The association between parental age differences and perinatal outcomes.

STUDY QUESTION: Are there significant associations existing between parental age differences and adverse perinatal outcomes? SUMMARY ANSWER: Large differences in parental age are associated with adverse perinatal outcomes, particularly with older mothers paired with younger fathers. WHAT IS KNOWN ALREADY: The association between advanced maternal age and perinatal outcomes is well-documented with women over 35 years showing an increased risk of several adverse outcomes. Other studies have identified potential associations between advanced paternal age and adverse perinatal outcomes. STUDY DESIGN, SIZE, DURATION: A historical (retrospective) cohort analysis was performed utilizing a multivariable logistic regression model to evaluate the association between varying differences in parental age and adverse perinatal outcomes while controlling for demographic and health-related covariates. Data were compiled from the National Vital Statistics System for 20 613 704 births between 2012 and 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Parental age differences, categorized into eleven 4-year intervals, were stratified by seven maternal age categories and evaluated for their associations with adverse perinatal outcomes. Main outcome measures included low birth weight, very low birth weight, preterm birth, very preterm birth, small size for gestational age, low 5-min appearance, pulse, grimace, activity, and respiration score, congenital defects, and chromosomal anomalies. MAIN RESULTS AND THE ROLE OF CHANCE: Increased parental age differences, in either direction, were associated with significant risks for all adverse outcomes, aside from congenital defects, even when controlling for maternal age. Restricting maternal age to the reference range of 25-29 years, infants born to fathers aged 9-12 years younger (n = 3773) had 27% (odds ratio (OR) 1.27, 95% CI, 1.17-1.37) higher odds of having any adverse perinatal outcome. Infants born to fathers aged >16 years older (n = 98 555) had 14% (OR 1.14, 95% CI, 1.12-1.16) higher odds of having any adverse perinatal outcome. LIMITATIONS, REASONS FOR CAUTION: Data extracted from US birth certificates may be compromised by errors in reporting or documentation. Information regarding the mother's socioeconomic status was estimated using proxy variables and may be susceptible to uncontrolled factors. Use of a pre-compiled dataset may potentially exclude additional maternal comorbidities that could impact perinatal outcomes. WIDER IMPLICATIONS OF FINDINGS: Older mothers paired with younger fathers demonstrated the highest risk, even when maternal age was below the threshold of 35 years. For the clinical setting, parental age differences should be considered alongside maternal and paternal age when assessing risks of adverse perinatal outcomes for potential parents. This is particularly relevant for older women with younger male partners as this may exacerbate the impact of advanced maternal age. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the NIH Research Fellowship T35 Training Grant. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

The impact of zinc and folic acid supplementation on sperm DNA methylation: results from the folic acid and zinc supplementation randomized clinical trial (FAZST).

OBJECTIVE: To determine if 6-month folic acid (5 mg) and zinc (30 mg) supplementation impacts sperm DNA methylation patterns. DESIGN: A multicenter, double-blind, block randomized, placebo-controlled trial titled "The Folic Acid and Zinc Supplementation Trial (FAZST)." SETTING: Infertility care centers. PATIENT(S): Male partners (18 years and older) from heterosexual couples (female partners aged 18-45 years) seeking fertility treatment were recruited. INTERVENTION(S): Men were randomized 1:1 to receive folic acid (5 mg) and elemental zinc (30 mg) (n = 713) or a matching placebo (n = 757) daily for 6 months. MAIN OUTCOME MEASURE(S): Sperm DNA methylation was analyzed using the EPIC methylation array (Illumina) at 6 months. Differential sperm DNA methylation was assessed at multiple levels (regional, single cytosine phosphate guanine, etc.). We additionally assessed the impact of supplementation on epigenetic age. RESULT(S): No significant differences were identified between the treatment and placebo groups although some trends appeared to be present. To determine if these trends were noteworthy, we implemented various permutations and found that the patterns we identified were no more than would be expected by random chance. CONCLUSION(S): The data presented here strongly suggest that this supplementation regimen is not effective at altering sperm DNA methylation. These data comport well with previous findings from the FAZST study that found no impact of supplementation on basic semen analysis parameters or live birth. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01857310.

Cancer treatment is associated with a measurable decrease in live births in a large, population-based study.

OBJECTIVE: To define the live birth rates in a large, population-based study of the most common reproductive-age cancers in women. DESIGN: Retrospective cohort study. SETTING: Population-based study. PATIENTS: Female cancer patients diagnosed with cancer at age 18 years old or older between 1952-2014 (n = 17,952) were compared to fertility of non-cancer controls (n = 89,436). INTERVENTIONS: Live births in cancer survivors were compared with those in healthy, age-matched controls. Cases and controls were matched in the ratio of 5:1 for birth year, birthplace (Utah, yes/no), and follow-up time in Utah. MAIN OUTCOME MEASURE: Rate of at least one live birth, reported as an incidence rate ratio (IRR). RESULTS: Of all cancer survivors, 3,127 (17.4%) had at least 1 live birth after treatment in comparison to 19,405 healthy, age-matched controls (21.7%) with the same amount of time exposure for attempting pregnancy. Breast cancer was the most common cancer type (23.1% of patients in cohort). Compared with age-matched, healthy controls, IRR of live birth was 0.69 (95% confidence interval [CI], 0.67-0.70) for all cancer types, 0.25 (95% CI, 0.20-0.33) for leukemia, 0.40 (95% CI, 0.28-0.59) for gastrointestinal cancers, 0.44 (95% CI, 0.41-0.48) for breast cancer, 0.53 (95% CI, 0.47-0.59) for central nervous system cancers, and 0.57 (95% CI, 0.44-0.73) for soft tissue cancers. With all cancer types stratified by age at diagnosis, IRR for live births in cancer survivors aged >41 years at diagnosis was 0.48 (95% CI, 0.44-0.52); IRR was 0.64 (95% CI, 0.61-0.67) in the group aged 31-40 years and 0.71 (95% CI, 0.69-0.74) in the group aged 18-30 years after their cancer treatment. CONCLUSIONS: Cancer and its treatment were associated with lower live birth rates when comparing women with cancer vs. age-matched, healthy controls.

Dissecting mammalian spermatogenesis using spatial transcriptomics.

Single-cell RNA sequencing has revealed extensive molecular diversity in gene programs governing mammalian spermatogenesis but fails to delineate their dynamics in the native context of seminiferous tubules, the spatially confined functional units of spermatogenesis. Here, we use Slide-seq, a spatial transcriptomics technology, to generate an atlas that captures the spatial gene expression patterns at near-single-cell resolution in the mouse and human testis. Using Slide-seq data, we devise a computational framework that accurately localizes testicular cell types in individual seminiferous tubules. Unbiased analysis systematically identifies spatially patterned genes and gene programs. Combining Slide-seq with targeted in situ RNA sequencing, we demonstrate significant differences in the cellular compositions of spermatogonial microenvironment between mouse and human testes. Finally, a comparison of the spatial atlas generated from the wild-type and diabetic mouse testis reveals a disruption in the spatial cellular organization of seminiferous tubules as a potential mechanism of diabetes-induced male infertility.

Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment: A Randomized Clinical Trial.

Importance: Dietary supplements marketed for male fertility commonly contain folic acid and zinc based on limited prior evidence for improving semen quality. However, no large-scale trial has examined the efficacy of this therapy for improving semen quality or live birth. Objective: To determine the effect of daily folic acid and zinc supplementation on semen quality and live birth. Design, Setting, and Participants: The Folic Acid and Zinc Supplementation Trial was a multicenter randomized clinical trial. Couples (n = 2370; men aged ≥18 years and women aged 18-45 years) planning infertility treatment were enrolled at 4 US reproductive endocrinology and infertility care study centers between June 2013 and December 2017. The last 6-month study visit for semen collection occurred during August 2018, with chart abstraction of live birth and pregnancy information completed during April 2019. Interventions: Men were block randomized by study center and planned infertility treatment (in vitro fertilization, other treatment at a study site, and other treatment at an outside clinic) to receive either 5 mg of folic acid and 30 mg of elemental zinc (n = 1185) or placebo (n = 1185) daily for 6 months. Main Outcomes and Measures: The co-primary outcomes were live birth (resulting from pregnancies occurring within 9 months of randomization) and semen quality parameters (sperm concentration, motility, morphology, volume, DNA fragmentation, and total motile sperm count) at 6 months after randomization. Results: Among 2370 men who were randomized (mean age, 33 years), 1773 (75%) attended the final 6-month study visit. Live birth outcomes were available for all couples, and 1629 men (69%) had semen available for analysis at 6 months after randomization. Live birth was not significantly different between treatment groups (404 [34%] in the folic acid and zinc group and 416 [35%] in the placebo group; risk difference, -0.9% [95% CI, -4.7% to 2.8%]). Most of the semen quality parameters (sperm concentration, motility, morphology, volume, and total motile sperm count) were not significantly different between treatment groups at 6 months after randomization. A statistically significant increase in DNA fragmentation was observed with folic acid and zinc supplementation (mean of 29.7% for percentage of DNA fragmentation in the folic acid and zinc group and 27.2% in the placebo group; mean difference, 2.4% [95% CI, 0.5% to 4.4%]). Gastrointestinal symptoms were more common with folic acid and zinc supplementation compared with placebo (abdominal discomfort or pain: 66 [6%] vs 40 [3%], respectively; nausea: 50 [4%] vs 24 [2%]; and vomiting: 32 [3%] vs 17 [1%]). Conclusions and Relevance: Among a general population of couples seeking infertility treatment, the use of folic acid and zinc supplementation by male partners, compared with placebo, did not significantly improve semen quality or couples' live birth rates. These findings do not support the use of folic acid and zinc supplementation by male partners in the treatment of infertility. Trial Registration: ClinicalTrials.gov Identifier: NCT01857310.

Sperm Epigenetics and Its Impact on Male Fertility, Pregnancy Loss, and Somatic Health of Future Offsprings.

Sperm epigenetic programming is tailored to meet the need of this specialized cell, which include its interaction with the oocyte during fertilization and early embryo development. The unique nature of the sperm epigenome has resulted in multiple studies investigating how perturbations in epigenetics might impact male fertility and early embryo development. In addition, sperm epigenetics appear to be altered by specific environmental exposures, which could provide a link for investigating the role of these triggers in somatic health of off springs produced. This has the potential of explaining otherwise missing heritability factors seen with several diseases. While this field of investigation is new and with limited validation, it is intriguing and further studies are warranted.

Cardiovascular autonomic neuropathy, erectile dysfunction and lower urinary tract symptoms in men with type 1 diabetes: findings from the DCCT/EDIC.

PURPOSE: We evaluated the association between cardiovascular autonomic neuropathy, and erectile dysfunction and lower urinary tract symptoms in men with type 1 diabetes. MATERIALS AND METHODS: Male type 1 diabetes participants (635) in the DCCT/EDIC were studied. Cardiovascular autonomic neuropathy was assessed by standardized cardiovascular reflex tests including changes in respiratory rate variation with deep breathing, Valsalva maneuver (Valsalva ratio) and changes in supine to standing diastolic blood pressure. Erectile dysfunction was assessed by a proxy item from the International Index of Erectile Function, and lower urinary tract symptoms were assessed with the AUASI (American Urological Association Symptom Index). Multivariable logistic regression models estimated the association between cardiovascular autonomic neuropathy and erectile dysfunction and/or lower urinary tract symptoms, adjusting for time weighted glycemic control, blood pressure, age and other covariates. RESULTS: Men in whom erectile dysfunction and/or lower urinary tract symptoms developed during EDIC had a significantly lower respiratory rate variation and Valsalva ratio at DCCT closeout and EDIC year 16/17 compared to those without erectile dysfunction or lower urinary tract symptoms. In adjusted analysis, participants with cardiovascular autonomic neuropathy had 2.65 greater odds of erectile dysfunction and lower urinary tract symptoms (95% CI 1.47-4.79). CONCLUSIONS: These data suggest that cardiovascular autonomic neuropathy predicts the development of urological complications in men with long-standing type 1 diabetes. Studies evaluating the mechanisms contributing to these interactions are warranted for targeting effective prevention or treatment.

Do inclusive trauma systems improve outcomes after renal trauma?

BACKGROUND: Our aim is to assess state variation in renal trauma outcomes. We hypothesize that states with more hospitals participating in a trauma system will have lower nephrectomy and mortality rates. METHODS: The Healthcare Cost and Utilization Project State Inpatient Database was used to conduct a retrospective cohort study of all patients hospitalized with renal injury from partnering states during 2001, 2004, and 2007. State trauma systems were categorized based on the proportion of all acute care hospitals designated as a trauma center (Levels I-V) with higher proportions correlating to a more inclusive system. Poisson regression for relative risks (RRs) of inpatient nephrectomy and case fatality were performed adjusting for patient and state level factors. RESULTS: Patients in states with the "most inclusive" trauma systems had a 30% lower risk of nephrectomy (RR, 0.70; 95% confidence interval [CI], 0.56-0.88) and a 2.06% lower unadjusted inpatient case fatality rate compared with states with "exclusive" trauma systems. Inpatient case fatality risk varied significantly by trauma system inclusiveness. Patients treated in states with either a "more inclusive" (RR, 0.85; 95% CI, 0.74-0.97) or "most inclusive" (RR, 0.74; 95% CI, 0.64-0.85) trauma system were independently associated with a lower inpatient case fatality risk compared with states with "exclusive" systems. CONCLUSIONS: A reduced risk of nephrectomy and inpatient case fatality are more common among states that have a higher proportion of acute care hospitals participating as a trauma center (Levels I-V). Standardization of care may correlate with improved patient outcomes after renal trauma. LEVEL OF EVIDENCE: II, exploratory cohort analysis.