The appraisal of body content (ABC) trial: obesity does not significantly impact gamete production in infertile men and women.

PURPOSE: As obesity becomes increasingly prevalent, its impact on fertility has been a subject of great debate. Nearly all prior research is retrospective and evaluates obesity utilizing body mass index (BMI), which may overestimate adiposity in individuals with a greater amount of lean muscle and underestimate adiposity in those with less muscle mass. METHODS: We prospectively evaluated 2013 couples undergoing infertility treatment with in vitro fertilization (IVF). Percent body fat (%BF) was measured by use of a bioelectric impedance analysis (BIA) scale at baseline. BMI was also determined. Ovarian reserve parameters, ovarian response to controlled ovarian hyperstimulation, and semen analyses were measured in correlation with their %BF and BMI. RESULTS: Females classified as obese based on %BF or BMI had lower serum FSH. However, when the analysis was limited to women without PCOS (n = 1706), obesity based on %BF or BMI was associated with lower serum AMH. Female obesity-regardless of a PCOS diagnosis-did not affect number of mature oocytes retrieved. Males who were in obese %BF category were found to have lower TMSC compared with normal weight counterparts (p < 0.05); however, the observed decrease was not significant enough to limit the success of assisted reproductive technologies. CONCLUSIONS: These findings suggest that while obesity may affect ovarian reserve in women variably depending on presence of PCOS, it does not affect number of mature oocytes available after COH. Similarly, while a high %BF in males is associated with lower TMSC, the observed difference is unlikely to affect IVF outcomes.

Sperm DNA fragmentation on the day of fertilization is not associated with embryologic or clinical outcomes after IVF/ICSI.

PURPOSE: To evaluate if sperm DNA fragmentation (SDF) in the sample used for intracytoplasmic sperm injection (ICSI) impacts outcomes after euploid blastocyst transfer. METHODS: Prospective cohort study of couples undergoing IVF with preimplantation genetic testing for aneuploidy from December 2014-June 2017. Sperm collected on the day of ICSI was analyzed for SDF using the sperm chromatin structure assay (SCSA®). Semen analysis parameters, embryologic outcomes, and clinical outcomes after euploid blastocyst transfer were compared between groups with DNA fragmentation index (DFI) ≤ 15% and DFI > 15% using Mann-Whitney U, t tests, and generalized linear mixed effects models. RESULTS: Two hundred thirty-four patients were included. One hundred seventy-nine men had DFI ≤ 15% (low DFI group) and 55 men had DFI > 15% group (high DFI group). Total motile sperm and sperm concentration were significantly lower in the group with DFI > 15% vs. DFI ≤ 15%. There was no difference in fertilization (86.3 vs. 84.2%, adjusted OR (95% CI) 0.86 (0.63-1.18)), blastulation (49.5 vs. 48.8%, adjusted OR 1.02 (0.75-1.36)), or euploidy (55.7 vs. 52.1%, adjusted OR 0.96 (0.7-1.31)) between the low and high DFI groups, respectively. Clinical outcomes were similar between low and high DFI groups, including implantation rate (68.8 vs. 79.8%), ongoing pregnancy rate (65.9 vs. 72.6%), and miscarriage rate (4.2 vs. 8.8%), respectively. CONCLUSION: Sperm DNA fragmentation on the day of ICSI is not associated with embryologic or clinical outcomes after euploid blastocyst transfer. Increasing levels of SDF are associated with low sperm concentration and total motile sperm count.

Complexities and potential pitfalls of clinical study design and data analysis in assisted reproduction.

PURPOSE OF REVIEW: The purpose of the current review is to describe the common pitfalls in design and statistical analysis of reproductive medicine studies. It serves to guide both authors and reviewers toward reducing the incidence of spurious statistical results and erroneous conclusions. RECENT FINDINGS: The large amount of data gathered in IVF cycles leads to problems with multiplicity, multicollinearity, and over fitting of regression models. Furthermore, the use of the word 'trend' to describe nonsignificant results has increased in recent years. Finally, methods to accurately account for female age in infertility research models are becoming more common and necessary. SUMMARY: The pitfalls of study design and analysis reviewed provide a framework for authors and reviewers to approach clinical research in the field of reproductive medicine. By providing a more rigorous approach to study design and analysis, the literature in reproductive medicine will have more reliable conclusions that can stand the test of time.

The slow growing embryo and premature progesterone elevation: compounding factors for embryo-endometrial asynchrony.

STUDY QUESTION: Is there an association of progesterone (P4) on the day of trigger with live birth in autologous ART transfer cycles on day 5 versus day 6? SUMMARY ANSWER: P4 had a greater negative effect on live birth in day 6 fresh transfers compared to day 5 fresh transfers. WHAT IS KNOWN ALREADY: Premature P4 elevation is associated with lower live birth rates in fresh autologous ART cycles, likely due to worsened endometrial-embryo asynchrony. Few studies have evaluated whether the effect of an elevated P4 on the day of trigger is different on live birth rates with a day 5 compared to a day 6 embryo transfer. STUDY DESIGN SIZE, DURATION: This was a retrospective cohort study with autologous IVF cycles with fresh embryo transfers on day 5 and day 6 from 2011 to 2014. A total of 4120 day 5 and 230 day 6 fresh autologous embryo transfers were included. The primary outcome was live birth, defined as a live born baby at 24 weeks gestation or later. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients from a large private ART practice were included. Analysis was performed with generalized estimating equations (GEE) modeling and receiver operating characteristic (ROC) curves. MAIN RESULTS AND THE ROLE OF CHANCE: Day 6 transfers were less likely to have good quality embryos (73% versus 83%, P < 0.001) but the cohorts had similar rates of blastocyst stage transfer (92% versus 91%, P = 0.92). Live birth was less likely in fresh day 6 versus day 5 embryo transfers (34% versus 46%, P = 0.01) even when controlling for embryo confounders. In adjusted GEE models, the effect of P4 as a continuous variable on live birth was more pronounced on day 6 (P < 0.001). Similarly, the effect of P4 > 1.5 ng/ml on day of trigger was more pronounced on day 6 than day 5 (P < 0.001). Day 6 live birth rates were 8% lower than day 5 when P4 was in the normal range (P = 0.04), but became 17% lower when P4 was > 1.5 ng/ml (P < 0.01). ROC curves for P4 predicting live birth demonstrated a greater AUC in day 6 transfers (AUC 0.59, 95% CI 0.51-0.66) than day 5 (AUC 0.54, 95% CI 0.52-0.55). Interaction testing of P4 × day of embryo transfer was highly significant (P < 0.001), further suggesting that the effect of P4 was more pronounced on day 6 embryo transfer. In fresh oocyte retrieval cycles with elevated P4, a subsequent 760 frozen-thaw transfers did not demonstrate a difference between embryos that were frozen after blastulation on day 5 versus 6. LIMITATIONS REASONS FOR CAUTION: Limitations include the retrospective design and the inability to control for certain confounding variables, such as thaw survival rates between day 5 and day 6 blastocysts. Also, the data set lacks the known ploidy status of the embryos and the progesterone assay is not currently optimized to discriminate between patients with a P4 of 1.5 versus 1.8 ng/ml. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests further endometrial-embryo asynchrony when a slow growing embryo is combined with an advanced endometrium, ultimately leading to decreased live births. This suggests that premature elevated P4 may be a factor in the lower live birth rates in day 6 fresh embryo transfers. Further studies are needed to evaluate if a frozen embryo transfer cycle can ameliorate the effect of elevated P4 on the day of trigger among these slower growing embryos that reach blastocyst staging on day 6. STUDY FUNDING/COMPETING INTERESTS: No external funding was received for this study. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Does premature elevated progesterone on the day of trigger increase spontaneous abortion rates in fresh and subsequent frozen embryo transfers?

Recent evidence has shown elevated progesterone (P) advances the endometrium in fresh ART cycles, creating asynchrony with the embryo and thus implantation failure and decreased live birth rates. If the window of implantation is closing as the embryo attempts to implant, there may be difficulty with trophoblastic invasion, leading to failure of early pregnancies. Our objective was to evaluate if P on the day of trigger was associated with spontaneous abortion (SAB) rates in fresh ART transfers. This was a retrospective cohort study involving fresh autologous and FET cycles from 2011 to 2013. The main outcome was spontaneous abortion rates. About 4123 fresh and FET transfer cycles were included which resulted in 1547 fresh and 491 FET pregnancies. The overall SAB rate was 20% among fresh cycles and 19% in FET cycles. P on the day of trigger, as a continuous variable or when > 2 ng/mL, was not associated with SAB in fresh cycles. Similar results were found after adjusting for age, embryo quality, and embryo stage. Despite elevated P likely advancing the window of implantation, once implantation occurs, pregnancies were no longer negatively impacted by progesterone.

Multiple thrombophilic single nucleotide polymorphisms lack a significant effect on outcomes in fresh IVF cycles: an analysis of 1717 patients.

PURPOSE: The aim of the study is to determine if thrombophilic single nucleotide polymorphisms (SNPs) affect outcomes in fresh in vitro fertilization (IVF) cycles in a large general infertility population. METHODS: A prospective cohort analysis was performed at a university-affiliated private IVF center of female patients undergoing fresh non-donor IVF cycles. The effect of the following thrombophilic SNPs on IVF outcomes were explored: factor V (Leiden and H1299R), prothrombin (G20210A), factor XIII (V34L), ß-fibrinogen (-455G → A), plasminogen activator inhibitor-1 (4G/5G), human platelet antigen-1 (a/b9L33P), and methylenetetrahydrofolate reductase (C677T and A1298C). The main outcome measures included positive pregnancy test, clinical pregnancy, embryo implantation, live birth, and pregnancy loss. RESULTS: Patients (1717) were enrolled in the study, and a total of 4169 embryos were transferred. There were no statistically significant differences in positive pregnancy test, clinical pregnancy, embryo implantation, live birth, or pregnancy loss in the analysis of 1717 patients attempting their first cycle of IVF. Receiver operator characteristics and logistic regression analyses showed that outcomes cannot be predicted by the cumulative number of thrombophilic mutations present in the patient. CONCLUSIONS: Individual and cumulative thrombophilic SNPs do not affect IVF outcomes. Therefore, initial screening for these SNPs is not indicated.

Genetic associations with diminished ovarian reserve: a systematic review of the literature.

PURPOSE: Diminished ovarian reserve (DOR) affects 10 % of women seeking fertility treatment. Although it is much more prevalent than premature ovarian failure, less is known about its etiology. The purpose of this article is to review the possible genetic causes of, and associations with, pathologic DOR. METHODS: A systematic review was conducted using PubMed from 1966 through November 2013. RESULTS: Twenty-one articles identified genes associated with DOR: one gene mutation (FMR1), three polymorphisms (GDF9, FSHR, and ESR1), and seven genes differentially expressed between women with DOR and controls (AMH, LHCGR, IGF1, IGF2, IGF1R, IGF2R and GREM1). Six candidate genes were discovered in mice, including Foxl2, Gdf9, Bmp15, Aire, Wnt4, and Gpr3. Two case reports of chromosomal translocations were also identified. CONCLUSIONS: While the etiology of pathologic DOR is likely multifactorial, it is possible that many cases attributed to an idiopathic cause may have a genetic component. Larger studies are needed to expose the impact gene mutations, polymorphisms, and epigenetics have on pathologic DOR.

The Appraisal of Body Content (ABC) trial: Increased male or female adiposity does not significantly impact in vitro fertilization laboratory or clinical outcomes.

OBJECTIVE: To investigate the impact of obesity as determined by bioelectric impedance analysis (BIA) and body mass index (BMI) on in vitro fertilization (IVF) laboratory and clinical outcomes. DESIGN: Prospective cohort study. SETTING: Academic-affiliated private practice. PATIENT(S): A total of 1,889 infertile couples undergoing IVF from June 2016 to January 2019. INTERVENTION(S): Female patients and male partners underwent BIA and BMI measurement at the time of oocyte retrieval. Embryology and clinical outcomes were prospectively tracked with comparison groups determined by percentage of body fat (%BF) and BMI categories. MAIN OUTCOME MEASURE(S): Fertilization rate, blastocyst formation rate, euploidy rate, miscarriage rate, sustained implantation rate, live birth rate, rates of low birth weight/very low birth weight, prematurity rates. RESULT(S): Fertilization rates and euploidy rates were equivalent among all women. Blastocyst formation rates were slightly higher (55%) in women with an obese %BF compared with all other %BF categories (51%); however, this trend was not noted in women defined as obese by BMI. Miscarriage rates, sustained implantation rates, and live birth rates were equivalent among all women. The rate of very low birth weight was low but increased in obese women (3%) versus underweight, normal-weight, and overweight counterparts (0%-1.3%) as determined by %BF and BMI. Obesity in men did not significantly affect any embryologic or clinical outcomes. CONCLUSION(S): Although maternal obesity imposes a small but increased risk of very low birth weight infants, most embryology and pregnancy outcomes are equivalent to normal weight patients. Paternal obesity does not appear to affect IVF, pregnancy, or delivery outcomes.