To evaluate trends in diminished ovarian reserve (DOR) assignment in the Society for Assisted Reproductive Technology (SART) Clinic Outcomes Reporting System database and to evaluate its accuracy in ...predicting poor ovarian response (POR) as defined in European Society of Human Reproduction and Embryology's Bologna criteria (2011).
Retrospective cohort study.
Not applicable.
A total of 181,536 fresh, autologous ART cycles reported to SART by U.S. clinics in 2004 and 2011 (earliest and most recent available reporting years).
None.
DOR assignment was the primary exposure. POR, defined as cycle cancellation for poor response or less than 4 oocytes retrieved after conventional gonadotropin stimulation (>149 IU FSH daily), was the primary outcome. Secondary outcomes were live birth and number of oocytes retrieved. DOR prevalence, power of DOR and FSH (</≥12 mIU/mL) to predict POR, and live birth in POR cycles were also calculated.
DOR prevalence increased from 19% to 26% from 2004 to 2011. Among cycles clinically assigned as DOR, incidence of POR decreased from 32% to 30%, and live birth improved from 15% to 17%. Comparing basal FSH ≥12 versus clinical assignment of DOR, basal FSH had a higher specificity (92.2% vs. 81.6%) and positive predictive value (38.3% vs. 30.9%) for predicting POR. Live birth among POR cycles was 4%.
DOR diagnosis is increasing, and accuracy remains poor, despite the availability of additional diagnostic parameters such as antral follicle count and antimüllerian hormone. POR entailed poor outcomes, but the majority of patients clinically assigned as DOR did not experience POR. Development and use of more accurate predictors of POR are needed to minimize patient distress resulting from overdiagnosis.
Summary Background Preconception-initiated low-dose aspirin might positively affect pregnancy outcomes, but this possibility has not been adequately assessed. Our aim was to investigate whether ...low-dose aspirin improved livebirth rates in women with one to two previous pregnancy losses. Methods In this multicentre, block-randomised, double-blind, placebo-controlled trial, women aged 18–40 years who were attempting to become pregnant were recruited from four medical centres in the USA. Participants were stratified by eligibility criteria—the original stratum was restricted to women with one loss at less than 20 weeks' gestation during the previous year, whereas the expanded stratum included women with one to two previous losses, with no restrictions on gestational age or time of loss. Women were block-randomised by centre and eligibility stratum in a 1:1 ratio. Preconception-initiated daily low-dose aspirin (81 mg per day) plus folic acid was compared with placebo plus folic acid for up to six menstrual cycles; for women who conceived, study treatment continued until 36 weeks' gestation. Participants, trial staff, and investigators were masked to the assigned treatment. The primary outcome was livebirth rate, which was analysed by intention to treat. The trial is registered with ClinicalTrials.gov , number NCT00467363. Findings Overall, 1228 women were recruited and randomly assigned between June 15, 2007, and July 15, 2011, 1078 of whom completed the trial and were included in the analysis (535 in the low-dose aspirin group and 543 in the placebo group). 309 (58%) women in the low-dose aspirin group had livebirths, compared with 286 (53%) in the placebo group (p=0·0984; absolute difference in livebirth rate 5·09% 95% CI −0·84 to 11·02). Pregnancy loss occurred in 68 (13%) women in the low-dose aspirin group, compared with 65 (12%) women in the placebo group (p=0·7812). In the original stratum, 151 (62%) of 242 women in the low-dose aspirin group had livebirths, compared with 133 (53%) of 250 in the placebo group (p=0·0446; absolute difference in livebirth rate 9·20% 0·51 to 17·89). In the expanded stratum, 158 (54%) of 293 women in the low-dose aspirin group and 153 (52%) of 293 in the placebo group had livebirths (p=0·7406; absolute difference in livebirth rate 1·71% −6·37 to 9·79). Major adverse events were similar between treatment groups. Low-dose aspirin was associated with increased vaginal bleeding, but this adverse event was not associated with pregnancy loss. Interpretation Preconception-initiated low-dose aspirin was not significantly associated with livebirth or pregnancy loss in women with one to two previous losses. However, higher livebirth rates were seen in women with a single documented loss at less than 20 weeks' gestation during the previous year. Low-dose aspirin is not recommended for the prevention of pregnancy loss. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development (US National Institutes of Health).
Abstract
STUDY QUESTION
Is couples’ body compositions associated with reduced fecundity as measured by a longer time-to-pregnancy (TTP)?
SUMMARY ANSWER
Couples whose BMI are within obese class II ...(≥35 kg/m2) have a longer TTP in comparison to leaner (BMI < 25 kg/m2) couples, observed only when both partner's BMI was jointly modeled.
WHAT IS KNOWN ALREADY
Extremes of BMI have been associated with a longer TTP and with less successful assisted reproductive technology (ART) outcomes. To our knowledge, the association between measured adiposity in both partners of the couple and prospectively measured TTP has not been investigated despite pregnancy being a couple-dependent outcome.
STUDY DESIGN, SIZE, DURATION
Prospective cohort with preconception recruitment of 501 couples trying for pregnancy and recruited from 16 counties in Michigan and Texas between 2005 and 2009. Couples were followed daily for up to a year of trying or until a hCG pregnancy.
PARTICIPANTS/MATERIALS, SETTING, METHODS
In-home standardized anthropometric assessment of couples upon enrollment included measured height and weight using calibrated stadiometers and scales, and measured waist and hip circumferences. Discrete-time Cox regression was used to estimate fecundability odds ratios (FORs) and 95% CIs, controlling for potential confounders including age, number of days of vigorous physical activity, serum cotinine concentration, race, education, free cholesterol levels for each partner in partner-specific models and for both partners in couple-based models as well as average acts of intercourse per menstrual cycle and menstrual cycle regularity.
MAIN RESULTS AND THE ROLE OF CHANCE
Neither male nor female partner's BMI was associated with TTP when modeled individually. However, obese class II (BMIs ≥ 35.0 kg/m2) couples experienced a reduction in fecundability in both unadjusted (FOR = 0.45; 95% CI: 0.23, 0.89) and adjusted analyses (aFOR = 0.41; 95% CI: 0.17, 0.98) resulting in a longer TTP in comparison to couples with normal BMI (<25 kg/m2). Female partners’ waist circumference ≥88.6 cm was associated with a significant reduction in fecundability in the unadjusted model (FOR = 0.64; 95% CI: 0.48, 0.86) but not in the adjusted model (aFOR = 0.77; 95% CI: 0.55, 1.08) in comparison to females with a smaller (<80 cm) circumference.
LIMITATIONS, REASONS FOR CAUTION
BMI and waist circumference are proxy measures of body composition and residual confounding cannot be eliminated. Findings may not be generalizable to clinical populations.
WIDER IMPLICATIONS OF THE FINDINGS
This is the first cohort study known to us with preconception enrollment of couples who underwent standardized anthropometric assessment and for whom TTP was prospectively measured. The findings underscore the importance of considering both partners’ body composition for fecundity outcomes and preconception guidance.
STUDY FUNDING/COMPETING INTEREST(S)
Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contracts #N01-HD-3–3355, N01-HD-3–3356 and N01-HD-3–3358). The authors have no competing interests.
TRIAL REGISTRATION NUMBER
N/A.
Evolutionary theory suggests that some animal species may experience shifts in their offspring sex ratio in response to maternal health and environmental conditions, and in some unfavorable ...conditions, females may be less likely to bear sons. Experimental data in both animals and humans indicate that maternal inflammation may disproportionately impact the viability of male conceptuses; however, it is unknown whether other factors associated with both pregnancy and inflammation, such as vitamin D status, are associated with the offspring sex ratio. Here, we show that among 1,228 women attempting pregnancy, preconception 25-hydroxyvitamin D concentrations are positively associated with the live birth of a male infant, with notably stronger associations among women with elevated high sensitivity C-reactive protein, a marker of systemic low-grade inflammation. Our findings suggest that vitamin D may mitigate maternal inflammation that would otherwise be detrimental to the implantation or survival of male conceptuses in utero.
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.
To determine the effect of daily folic acid and zinc supplementation on semen quality and live birth.
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.
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.
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.
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%).
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.
ClinicalTrials.gov Identifier: NCT01857310.
To determine whether oocyte cryopreservation for deferred reproduction is cost effective per live birth using a model constructed from observed clinical practice.
Decision-tree mathematical model ...with sensitivity analyses.
Not applicable.
A simulated cohort of women wishing to delay childbearing until age 40 years.
Not applicable.
Cost per live birth.
Our primary model predicted that oocyte cryopreservation at age 35 years by women planning to defer pregnancy attempts until age 40 years would decrease cost per live birth from $55,060 to $39,946 (and increase the odds of live birth from 42% to 62% by the end of the model), indicating that oocyte cryopreservation is a cost-effective strategy relative to forgoing it. If fresh autologous assisted reproductive technology (ART) was added at age 40 years, before thawing oocytes, 74% obtained a live birth, and cost per live birth increased to $61,887. Separate sensitivity analyses demonstrated that oocyte cryopreservation remained cost effective as long as performed before age 38 years, and more than 49% of those women not obtaining a spontaneously conceived live birth returned to thaw oocytes.
In women who plan to delay childbearing until age 40 years, oocyte cryopreservation before 38 years of age reduces the cost to obtain a live birth.
To estimate the prevalence of unintended pregnancies under relaxed assumptions regarding birth control use compared with a traditional constructed measure.
Cross-sectional survey.
Not applicable.
...Nationally representative sample of U.S. women aged 15-44 years.
None.
Prevalence of intended and unintended pregnancies as estimated by 1 a traditional constructed measure from the National Survey of Family Growth (NSFG), and 2 a constructed measure relaxing assumptions regarding birth control use, reasons for nonuse, and pregnancy timing.
The prevalence of unintended pregnancies was 6% higher using the traditional constructed measure as compared with the approach with relaxed assumptions (NSFG: 44%, 95% confidence interval CI 41, 46; new construct 38%, 95% CI, 36, 41). Using the NSFG approach, only 92% of women who stopped birth control to become pregnant and 0 women who were not using contraceptives at the time of the pregnancy and reported that they did not mind getting pregnant were classified as having intended pregnancies, compared with 100% using the new construct.
Current measures of pregnancy intention may overestimate rates of unintended pregnancy, with over 340,000 pregnancies in the United States misclassified as unintended using the current approach, corresponding to an estimated savings of $678 million in public health-care expenditures. Current constructs make assumptions that may not reflect contemporary reproductive practices, so improved measures are needed.
Abstract
Variability in sleep duration and cardiovascular health have been infrequently investigated, particularly among reproductive-age women. We examined these associations across the menstrual ...cycle among a cohort of 250 healthy premenopausal women, aged 18-44 years. The BioCycle study (New York, 2005–2007) collected cardiovascular biomarkers (serum high- and low-density lipoprotein (HDL, LDL), total cholesterol, triglycerides, and C-reactive protein (CRP)) at key time points along the menstrual cycle (follicular, ovulatory, and luteal phases). Women also recorded sleep duration in daily diaries. From these data, we computed L-moments, robust versions of location, dispersion, skewness, and kurtosis. We fitted linear mixed models with random intercepts and inverse probability weighting to estimate associations between sleep variability and cardiovascular biomarkers, accounting for demographic, lifestyle, health, and reproductive factors. Sleep dispersion (any deviation from mean duration) was associated with lower mean LDL for nonshift workers and non-White women. Skewed sleep duration was associated with higher mean CRP and lower mean total cholesterol. Sleep durations with extreme short and long bouts (kurtosis) were associated with a lower mean HDL, but not mean CRP, LDL, or triglycerides. Sleep duration modified associations between sleep dispersion and LDL, HDL, and total cholesterol. Even in young and healthy women, sleep duration variability could influence cardiovascular health.
Patients with PCOS are at high risk of depression, anxiety, and metabolic syndrome (MetSyn), a key predictor of cardiovascular disease. The impact of depression and/or anxiety on MetSyn is unknown in ...this population.
To compare the risk of developing MetSyn in patients with PCOS with and without a history of depression and/or anxiety.
Retrospective longitudinal cohort study (2008-2022) with median follow-up of 7 years.
Tertiary care ambulatory practice.
Patients with hyperandrogenic PCOS and at least 2 evaluations for MetSyn ≥3 years apart (n=321).
N/A.
The primary outcome was risk of developing MetSyn. We hypothesized that this risk would be higher with a history of depression and/or anxiety.
At the first visit, 33.0% had a history of depression and/or anxiety, with a third prescribed antidepressants or anxiolytics. Depression and/or anxiety increased risk of developing MetSyn during the study period (adjusted hazard ratio aHR 1.45, 95% CI 1.02-2.06, p=0.04) with an incidence of MetSyn of 75.3 compared to 47.6 cases per 100 person-years among those without (p=0.002). This was primarily driven by depression (aHR 1.56, 95% CI 1.10-2.20, p=0.01).
Patients with PCOS and depression and/or anxiety have a high risk of developing MetSyn, with a stronger association between depression and MetSyn. Our findings highlight the urgent need for guideline-directed screening for depression and anxiety at time of diagnosis of PCOS as well as screening at subsequent visits to facilitate risk stratification for metabolic monitoring and early intervention in this high-risk group.
It is common practice in perinatal epidemiology to calculate gestational-age-specific or birth-weight-specific associations between an exposure and a perinatal outcome. Gestational age or birth ...weight, for example, might lie on a pathway from the exposure to the outcome. This practice of conditioning on a potential intermediate has come under critique for various reasons. First, if one is interested in assessing the overall effect of an exposure on an outcome, it is not necessary to stratify, and indeed, it is important not to stratify, on an intermediate. Second, if one does condition on an intermediate, to try to obtain what might conceived of as a "direct effect" of the exposure on the outcome, then various biases and paradoxical results can arise. It is now well documented theoretically and empirically that, when there is an unmeasured common cause of the intermediate and the outcome, associations adjusted for the intermediate are subject to bias. In this paper, we propose 3 approaches to facilitate valid inference when effects conditional on an intermediate are in view. These 3 approaches correspond to (i) conditioning on the predicted risk of the intermediate, (ii) conditioning on the intermediate itself in conjunction with sensitivity analysis, and (iii) conditioning on the subgroup of individuals for whom the intermediate would occur irrespective of the exposure received. The second and third approaches both require sensitivity analysis, and they result in a range of estimates. Each of the 3 approaches can be used to resolve the "birth-weight paradox" that exposures such as maternal smoking seem to have a protective effect among low-birth-weight infants. The various methodologic approaches described in this paper are applicable to a number of similar settings in perinatal epidemiology.
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