth among women with a history of pregnancy loss.

OBJECTIVE: To evaluate the associations between preconception sleep characteristics and shift work with fecundability and live birth. DESIGN: Secondary analysis of the Effects of Aspirin in Gestation and Reproduction study, a preconception cohort. SETTING: Four US academic medical centers. PATIENT(S): Women aged 18-40 with a history of 1-2 pregnancy losses who were attempting to conceive again. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURES(S): We evaluated baseline, self-reported sleep duration, sleep midpoint, social jetlag, and shift work among 1,228 women who were observed for ≤6 cycles of pregnancy attempts to ascertain fecundability. We ascertained live birth at the end of follow up via chart abstraction. We estimated fecundability odds ratios (FORs) using discrete, Cox proportional hazards models and risk ratios (RRs) for live birth using log-Poisson models. RESULT(S): Sleep duration ≥9 vs. 7 to <8 hours (FOR: 0.81, 95% confidence interval [CI], 0.61; 1.08), later sleep midpoints (3rd tertile vs. 2nd tertile: FOR: 0.85; 95% CI, 0.69, 1.04) and social jetlag (continuous per hour; FOR: 0.93, 95% CI: 0.86, 1.00) were not associated with reduced fecundability. In sensitivity analyses, excluding shift workers, sleep duration ≥9 vs. 7 to <8 hours (FOR: 0.62; 95% CI, 0.42; 0.93) was associated with low fecundability. Night shift work was not associated with fecundability (vs. non-night shift work FOR: 1.17, 95% CI, 0.96; 1.42). Preconception sleep was not associated with live birth. CONCLUSION(S): Overall, there does not appear to be a strong association between sleep characteristics, fecundability, and live birth. Although these findings may suggest weak and imprecise associations with some sleep characteristics, our findings should be evaluated in larger cohorts of women with extremes of sleep characteristics. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT00467363.