BACKGROUND: Declining total fertility rates have been observed in low- and middle-income countries (LMICs). However, it remains unclear if this trend is related to a reduction in fecundity of general population. Research evidence on contributing factors to fecundity reduction is also limited. We aimed to first estimate couple fecundity in LMICs and then investigate its association with ambient particulate matter (PM) exposure.
METHODS: Using the information from Demographic and Health Surveys between 2003 and 2019, we estimated median time to pregnancy (TTP) and infertility prevalence across 30 LMICs, by employing a current duration approach. Individual PM (PM1, PM2.5, and PM10) exposure during the period of \'at risk\' of pregnancy was assessed by months. An accelerated failure model was used to elucidate the association between monthly time-varying PM exposure and TTP. Subsequently, we estimated the prolonged TTP attributable to PM exposures above the World Health Organization (WHO)\'s recommended air quality level in 2021.
RESULTS: Within the study regions, median TTP ranged from 6.90 (95 % CI 6.02-7.87) months in Latin America & Caribbean to 10.29 (95 % CI 9.28-11.36) months in East Asia & Pacific, with corresponding infertility prevalence varying from 33 % (95 % CI 29 %-36 %) to 44 % (95 % CI 41 %-48 %). Our estimations indicated that TTP was 1.08 (95 % CI: 0.99-1.18), 1.12 (95 % CI 1.06-1.19), and 1.05 (95 % CI 1.03-1.07) times longer for every 10 μg/m3 increment in PM1, PM2.5, and PM10, respectively. The prolonged TTP attributable to PM exposures surpassing the WHO guideline ranged from 0.11 to 2.81 months across the studied regions.
CONCLUSIONS: Ambient particulate matter is identified as a potential contributing factor to impaired fecundity in general population of LMICs. The findings underscore the importance of coordinated efforts to control ambient air pollution to mitigate the risk of fecundity reduction among the general population.

OBJECTIVE: To investigate the impact of antibiotic treatment for chronic endometritis (CE) on the pregnancy outcome of frozen-thawed embryo transfer (FET) cycles and the relevant clinical risk factors associated with CE.
METHODS: A retrospective cohort analysis was conducted on 1352 patients who underwent hysteroscopy and diagnostic curettage at Nanjing Maternal and Child Health Hospital from July 2020 to December 2021. All patients underwent CD138 immunohistochemical (IHC) testing to diagnose CE, and a subset of them underwent FET after hysteroscopy. Patient histories were collected, and reproductive prognosis was followed up.
RESULTS: Out of 1088 patients, 443 (40.7%) were diagnosed with CE. Univariate and multivariate binary logistic regression analyses revealed that parity ≥ 2, a history of ectopic pregnancy, moderate-to-severe dysmenorrhea, hydrosalpinx, endometrial polyps, a history of ≥ 2 uterine operations, and RIF were significantly associated with an elevated risk of CE (P < 0.05). Analysis of the effect of CE on pregnancy outcomes in FET cycles after antibiotic treatment indicated that treated CE patients exhibited a significantly lower miscarriage rate (8.7%) and early miscarriage rate (2.9%) than untreated non-CE patients (20.2%, 16.8%). Moreover, the singleton live birth rate (45.5%) was significantly higher in treated CE patients than in untreated non-CE patients (32.7%). Survival analysis revealed a statistically significant difference in the first clinical pregnancy time between treated CE and untreated non-CE patients after hysteroscopy (P = 0.0019). Stratified analysis based on the presence of recurrent implantation failure (RIF) demonstrated that in the RIF group, treated CE patients were more likely to achieve clinical pregnancy than untreated non-CE patients (P = 0.0021). Among hysteroscopy-positive patients, no significant difference was noted in pregnancy outcomes between the treatment and control groups (P > 0.05).
CONCLUSIONS: Infertile patients with a history of parity ≥ 2, hydrosalpinx, a history of ectopic pregnancy, moderate-to-severe dysmenorrhea, endometrial polyps, a history of ≥ 2 uterine operations, and RIF are at an increased risk of CE; these patients should be recommended to undergo hysteroscopy combined with CD138 examination before embryo transfer. Antibiotic treatment can improve the reproductive outcomes of FET in patients with CE, especially those with RIF.

BACKGROUND: Exposure to ambient fine particulate matter (PM2.5) has been associated with reduced human fecundity. However, the attributable burden has not been estimated for low- and middle-income countries (LMICs), where the exposure-response function between PM2.5 and the infertility rate has been insufficiently studied.
OBJECTIVE: This study examined the associations between long-term exposure to PM2.5 and human fecundity indicators, namely the expected time to pregnancy (TTP) and 12-month infertility rate (IR), and then estimated PM2.5-attributable burden of infertility in LMICs.
METHODS: We analyzed 164,593 eligible women from 100 Demographic and Health Surveys conducted in 49 LMICs between 1999 and 2021. We assessed PM2.5 exposures during the 12 months before a pregnancy attempt using the global satellite-derived PM2.5 estimates produced by Atmospheric Composition Analysis Group (ACAG). First, we created a series of pseudo-populations with balanced covariates, given different levels of PM2.5 exposure, using a matching approach based on the generalized propensity score. For each pseudo-population, we used 2-stage generalized Gamma models to derive TTP or IR from the probability distribution of the questionnaire-based duration time for the pregnancy attempt before the interview. Second, we used spline regressions to generate nonlinear PM2.5 exposure-response functions for each of the two fecundity indicators. Finally, we applied the exposure-response functions to estimate number of infertile couples attributable to PM2.5 exposure in 118 LMICs.
RESULTS: Based on the Gamma models, each 10 µg/m3 increment in PM2.5 exposure was associated with a TTP increase by 1.7 % (95 % confidence interval [CI]: -2.3 %-6.0 %) and an IR increase by 2.3 % (95 %CI: 0.6 %-3.9 %). The nonlinear exposure-response function suggested a robust effect of an increased IR for high-concentration PM2.5 exposure (>75 µg/m3). Based on the PM2.5-IR function, across the 118 LMICs, the number of infertile couples attributable to PM2.5 exposure exceeding 35 µg/m3 (the first-stage interim target recommended by the World Health Organization global air quality guidelines) was 0.66 million (95 %CI: 0.061-1.43), accounting for 2.25 % (95 %CI: 0.20 %-4.84 %) of all couples affected by infertility. Among the 0.66 million, 66.5 % were within the top 10 % high-exposure infertile couples, mainly from South Asia, East Asia, and West Africa.
CONCLUSIONS: PM2.5 contributes significantly to human infertility in places with high levels of air pollution. PM2.5-pollution control is imperative to protect human fecundity in LMICs.

OBJECTIVE: Is preconception depression associated with time to pregnancy (TTP) and infertility?
CONCLUSIONS: Couples with preconception depression needed a longer time to become pregnant and exhibited an increased risk of infertility.
BACKGROUND: Preconception depression in women contributes to impaired fertility in clinical populations. However, evidence from the general population-especially based on couples-is relatively scant.
UNASSIGNED: A couple-based prospective preconception cohort study was performed in 16 premarital examination centers between April 2019 and June 2021. The final analysis included 16 521 couples who tried to conceive for ≤6 months at enrollment. Patients with infertility were defined as those with a TTP ≥12 months and those who conceived through ART.
METHODS: Couples\' depression was assessed using the Patient Health Questionnaire-9 at baseline. Reproductive outcomes were obtained via telephone at 6 and 12 months after enrollment. Fertility odds ratios (FORs) and infertility risk ratios (RRs) in different preconception depression groups were analyzed using the Cox proportional-hazard models and logistic regression, respectively.
RESULTS: Of the 16 521 couples analyzed, 10 834 (65.6%) and 746 (4.5%) couples achieved pregnancy within the first 6 months and between the 6th and 12th months, respectively. The median (P25, P75) TTP was 3.0 (2.0, 6.0) months. The infertility rate was 13.01%. After adjusting for potential confounders, in the individual-specific analyses, we found that preconception depression in women was significantly related to reduced odds of fertility (FOR = 0.947, 95% CI: 0.908-0.988), and preconception depression in either men or women was associated with an increased risk of infertility (women: RR = 1.212, 95% CI: 1.076-1.366; men: RR = 1.214, 95% CI: 1.068-1.381); in the couple-based analyses, we found that-compared to couples where neither partner had depression-the couples where both partners had depression exhibited reduced fertility (adjusted FOR = 0.904, 95% CI: 0.838-0.975). The risk of infertility in the group where only the woman had depression and both partners had depression increased by 17.8% (RR = 1.178, 95% CI: 1.026-1.353) and 46.9% (RR = 1.469, 95% CI: 1.203-1.793), respectively.
CONCLUSIONS: Reporting and recall bias were unavoidable in this large epidemiological study. Some residual confounding factors-such as the use of anti-depressants and other medications, sexual habits, and prior depressive and anxiety symptoms-remain unaddressed. We used a cut-off score of 5 to define depression, which is lower than prior studies. Finally, we assessed depression only at baseline, therefore we could not detect effects of temporal changes in depression on fertility.
CONCLUSIONS: This couple-based study indicated that preconception depression in individuals and couples negatively impacts couples\' fertility. Early detection and intervention of depression to improve fertility should focus on both sexes.
BACKGROUND: This work was supported by grants from the National Natural Science Foundation of China (No. 82273638) and the National Key Research and Development Program of China (No. 2018YFC1004201). All authors declare no conflicts of interest.
BACKGROUND: N/A.

OBJECTIVE: To investigate the relationship between ambient fine particulate matter (PM2.5) exposure and fecundability.
METHODS: This study included 751,270 female residents from Henan Province who participated in the National Free Pre-conception Check-up Projects during 2015-2017. Ambient cycle-specific PM2.5 exposure was assessed at the county level for each participant using satellite-based PM2.5 concentration data at 1-km resolution. Cox proportional hazards models with time-varying exposure were used to estimate the association between fecundability and PM2.5 exposure, adjusted for potential individual risk factors.
RESULTS: During the study period, 568,713 participants were pregnant, monthly mean PM2.5 concentrations varied from 25.5 to 114.0 µg/m3 across study areas. For each 10 µg/m3 increase in cycle-specific PM2.5, the hazard ratio for fecundability was 0.951 (95 % confidence interval: 0.950-0.953). The association was more pronounced in women who were older, with urban household registration, history of pregnancy, higher body mass index (BMI), hypertension, without exposure to tobacco, or whose male partners were older, with higher BMI, or hypertension.
CONCLUSIONS: In this population-based prospective cohort, ambient cycle-specific PM2.5 exposure was associated with reduced fecundability. These findings may support the adverse implications of severe air pollution on reproductive health.

OBJECTIVE: This study aimed to investigate the influence of bacterial vaginosis on time to pregnancy in subfertile couples.
METHODS: Couples attending a teaching hospital in the Netherlands having an initial fertility assessment (IFA) between July 2019 and June 2022 were included in this prospective study, with follow-up of pregnancies until June 2023. Vaginal samples at IFA were analyzed on pH, qPCR BV, and 16S rRNA gene microbiome analysis of V1-V2 region. Main outcome measures were time from initial fertility assessment to ongoing pregnancy at 12 weeks and live birth, analyzed by Kaplan-Meier and Cox regression with adjustment for potential confounders.
RESULTS: At IFA, 27% of 163 included participants tested positive for BV. BV status had no influence on time to ongoing pregnancy (HR 0.98, 0.60-1.61, aHR 0.97, 0.58-1.62). In persons with unexplained subfertility, positive BV status had a tendency of longer time to pregnancy. When persons had an indication for fertility treatment, positive BV status (HR 0.21, 0.05-0.88, aHR 0.19, 0.04-0.85) and microbiome community state type III and type IV had significant longer time to pregnancy.
CONCLUSIONS: This study indicates that BV may have a potential negative impact on time to live birth pregnancy in subfertile persons with an indication for fertility treatment. This study did not find an association between BV and time to live birth pregnancy in a general group of subfertile couples or in unexplained subfertility. More research should be done in persons with unexplained subfertility and if treatment improves time to pregnancy.

BACKGROUND: Phthalates (PAEs) are endocrine-disrupting chemicals ubiquitously found in the environment. This study aimed to examine the association between exposure of PAEs and subfecundity in preconception couples.
METHODS: This is a nested case-control study based on preconception cohort. Preconception couples with intention to conceive were enrolled and followed up until a clinically confirmed pregnancy or 12 menstrual cycles of preparation for conception. A total of 107 couples with subfecundity- time to pregnancy (TTP) more than 12 menstrual cycles, and 144 couples ≤12 cycles were included in the analysis. The levels of PAE metabolites in one spot urine samples were detected and compared between the groups. The weighted quantile sum (WQS) regression model and Bayesian kernel machine regression (BKMR) model were used to examine the joint effects of couples\' exposure to PAEs on subfecundity.
RESULTS: Using the multivariate binary logistic regression model, compared to the lowest quartile of urinary ∑PAEs concentration group, both preconception females (aOR=2.42, 95% CI: 1.10-5.30, p=0.027) and males (aOR=2.99, 95% CI: 1.36-6.58, p=0.006) in the highest quartile group had an increased risk of subfecundity, and a dose-response relationship was observed between PAEs and the risk of subfecundity. The WQS analyses found that co-exposure to PAE mixture was a risk factor for subfecundity in preconception female (aOR=1.76, 95% CI: 1.38-2.26, p<0.001), male (aOR=1.58, 95% CI: 1.20-2.08, p=0.001), and couple (aOR=2.39, 95% CI: 1.61-3.52, p<0.001). The BKMR model found a positive combined effect of mixed exposure to PAEs on the risk of subfecundity.
CONCLUSIONS: PAEs increase the risk of subfecundity in preconception couples. Our research reinforced the need of monitoring PAE exposure for the purpose of improving human reproductive health.

OBJECTIVE: Could EMBRYOLY, an artificial intelligence embryo evaluation tool, assist embryologists to increase first cycle pregnancy rate and reduce cycles to pregnancy for patients?
METHODS: Data from 11,988 embryos were collected via EMBRYOLY from 2666 egg retrievals (2019-2022) across 11 centres in France, Spain and Morocco using three time-lapse systems (TLS). Data from two independent clinics were also examined. EMBRYOLY\'s transformer-based model was applied to transferred embryos to evaluate ranking performances against pregnancy and birth outcomes. It was applied to cohorts to rank sibling embryos (including non-transferred) according to their likelihood of clinical pregnancy and to compute the agreement with the embryologist\'s highest ranked embryo. Its effect on time to pregnancy and first cycle pregnancy rate was evaluated on cohorts with multiple single blastocyst transfers, assuming the embryologist would have considered EMBRYOLY\'s ranking on the embryos favoured for transfer.
RESULTS: EMBRYOLY\'s score correlated significantly with clinical pregnancies and live births for cleavage and blastocyst transfers. This held true for clinical pregnancies from blastocyst transfers in two independent clinics. In cases of multiple single embryo transfers, embryologists achieved a 19.8% first cycle pregnancy rate, which could have been improved to 44.1% with the adjunctive use of EMBRYOLY (McNemar\'s test: P < 0.001). This could have reduced cycles to clinical pregnancy from 2.01 to 1.66 (Wilcoxon test: P < 0.001).
CONCLUSIONS: EMBRYOLY\'s potential to enhance first cycle pregnancy rates when combined with embryologists\' expertise is highlighted. It reduces the number of unsuccessful cycles for patients across TLS and IVF centres.

BACKGROUND: IVF and IUI with ovarian stimulation (IUI-OS) are widely used in managing unexplained infertility. IUI-OS is generally considered first-line therapy, followed by IVF only if IUI-OS is unsuccessful after several attempts. However, there is a growing interest in using IVF for immediate treatment because it is believed to lead to higher live birth rates and shorter time to pregnancy.
OBJECTIVE: Randomized controlled trials (RCTs) comparing IVF versus IUI-OS had varied study designs and findings. Some RCTs used complex algorithms to combine IVF and IUI-OS, while others had unequal follow-up time between arms or compared treatments on a per-cycle basis, which introduced biases. Comparing cumulative live birth rates of IVF and IUI-OS within a consistent time frame is necessary for a fair head-to-head comparison. Previous meta-analyses of RCTs did not consider the time it takes to achieve pregnancy, which is not possible using aggregate data. Individual participant data meta-analysis (IPD-MA) allows standardization of follow-up time in different trials and time-to-event analysis methods. We performed this IPD-MA to investigate if IVF increases cumulative live birth rate considering the time leading to pregnancy and reduces multiple pregnancy rate compared to IUI-OS in couples with unexplained infertility.
METHODS: We searched MEDLINE, EMBASE, CENTRAL, PsycINFO, CINAHL, and the Cochrane Gynaecology and Fertility Group Specialised Register to identify RCTs that completed data collection before June 2021. A search update was carried out in January 2023. RCTs that compared IVF/ICSI to IUI-OS in couples with unexplained infertility were eligible. We invited author groups of eligible studies to join the IPD-MA and share the deidentified IPD of their RCTs. IPD were checked and standardized before synthesis. The quality of evidence was assessed using the Risk of Bias 2 tool.
RESULTS: Of eight potentially eligible RCTs, two were considered awaiting classification. In the other six trials, four shared IPD of 934 women, of which 550 were allocated to IVF and 383 to IUI-OS. Because the interventions were unable to blind, two RCTs had a high risk of bias, one had some concerns, and one had a low risk of bias. Considering the time to pregnancy leading to live birth, the cumulative live birth rate was not significantly higher in IVF compared to that in IUI-OS (4 RCTs, 908 women, 50.3% versus 43.2%, hazard ratio 1.19, 95% CI 0.81-1.74, I2 = 42.4%). For the safety primary outcome, the rate of multiple pregnancy was not significantly lower in IVF than IUI-OS (3 RCTs, 890 women, 3.8% versus 5.2% of all couples randomized, odds ratio 0.78, 95% CI 0.41-1.50, I2 = 0.0%).
CONCLUSIONS: There is no robust evidence that in couples with unexplained infertility IVF achieves pregnancy leading to live birth faster than IUI-OS. IVF and IUI-OS are both viable options in terms of effectiveness and safety for managing unexplained infertility. The associated costs of interventions and the preference of couples need to be weighed in clinical decision-making.

OBJECTIVE: Is fecundity, measured as time to pregnancy (TTP), associated with mortality in parents?
CONCLUSIONS: Prolonged TTP is associated with increased mortality in both mothers and fathers in a dose-response manner.
BACKGROUND: Several studies have linked both male and female fecundity to mortality. In women, infertility has been linked to several diseases, but studies suggest that the underlying conditions, rather than infertility, increase mortality.
METHODS: A prospective cohort study was carried out on 18 796 pregnant couples, in which the pregnant women attended prophylactic antenatal care between 1973 and 1987 at a primary and tertiary care unit. The couples were followed in Danish mortality registers from their child\'s birth date until death or until 2018. The follow-up period was up to 47 years, and there was complete follow-up until death, emigration or end of study.
METHODS: At the first antenatal visit, the pregnant women were asked to report the time to the current pregnancy. Inclusion was restricted to the first pregnancy, and TTP was categorised into <12 months, ≥12 months, not planned, and not available. In sub-analyses, TTP ≥12 was further categorized into 12-35, 36-60, and >60 months. Information for parents was linked to several Danish nationwide health registries. Survival analysis was used to estimate the hazard ratios (HRs) with a 95% CI for survival and adjusted for age at the first attempt to become pregnant, year of birth, socioeconomic status, mother\'s smoking during pregnancy, and mother\'s BMI.
RESULTS: Mothers and fathers with TTP >60 months survived, respectively, 3.5 (95% CI: 2.6-4.3) and 2.7 (95% CI: 1.8-3.7) years shorter than parents with a TTP <12 months. The mortality was higher for fathers (HR: 1.21, 95% CI: 1.09-1.34) and mothers (HR: 1.29, 95% CI: 1.12-1.49) with TTP ≥12 months compared to parents with TTP <12 months. The risk of all-cause mortality during the study period increased in a dose-response manner with the highest adjusted HR of 1.98 (95% CI: 1.62-2.41) for fathers and 2.03 (95% CI: 1.56-2.63) for mothers with TTP >60 months. Prolonged TTP was associated with several different causes of death in both fathers and mothers, indicating that the underlying causes of the relation between fecundity and survival may be multi-factorial.
CONCLUSIONS: A limitation is that fecundity is measured using a pregnancy-based approach. Thus, the cohort is conditioned on fertility success and excludes sterile couples, unsuccessful attempts and spontaneous abortions. The question used to measure TTP when the pregnant woman was interviewed at her first attended prophylactic antenatal care: \'From the time you wanted a pregnancy until it occurred, how much time passed?\' could potentially have led to serious misclassification if the woman did not answer on time starting unprotected intercourse but on the start of wishing to have a child.
CONCLUSIONS: We found that TTP is a strong marker of survival, contributing to the still-emerging evidence that fecundity in men and women reflects their health and survival potential.
BACKGROUND: The authors acknowledge an unrestricted grant from Ferring. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. M.L.E. is an advisor to Ro, VSeat, Doveras, and Next.
BACKGROUND: N/A.